Cited in Index Medicus/MEDLINE, BIOSIS Previews, SCOPUS
Journal of the Italian Society of Anatomic Pathology
and Diagnostic Cytopathology,
Italian Division of the International Academy of Pathology
Periodico bimestrale – POSTE ITALIANE SPA - Spedizione in Abbonamento Postale - D.L. 353/2003 conv. in L. 27/02/2004 n° 46 art. 1, comma 1, DCB PISA
Aut. Trib. di Genova n. 75 del 22/06/1949
History of anatomic Pathology
53 From the new moon to the full moon: Anatomic Pathology in Bologna
from the 1500s to Armando Businco
P. Scarani, V. Eusebi
Storia di anatomia patologica
64 Dalla luna nuova al plenilunio: l’Anatomia Patologica bolognese dal Cinquecento
ad Armando Businco
P. Scarani, V. Eusebi
Original articles
76 Cervical cancer screening programs in low-income communities.
Experiences from Ecuador. Low cost detection of HPV infection in a developing
country
G. Cecchini, G. Paganini, M. D’Amico, M. Cannone, C. Bertuletti, M.C.P. Barberis
80 Liquid-based endometrial cytology: the Florence and Bari experience
A.M. Buccoliero, L. Resta, A. Napoli, G.L. Taddei
Case reports
85 Primary linitis plastica of the right colon
M. Onorati, M.R. Ambrosio, V. Mourmouras, M.G. Mastrogiulio, B.J. Rocca
89 Renal hilus paraganglioma: a case report and brief review
F. Pagni, E. Galbiati, F. Bono, C. Di Bella
93 Endometrial stromal sarcoma presenting as a cystic abdominal mass
R. Doghri, K. Mrad, M. Driss, S. Sassi, I. Abbes, R. Dhouib, M. Hechiche, K. Ben Romdhane
97 Primary CD30/ALK-1 positive anaplastic large cell lymphoma of the skeletal muscle
in a child
M. Driss, I. Abbes, K. Mrad, S. Sassi, F. Oubich, S. Barsaoui, K.B. Romdhane
101Small cell osteosarcoma: a case report
R. Kallel, L. Ayadi, N. Toumi, E. Daoud, A. Khabir, Z. Ellouze, S. Charfi, S. Makni,
T. Sellami Boudawara
105Extraventricular neurocytoma in a child mimicking oligodendroglioma: a diagnostic pitfall
F. Limaiem, S. Bellil, I. Chelly, A. Mekni, K. Bellil, H. Jemel, S. Haouet, M. Zitouna, N. Kchir
Società Italiana di Anatomia Patologica e Citopatologia Diagnostica,
Divisione Italiana della International Academy of Pathology
Vol. 101 April 2009
pathologica 2009;101:53-63
History
of
Anatomic Pathology
From the new moon to the full moon:
Anatomic Pathology in Bologna
from the 1500s to Armando Businco
*
P. Scarani* **, V. Eusebi*
Dipartimento di Ematologia e Scienze Oncologiche L. e A. Seragnoli, Sezione di Anatomia, Istologia e Citologia
“Marcello Malpigli”; **Museo delle Cere “Luigi Cattaneo”, Università di Bologna, Italia
On July 12, 1989, Antonmaria Mancini (1929-2007)
celebrated the 130th anniversary of the Department of
Anatomic Pathology of the University of Bologna. July
12, 1859 was also notable as the day that Bologna was
formally considered as part of the kingdom of Vittorio
Emanuele II. On that day, in those confused times,
Cesare Taruffi (1821-1902) received orders from Luigi
Carlo Farini to establish the Department of Anatomic
Pathology 1. During the festivities, the University of
Bologna also inaugurated the Museum of Anatomic
Pathology. For the occasion, Prof. Mancini received
many compliments from a veterinarian on the presentation of the museum. The Professor answered by pointing towards a lesser colleague saying, “I am not the one
to thank: I told him to do it, and he acted in full autonomy”. The veterinarian responded, “It is certainly a
great merit on your part to have given him such liberty”.
Antonmaria Mancini was like this, often saying, “If God
gave free men the capacity to do evil, then I must do the
same with my collaborators”.
Prologue
Without achieving practical results for the sick, medicine would not have a great reputation, and indeed such
a situation was evident until the end of World War II.
The discoveries of Koch in the late 1800s 2, for example,
were not well received due to the lack of knowledge in
pharmacology, and despite advances in knowledge of
disease, the available therapies still had an efficacy that
was only slightly better than that of faith healers or charlatans. After the war, an epoch of optimism emerged
following a series of tangible therapeutic successes. It is
this long period of darkness that inspired the somewhat
unconventional title of this article on lunar phases. This
is not related to the quality of previous discoveries, but
rather to their practical applicability and the difficulty
in defining anatomic pathology, and starting from the
1800s, how to define anatomic pathologists 3.
Acknowledgements
Professors M. Baccarani (Bologna) and G. Bussolati (Turin) are
thanked for their critical reading of the manuscript.
The new moon: morphology in the 1500s
at Bologna
The study of forensic medicine at Bologna was reported
as early as the time of Dante (1265-1321) when physicians were called upon to determine if the sudden and
unexpected death of some famous person was due to
either natural causes or poisoning 4. It is not surprising
that these experiences have been remembered, as they
are connected to legal services, the principal science
of the antique University of Bologna: medicine was
considered as just a minor art. Nonetheless, apart from
such activities, what physicians actually did was not of
great interest.
Until the time of Giulio Cesare Aranzi when anatomic
studies began to flourish, in spite of the contribution
of Mondino de’ Liuzzi (1275-1326), there had been no
correlation between pathological and anatomical studies 5. The first autopsy to understand the cause of death
was performed by the Florentine Antonio Benivieni in
Bologna (1430-1502) 5.
Giulio Cesare Aranzi (1530-1589)
Aranzi (Aranzio is the Latin name) was an authentic
Bolognese (Fig. 1). He splendidly described foetal circulation 6, although the only trace of his studies that has
persisted is the venous duct of Arantius. He also discovered the hippocampus, which in lay terms, was referred
to as the ‘silkworm’, and it is curious that this analogy
was easy to understand in Bologna given the large development of the silk industry there at that time. At any
rate, the discovery was a revolution for neuroscience.
By identifying the hippocampus, Aranzi had become
aware of the existence of another horn (the temporal
horn) of the lateral ventricle, which was also known by
his mentor Vesalio. This was an enormous discovery
considering the difficulties encountered in macroscopic
study of the brain before the development of fixatives
Correspondence
Prof. V. Eusebi, Sezione Anatomia, Istologia e Citologia Patologica
“M. Malpigli”, Università di Bologna, Ospedale Bellaria, via Altura
3, 40139 Bologna, Italia - E-mail: [email protected]
54
Fig. 1. Giulio Cesare Aranzi (from Brambilla Giovanni Alessandro:
Storia delle scoperte fisico-medico-anatomico-chirurgiche fatte
dagli uomini illustri Italiani. Milano 1782. Bologna: Arnaldo Forni
Edition 1977, page 188).
p. scarani, v. eusebi
the calendar), who had huge practical advantages from
the scientific studies of Aldrovandi 10. The precursor
of Bolognese studies on anatomic pathology, Marcello
Malpighi, should also be remembered as curator of the
naturalistic collections of Aldrovandi.
The crescent moon
in the 1800s. The vague knowledge of brain anatomy is
also apparent from Vesalio, who illustrated the nervous
system in “De humani corporis fabrica” in 1543. In this
regard, it is still difficult for us to understand how the
representation of a human brain in the group of subjects
surrounding God in the creation of Adam in the Sistine
Chapel could have been attributed to Michelangelo in
1512, especially considering the comparison was made
using drawings made in the 1900s by Netter 7 and not
those made during Michaengelo’s time. At any rate,
in addition to the individuation of anatomic structures,
Aranzi published the first anatomic-pathologic work
from Bologna that combined anatomy with a description
of pathologic processes.
Another work by Aranzi, edited in Venice the same
year, together with anatomical studies, De tumoribus
secundum locos affectos 6, consisted in a heterogeneous collection (hydrocephalies, cysts, abscesses, solid
masses) of tumefactions (tumours) divided by anatomic
area. These studies were the result of the activity of a
practical physician who was also dedicated to surgery.
Today, almost no one remembers Aranzi at Bologna.
In the Bolognese medicine of the 1500s, there was truly
a darkness associated with the new moon if one considers the dominant figurehead of the university, Gerolamo
Cardano 8. Students, however, preferred Ulisse Aldrovandi (1522-1605) 9, although he was a naturalist more
than a physician. Nonetheless, he had a modern vision
of morphology and carefully studied the internal organs
of animals. His teratology studies were extremely rigorous. Even Aldrovandi did not have significant success
at Bologna, in spite of his international reputation, and
was only able to publish a small fraction of his work.
Likewise, he did not want any help from his Bolognese
cousin, Pope Gregory XIII (the same who reformed
Marcello Malpighi (1628-1694) and his followers.
Malpighi, born in Crevalcore (Bologna), was a great
anatomist, anatomic pathologist and clinician (Fig. 2).
He was the first to use a microscope for the study of
internal organs, and his name is still associated with
structures of the kidney, spleen and skin. He is also
known for his studies on the lung and embryonic development. Malpighi, however, should be considered as an
anatomic pathologist that carried out accurate autopsies
accompanied by clinical data. His referrals were often
preceded by both biographical information and detailed
clinical history, and his autopsy methods were similar
to those used today. He proceeded by observation of the
cadaver before examining the internal organs starting
with the intrathoracic ones 11. He was primarily a practical clinician, and all of his interests in normal anatomy
and pathology derived from problems that had clinical
relevance. Unfortunately, his work was ahead of his
time. Despite his undisputed successes and the fact that
his name is still found in modern texts on anatomy and
embryology, it was one of his students, Giovanbattista
Morgagni, who brought under question his microscopic
findings thereby postponing such discoveries until the
second half of the 1800s 12.
Fig. 2. Marcello Malpighi (painted by Carlo Cignani, Galleria Borghese, Rome).
from the new moon to the full moon
Malpighi’s talent as an anatomic pathologist was repeatedly demonstrated. One such example can be found in
a study by Salfi 13 on a brilliant diagnosis by Malpighi
on Paget’s disease of the bone, which was certainly
ahead of his time, and often misunderstood by today’s
paleopathologists. There are still many unexplored
drawings and manuscripts by Malpighi in the archives
at Bologna.
Antonmaria Valsalva (1666-1723) was the greatest pupil of Malpighi. He was born in Imola (Bologna), and
like his master lived on the margins of academic life.
In 2004, a memorial edition of his work on the human
ear was published (not in Bologna) which was certainly
a monument to his meticulous study of morphology,
comparable to that of Aranzi’s studies of foetal circulation. The favoured apprentice Giovanbattista Morgagni
described the death of Valsalva with extraordinary affection, noting his passion for morphology. Valsalva
carried out his autopsies in a ‘total’ immersion and even
tasted what he saw. In spite of the fears of modern pathologists, he did not die of infection.
Giovanbattista Morgagni (1682-1771), from Forlì, can
be considered as the deity of autoptic anatomic pathology of the Bolognese school. Bologna nonetheless
rejected him and never treated him well, despite his affection for the city, thanks to his bond with Valsalva.
Towards the full moon: from Napoleon
to the Roman Republic
In 1888, when the 800th anniversary of our university
was celebrated, the department of anatomical pathology
in Bologna was just a few years old, as it was founded
in 1859 when the university was reorganized following
the cessation of its administration by the Vatican 1 14.
Unfortunately for Bologna, this was not the first department of anatomic pathology established in Italy, and
was preceded by Florence, where it was instituted by
Granduca Leopoldo II in 1840, and by Genoa 5 15. In
Bologna, anatomic pathology was founded at the same
time as the University of Modena 16. However, anatomic
pathology in Bologna, independently of when it was
formally founded, had already been firmly established
since the beginning of the century. Along these lines,
a University Museum of Pathology was founded by
Napoleon (then president of the newly-formed Roman
Republic) in 1804 17 in which dried samples and wax
models from organs affected by various diseases were
collected. Other than the materials still conserved at
the Museum of Anatomy, little remains of the museum
founded by Napoleon, with the exception of a series
of notes in Latin in which the collection of samples is
described. The notes were published in the Opuscoli
Scientifici dell’accademia delle scienze dell’istituto di
Bologna between 1818 and 1823 18-21, and were written
by Luigi Rodati who was the curator of the museum
55
from 1815 to 1832. The dissertations of Rodati, however, were limited to dried samples. During that time,
the museum was already one of the largest in Europe
and housed wax models that are still in excellent condition, the most well renowned of which is a bust of a case
of acromegaly (1811).
The use of anatomical wax models was flourishing
at that time, and as in Florence with the birth of anatomic pathology, many types of pathologies began to
be modelled 22. Wax models from the early-mid 1800s
can still be found in the museum (presently located
in the Institute of Anatomy known as the Luigi Cattaneo Anatomical Wax Museum). They were made by
Giuseppe Astorri, who was part of the anatomical wax
school in Bologna dating to the 1700s. The activity of
the Bologna school has been documented in the form of
a catalogue conserved in the State Archives in Bologna.
After the fall of Napoleon, the Bologna institutions were
placed under the control of Cardinal Carlo Oppizzoni,
a man of outstanding moral character. In this regard,
he sharply criticized, and from a theological standpoint
motivated, the excommunication led by Pope Pio IX
against the Roman Republic 23.
Oppizzoni passionately cured the growth of the medical faculty in Bologna, providing it with guidelines that
were also considered a model for more recent Chairs
of Medicine. As one example, he proposed that an
award should be given to the physician that performed
the most autopsies during the year. Antonio Alessandrini (1786-1861) 24, a legendary figure of the medical
school in Bologna, was particularly outstanding in this
regard. In contrast to the majority of professors at the
university, he was from very modest origins and is best
remembered as the founder of the museum of anatomic
veterinary pathology (which he called comparative
pathology) and palaeontology. Luigi Calori, author of
a splendid biography on Alessandrini, is probably the
only morphologist that can be compared with him 25-27.
A systematic study of the immense activity of Antonio
Alessandrini has never been carried out. Nonetheless,
the large amount of work that he left behind is amazing,
and for example many skeletons of exotic animals, still
housed in the Museum of Zoology and Comparative
Anatomy, appear to correspond to the multitude of his
original publications. Alessandrini was part of the generation that went from macroscopic morphology to histology and histopathology. He was undoubtedly a person
with a powerful vision of the future, as demonstrated by
his close association with the physicist and naturalist
Giovanbattista Amici (1786-1863) who introduced the
immersion objective to microscopy. The activities of
Alessandrini were so intense that he had little time for
private life. Later, due to an infection, his right hand was
amputated by Francesco Rizzoli, and his colleagues had
expressed the desire to conserve it in the Museum of
Pathology. This should not be shocking, however, as the
skeleton of Cesare Lombroso is still housed there. Sur-
56
prisingly, Antonio Alessandrini did find some time for
politics and was part of the triumvirate that organized
the Bolognese resistance to the Austrians, which ended
on May 17, 1849, after four days of bombing 23.
The founding of the Society of Medical Surgeons
also played an important role in anatomical pathology
(1823), which encouraged the presentation of autopsy
cases during its gatherings 17 28. The cases were published, and the removed organs were destined, together
with an accurate description, to the Museum of Pathology which became their perpetual custodian (many are
still there today!).
The moon on the insignia: Cesare Taruffi
In 1844 Cesare Taruffi, then a young surgeon, was
nominated as temporary anatomist and curator of the
Museum of Pathology, and after a brief time became
the first Professor of Anatomical Pathology at Bologna
(Fig. 3). Taruffi, who came from an important and historic family, was born in Bologna on March 23, 1821 1.
Curiously, for our analogy, Taruffi always wore an
insignia of a crescent moon that was later reproduced
by the Society of Medical Surgeons in Bologna over
which he presided, in addition to being the Dean of
Medicine.
Fig. 3. Cesare Taruffi.
p. scarani, v. eusebi
He initially dedicated himself to surgery and was a
pupil of Francesco Rizzoli, founder of the Orthopaedic
Institute at Bologna that carries his name. From the
beginning, however, he had a great interest in anatomic
pathology. Soon thereafter, he also became involved in
politics 17, and documents at the archives of the Museum
of the Risorgimento in Bologna show that on November 6, 1847 he was nominated second lieutenant of the
third battalion of the civil protection unit that had just
been created by Pio IX. What came next is less clear,
and the precise role of Taruffi in the war from 1848-’49
is not known with certainty. A letter dated April 30,
1848, signed by Carlo Bignami, one of the defenders
of Venice after the fall of Vicenza and the surrender
of the volunteers of the Vatican on June 11, nominated
him as surgeon of the first battalion destined for military operations in the Veneto region to fight against the
Austrians. Another letter, dated June 1, was from Padua
close to where the Bolognese volunteers were fighting
the Austrians. Successive documents showed that he
had an intense activity in Venetian hospitals, where he
stayed from June 30, 1848 until January of 1849 before
being recalled to Bologna for the planning of a military
hospital. Even if fragmentary, the records of his activities lead one to believe that Taruffi was united with the
volunteers of Bignami after the surrender on June 11.
Information about what happened later is even more
scarce. A letter from the Minister of War of the Roman
Republic dated June 1, 1849 nominated him as Surgeon
General of the Bologna Legion, although it is not clear
what his precise role actually was. From extradition
papers of the command of the French army, on July 7
it was apparent that he was in Rome until the fall of the
Roman Republic on July 4, 1849. Nonetheless, Taruffi
was not identified as particularly dangerous as he was
able to leave the city armed and in uniform, in accordance with the conciliatory strategy initially adopted
by the French. The large number of marks and stamps
on his extradition papers indicate that his movements
towards Bologna were left largely undisturbed by both
the Republicans, who were marching with Garibaldi,
and the Vatican Authorities. There is no tangible proof
that Taruffi carried out any patriotic activities in either
Venice or Rome. Likewise, there is no evidence that his
career suffered any impediments from the Vatican or
from his relationship with the liberal group in Bologna,
and in particular with Marco Minghetti.
Without doubt, the numerous positions in healthcare
held by Taruffi, conferred by the government in Bologna in autumn of 1859, demonstrate that he had the
complete trust of the liberals: this is in agreement with
the moderate stance held by Taruffi during the revolt of
1848-’49, and in concordance with the criticisms of the
Republicans by Luigi Carlo Farini, the physician and
politician from the region that helped join the Emilia
and Romagna areas, and also instituted the Department
of Anatomic Pathology.
from the new moon to the full moon
In any case, it wouldn’t seem correct to attribute the
academic career of Taruffi to his patriotic merits. The
enormous amount of work carried out by Taruffi until
his death in 1902 demonstrates that he had an excellent knowledge of anatomic pathology. In addition to
creating a new institution from practically nothing 29,
he dedicated a large part of his activities to teratology.
His work in this area was incredibly tenacious, and he
collected a massive amount of materials that were collected in the museum, which in 1859 was renamed the
Museum of Anatomic Pathology. He conserved foetuses
and malformed infants in alcohol, and he also commissioned reproductions in wax and other materials.
Much of the material he collected for his studies on teratology was left to him by other scholars. After 1863, in
fact, many human specimens previously conserved by
veterinarians, for the most part the illustrious morphologist and patriot Antonio Alessandrini, were bought by
the Museum of Anatomic Pathology. At the same time,
Francesco Rizzoli gave Taruffi a large number of gynaecological specimens, which he had collected as head of
the Obstetrics Clinic during which time he also carried
out a number of particularly audacious interventions 30.
The most faithful teratological preparations in Bologna were the work of the anatomist Luigi Calori 25
together with Cesare Bettini, a famous wax sculptor and
anatomic designer; having examined the internal organs
and described the malformations, Calori conserved the
skeletons and internal organs that were then dried and
injected using a sophisticated technique.
57
work of Taruffi is still known abroad, even though it has
been largely forgotten in Italy and Bologna 32 33. Taruffi
did not finish what he had set out to do: the publication of Storia della teratologia began in 1881 and was
finished in 1894 when he was old and in bad health.
His intent was, however, to complete an even larger
systematic monograph, which was left unfinished when
he died in 1902.
We know little about his abilities as a teacher, although
he did author an essential text on anatomic pathology in
1870 34 in which it is apparent that he was well versed
with the relevant topics in Europe, namely those of
Virchow. Certainly this was a point in his favour as the
Vatican Government had ceased its control 10 years earlier, and Taruffi was already able to take part in a more
European atmosphere.
Cesare Taruffi died in July 1902, and Frank GonzalezCrussi dedicated a large part of his famous volume to
him 32, as well as another work on conservation of the
human body, which was in part inspired by the Museum
of Anatomic Pathology in Bologna 33.
Taruffi’s fame as a classifier of malformations was merited. For years there was talk of a volume in German by
Taruffi at the library of the University of Heidelberg 35,
which would have been the third and last part (incomplete) of his classification of teratology. Contemporary
progresses in morphology and collection of epidemiological data prompted Taruffi to greatly enlarge
his original outline for Storia della teratologia, and he
wrote several articles on the subject 36 39.
Calori is an excellent example of the intellectuals in the
1800s who studied natural science and morphology 25 27.
He had the capacity to prepare specimens with great
efficiency, which is demonstrated by the fact that many
are still preserved 200 years later. He made even greater
contributions through his scientific publications, which
were always illustrated with figures drawn with great
precision. When reorganizing the museum, it was noted
that Cesare Bettini created his illustrations with such
rigour that there was little difference from the original
specimen. In fact, many experts were astounded by
the impressive similarity between the original and the
illustrations, already evident from the publications of
Rodati. During the reorganization of the Museum of
Anatomy at Bologna (which is now part of the Museum
of Anatomic Pathology), we highlighted the close relationship between specimens present in the museum and
their corresponding illustration, and how publications
dating to the 1800s can allow the recovery of specimens
whose original purpose was forgotten 22.
Even at an advanced age, Taruffi appeared to be extremely coherent and accurate, and was perturbed by a
problem that had troubled the West from the 1700s until
the 1900s: the determination of gender and the existence
or negation of a true confine between men and women 40. Along these lines, it was the psychological aspects
of carriers of malformed sex organs that led Taruffi to
study some of the most disturbing themes of the late
1800s: homosexuality, bisexuality and pedophilia.
In addition to teratological publications, Taruffi also left
a monumental composition, Storia della teratologia 31.
This masterpiece abounds with historical information
and erudition; it is also notable for the enormous effort
needed to complete such a complex volume. This great
It was in this context that the works of Taruffi were
translated into German, which demonstrated that in spite
of his age, he was particularly up-to-date on the problem
and among the most well-known specialists at that time.
Most likely, at the beginning of the 1900s, Germany
The French revolution led to a strong exaltation of virility, in contrast to the attribution of a maternal-family
role of women, and the 1800s were transformed into a
battleground between a patriarchal role and emancipation for women. A typical example of this conflict in
Italy is the life of Giuseppina Cattani 41. Such conflicts,
together with the discoveries on the complexities of
gender determination by embryologists and the realization of the extent of homosexuality in Western society,
made for very interesting studies in sexology.
58
was the most open and lively culture in the world and
may be considered the cradle of sexology. It is not
surprising, therefore, that a volume that was so rich in
information, such as that by Taruffi, was translated into
German. Likewise, it is not surprising that Sigmund
Freud (1856-1939) was interested in Taruffi’s work 42.
At the beginning of the 1900s, Freud became aware of
the close relationship between psychological affections
and ‘anomalies’ in sexual behaviour. The search for a
physical explanation of ‘abnormal’ sexual behaviour
led Freud to the works of Taruffi, and in fact Taruffi
was cited at the beginning of Freud’s three publications
on sexual doctrine 43 44. For Freud, morphology was a
critical aspect, and he demonstrated the indistinctness of
embryological development on gender, contributing to
the Freudian revolution. The dynamics of the determination of gender also led Freud to see a type of embryogenesis in the development of a psyche, for example in
the discovery of infant sexuality and its development.
Taruffi was, albeit involuntarily, a sort of detonator that
led to an explosion in the research activities of Freud,
which characterized his work from 1905 to 1910 and
radically changed the way we think 1.
Little is known about the private life of Taruffi. He was
widowed at a young age, and did not remarry. He was
a fervent polemicist, but nothing in his writings would
lead one to think that he was a bizarre person. One
recently solved enigma was the discovery that many at
Bologna had confused Taruffi with the oculist Tartuferi
(with the accent on the ‘u’: strangely, Taruffi is known
in Austria as Tartuffi), founder of the oculist clinic in S.
Orsola during the war in Libya. Tartuferi was perhaps
a bit unconventional: he had a great fear of thieves
and swindlers and had transformed his villa in the hills
of Bologna into a sort of fortress, with windows that
opened by themselves in a haphazard manner, allowing
him to shoot upon eventual robbers. Interestingly, such
a model was later adopted for the fortifications on the
Maginot line.
p. scarani, v. eusebi
Fig. 4. Giovanni Martinotti.
in Palazzo Malvezzi Lupari, and even the museum was
restored. From the time of Martinotti there were still
several autopsy registers that were later transferred to
the institute of normal anatomy. In later years under
the direction of Martinotti, autopsies were officially
and definitively the responsibility of pathologists 3 45-49.
This led to a large increase in the number of autopsies
performed (from 100 to almost 1000 per year).
The moon rises … and the amount
of work increases
During the same period, the first histological diagnoses
were carried out on biopsies and surgical specimens.
Histopathologic techniques were a major interest for
Martinotti, probably because at that time diagnostic biopsies from malignant neoplasms had just begun to have
practical relevance. In our opinion, it was Martinotti that
first began to collaborate with clinicians and radiologists to systemically study malignant neoplasms. This
supposition is demonstrated by statistical studies started
by Vigi 50 51 that continued until Armando Businco was
no longer head of the department.
When Taruffi retired from teaching in 1893, Giovanni
Martinotti (1857-1928) took his place in Bologna at the
peak of his academic career which started in Turin (Fig.
4). From 1889 to 1891 he was the head of anatomic
pathology at the University of Modena, where he began an intense interest in microbiology, then a branch
of anatomic pathology. From 1891 until he arrived at
Bologna, he was at Siena. At Bologna, he dedicated a
large part of his time to teaching. Along these lines, he
was passionate about the creation of a new institute of
anatomic pathology, the present institute in Via Irnerio,
which was completed in 1907. The new institute combined both anatomic pathology and normal anatomy.
The previous institute was crumbling, and was located
Martinotti published many articles, but his work in anatomic pathology was almost never particularly exciting,
with one exception to be considered later. One reason
for this was perhaps that Martinotti was more interested
in microbiology, and in particular on finding an antituberculosis vaccine. He claimed that his vaccine provided excellent protection, but in reality it worked only
in cases that were not severe, and it couldn’t eliminate
recurrences. Apart from the tangible results, however,
his research demonstrated a notable understanding of
tuberculosis and the problems associated with it. Curiously, there is now a renewed interest in his work,
probably linked to the increased incidence of tuberculosis due to chemoresistance and the poor efficacy of
from the new moon to the full moon
the BCG vaccine. Bindo De Vecchi brought to light
that it was not Giovanni Martinotti, in contrast to what
had been previously reported by many, who discovered
the cortical neurons called “Marinotti cells”: their real
discoverer was a pupil of Camillo Golgi, namely Carlo
Martinotti 52 53.
Martinotti died suddenly and tragically, and the arrival
of Giulio Tarozzi from Turin (1868-1948) as head of the
department was somewhat unexpected. Before discussing Tarozzi, however, an extraordinary event should
be described that can be compared to the passage of a
comet: the period of Bindo De Vecchi.
The years of Halley’s comet:
Bindo De Vecchi (Fig. 5)
Fig. 5. Bindo De Vecchi.
As a young and brilliant student of medicine, De Vecchi
made a great impression on the famed clinician Augusto
Murri, who directed him towards anatomic pathology.
Even if De Vecchi did not reach the height of his career
at Bologna, he still maintained a solid relationship with
Martinotti, and even wrote his eulogy. This latter event
was extremely important since it was the only publication that did not consider him to be the discoverer of
Martinotti cells, in contrast to later historians 54.
De Vecchi as a talented morphologist. In 1903, he diagnosed a myocardial infarct in an autopsy report (now in
the Institute of Anatomy). This was not a trivial insight
since most believe that the anatomical concepts behind
myocardial infract were elaborated in the United States
after the First World War. In reality, the correlation between myocardial necrosis and occlusion of a coronary
vessel had already been clearly stabilized during the
second half of the 1800s by Cohnheim 14, whose publications were in the library of Giovanni Martinotti. His
59
abilities as a morphologist are also evident in the area
of neoplastic pathologies. De Vecchi had a perspective that was very modern for his time, and more like
that of a surgical pathologist, and one of his reports on
oncology was published in English in a medical journal in New York 55. His knowledge of English and his
interest in American research was unusual at the beginning of the 1900s 47. For example, De Vecchi, in 1908,
preferred the school of Schmorl at Dresden, to deepen
his knowledge. His interest in studies carried out in the
United States thus makes him person of noteworthy
foresight, similar to Vittorio Putti, the well-known
orthopaedist who gave worldwide fame to the Rizzoli
institute in Bologna.
De Vecchi was the son of an army officer, to which his intense sense of patriotism can be attributed. It is not known,
however, if this fact can adequately explain his restless
existence. To us, it seems that De Vecchi was a generous
person in both public and private life, and was admired by
his students. It should be remembered that he volunteered
for the First World War, provided medical aid to the victims of the earthquake in Messina and Calabria in 1909
and was intensely involved in the fight against cholera in
Syracuse (1911). This was a very successful time for De
Vecchi, and he was awarded a medal of honour in the war
and promoted to a high-ranking medical officer.
His professionalism as a pathologist should not be
forgotten during wartime, and he published a report
in 1919 in which he presented death statistics among
draftees after the war had ended (Autumn 1918) 56 on
the influenza epidemic. De Vecchi and his colleagues
were surprised by the severity of the pulmonary damage seen in most victims. They were also aware that
they were facing a disease that gave rise to extensive
pulmonary symptoms with unusual morphology. They
did not characterize it as acute interstitial pneumonia,
and adhered to the common idea that it was caused
by bacteria, which led to death in more serious cases.
De Vecchi is also considered a clever experimental
pathologist, and his studies on Addison’s disease
secondary to tuberculosis of the adrenal glands, were
published in various journals as well as in the Medical
News 57.
Lastly, there was the spectacular academic career of De
Vecchi. He headed the first anatomic pathology department in Perugia in 1920 (a sort of recovery after he left
as a war volunteer in 1915), then at Palermo, and finally
at the Medical School in Florence where he succeeded
Guido Banti (1925). In Florence, De Vecchi reached the
apex of his fame and became President of the university;
when he died in 1936, he was celebrated as a national
hero. He was a fervent fascist, which today we can only
talk about, but cannot fully understand. One thing however is certain: De Vecchi wasn’t just anyone, but was
a feather in the cap of Mussolini, along with Guglielmo
Marconi.
60
Approaching the full moon: Giulio Tarozzi
While Taruffì is remembered, thanks to the Museum,
and Martinotti, thanks to a commemorative plaque in
the main lecture hall of the Institute, at least a small
remembrance is still present, Tarozzi has been largely
forgotten. The only traces we found were a commemorative text written by one of his students and successor
at Bologna: Armando Businco 58. The commemoration
was a very precise appraisal of the scientific activity of
Tarozzi, who published numerous papers in German
and English, especially during the period before his arrival in Bologna, when he was in Pisa, Siena, Cagliari
and Modena. Nonetheless, his assessment did not allow for an understanding of the man during his most
active period, when he should have been at the peak
of his productivity 59. Tarozzi was nonetheless a good
morphologist, and conformed to the German school as
demonstrated by his very last studies on postencephalitic Parkinsonism 60.
During his last years, Tarozzi seemed fascinated with
philosophical problems related to the meaning of life
and the mysterious world that surrounds us. We know
from one of his brothers that Tarozzi had been a professor of philosophy, which had a profound influence on
him. Evidently, however, Giulio Tarozzi lived an autonomous, lively life in his philosophical undertakings.
Recently, in fact, Sandra Linguerri and Raffaella Simili
discovered that he was part of a group of Bolognese
scholars that had invited Einstein to Bologna for a series
of lectures 61. The group was among the minority in the
country that still had relations with Einstein after he was
publicly condemned by Italy following its adhesion to
the racist politics of Hitler.
Similar to Martinotti, Tarozzi also carried out microbiological studies and was particularly interested in culture
medium for anaerobic bacteria 62. When the Museum
was transferred at the turn of the millennium, several
autopsy specimens were found that dated to Tarozzi’s
time. Probably, it is not by chance that the specimens
were from neoplastic pathologies that were intensely
studied by his colleagues 63 64. A series of smears without cover slips were completely unexpected, which were
specimens of tetanus and anthrax, and still in an optimal
state of conservation. Undoubtedly, these were among
the last traces of the microbiological collection of Giulio
Tarozzi. According to Mario Alberto Dina, the only
surviving pathologist that knew him personally, these
pathogens were indeed studied by Tarozzi.
p. scarani, v. eusebi
Full moon or dawn? Armando Businco
(Fig. 6)
Fig. 6. Armando Businco.
Tarozzi retired from teaching in 1938, and his position
was filled by Armando Businco (1886-1967), from
Ierzu (Nuoro), the father of anatomic pathology in Bologna and of a generation of pathologists that are still
alive. Businco began his studies in Cagliari, but they
were soon interrupted by the war when he volunteered
in 1916 as a medical officer. He was extremely active
during that period in revising histological samples on
the effects of toxins on animals obtained by experiments
commissioned by the Minister of War. The study predated the massive use of poisons in the First World War.
Businco began the histopathological revision when the
use of chemicals on humans had just begun, and he was
thus able to compare experimental data with that on human victims. Several publications dating to 1920 were
also published, one of which was in English 65-67, which
demonstrate the attention he gave to damage induced by
inhaled substances on the alveolocapillary membrane in
the lung.
After the war, Businco taught anatomic pathology at
several universities including Perugia, Cagliari and
Palermo, until he returned to Bologna in 1938 where
he remained until 1956. His arrival in Bologna corresponded to the height of his national fame, and he
was well known for his studies on endemic malaria in
Sardinia. He took particular interest in educating physicians on the problem of malaria and wrote L’infezione
malarica 68, which was re-examined in the 1990s by
Antonmaria Mancini 69 and later made an obligatory
text for anatomic pathology students in Bologna. Both
before and after the Second World War, Businco passionately contributed to antimalarial efforts in Italy.
Today, his contribution is admired to the point that Italy
is often considered as a model for the eradication of malaria. It is disappointing that in recent studies on malaria
Businco was not remembered 70.
from the new moon to the full moon
His permanency in Bologna is connected with a dramatic and mysterious event: in 1944, Businco was arrested by the Nazis and deported, although he was able
to escape and hide until the end of the war. Prior to the
war, Businco did not seem to openly oppose the fascist
regime. During the German occupation, however, something appeared to change, and he countered an attempt
by the Germans to obtain radio equipment at the Radio
Institute in Bologna. Moreover, he was also in contact
with a group of students and young underground physicians that was brutally massacred. He later commemorated the group with a plaque placed in the new Institute
inaugurated in 1948. The speech that Businco gave for
the inauguration was published. The clear and moving
demonstration of the strong sentiments in place at that
time were further confirmed in a letter sent by Bartolo
Nigrisoli, a professor of surgery at Bologna, who was
also distanced from the University for not having pronounced his loyalty to the fascist regime.
Even after many years, the specific details of what happened to Businco at that time are still unclear. Most
likely, an explanation lies in the ambiguous role that the
healthcare system in Bologna had from 1943 to 1945.
The Rizzoli Orthopaedics Institute and the Institute of
Traumatology, headed by Oscar Scaglietti, was one of
the most important military hospitals for the German
retreat. While the Italian Red Cross was in contact with
both the underground and the Allies, there was undoubtedly a sort of consent by the Germans. The tragedy
of Businco and his medical students was perhaps an
‘anomaly’. This would explain how Businco, even if
nominated president of the Commission for ‘Purging’,
was not able to overcome his symbolic role after the liberation. In addition, the supposed evidence that linked
the physicians in Bologna to German opposition was
never followed up.
Businco was a decisive believer in the use of autopsies 71,
and held that clinicians should personally be present in
order to provide a frank exchange of ideas with pathologists. Even the directors of other institutes were invited
to be present during autopsies. The complete reconstruction of the autopsy archives of the university, from 1838
to 1999, certainly presented some inconsistencies with
the myth created among the pupils of the famed Sardinian pathologist. Until the 1920s, autopsies were almost
exclusively performed for educational purposes. During
the time of Taruffi, they were carried out only from
October to June, and autopsy reports were compiled and
signed by students, and revised by Taruffi and his colleagues. This activity in itself was considered a preliminary experience in order to be admitted for final exams.
It was also documented that, in accordance with the tradition of Malpighi and Morgagni, clinicians personally
performed autopsies on their patients 72, in what Juan
Rosai has proposed as “posthumous analysis” 73. Following the birth of modern histopathology, the pathologist was involved with the clinician only when it was
61
necessary to complete the histopathological study as a
result of increasing specialization and costs related to
maintaining a histological laboratory. As already mentioned, it was Virchow who suggested that autopsies be
performed by pathologists due to the large increase in
autopsies performed in the 1900s, which didn’t begin
in Bologna until the 1920s under the direction of Martinotti 3 28. Later, the number of autopsies levelled off,
until the 1960s when they began to decline in number 74.
A disconcerting fact is that the introduction of dictation
actually lowered the quality of autopsy reports, with a
slow but progressive growth in the number of reports
that were left outstanding. What is even more surprising
is that histopathology was used only rarely for diagnosis, and often with alarming results, as for the diagnosis
of bronchopneumonia 75.
Such a disappointing situation, in an area that was
always considered vital for pathologists, was often
brought into question by anatomic pathologists, starting with Martinotti, who strangely makes reference
to the ‘Golden Age’ of autopsies, which perhaps with
the exception of the Viennese school, probably never
existed 45 46 48 49 71 76.
Nonetheless, apart from autopsies, even before the
war, and at the same time and perhaps independently
of the Americans given the cultural barrier that was
still present, Businco understood the changes that were
taking place at the time in anatomic pathology. This
mainly involved improvements in surgical technique
that permitted a greater number of interventions needing biopsy information on organs that were previously
inaccessible. For the pathologist, this was a new and
challenging type of diagnostic histopathology that
required precise clinical information and close collaboration with the clinician. This profound change in
modern anatomic pathology was anticipated by Businco, and he inspired the idea that a new approach was
needed, which he called an ‘anatomo-clinical approach
to anatomic pathology’ that he introduced in 1938 71.
His insistence was fundamental for renewing the Institute after the Second World War when other European
schools were permeated with the new American concept of surgical pathology.
In Businco, the roots of the merits and deficits of anatomic pathology can be found in the identity crisis that
had afflicted the discipline for some time. From the
second half of the 1800s up to the 1950s, the pathologist
had complete control over medical laboratories, exerting
his influence over clinicians in a manner that was not
always well accepted 3 77. The influence of this dominant
role is evident in the writings of Businco, especially between the two World Wars, in which he had forwarded
the idea that each large clinic should be under the
direction of a pathologist. As for many other pathologists, Businco perceived the importance of radiology, in
addition to the potential threat that radiology posed in
terms of control exercised by the pathologist. For this
62
p. scarani, v. eusebi
reason, he sustained that radiology was a morphological
science, and that radio-diagnostics should be a branch
of anatomic pathology. Similarly, it was his desire that
radiotherapy should be a branch of pathology as it was
widely used in diagnostic oncology.
Businco was fortunate enough to not experience the
crisis of modern anatomic pathology. We believe that
if he had lived long enough, he would probably have
understood the new orientation needed for its rebirth. In
our opinion, he was a person with great intuition, even
during the last years of his long career. After he first
came to Bologna, he began to recognize the increase in
lung cancer, which until that time was relatively rare. In
the last years of his career, Businco was also interested
in other ‘popular’ diseases such as atherosclerosis and
disease involving histocytes and the immune system.
For him, lung cancer was truly worrisome. In 10 years
of publications, he noticed a vast increase in the number
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Businco A. Direttive anatomo-cliniche per l’educazione del
medico. Archivio di Anatomia Patologica e Clinica Medica
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Scarani P, Lacchini G. L’autopsia clinica dell’ottocento a Bologna. Nuove prospettive. Pathologica 1999;91:128.
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pathologica 2009;101:64-75
Storia
di
Anatomia Patologica
Dalla luna nuova al plenilunio: l’Anatomia Patologica
bolognese dal Cinquecento ad Armando Businco
*
P. Scarani* **, V. Eusebi*
Dipartimento di Ematologia e Scienze Oncologiche L. e A. Seragnoli, Sezione di Anatomia, Istologia e Citologia
“Marcello Malpigli”; **Museo delle Cere “Luigi Cattaneo”, Università di Bologna, Italia
Antonmaria Mancini (1929-2007) celebrò il 12 Giugno
1989 i 130 anni dell’istituzione della I Cattedra di Anatomia Patologica dell’Ateneo Bolognese.
Il 12 giugno del 1859, giorno dell’annessione di Bologna al Regno di Vittorio Emanuele II, era una data
emblematica, in quanto Cesare Taruffi (1821-1902)
ricevette da Luigi Carlo Farini l’incarico per la prima cattedra di Anatomia Patologica proprio in quelle
giornate convulse 1. Nel giorno della festa fu anche
presentato agli studiosi di Bologna il recuperato museo
di anatomia patologica. In quell’occasione, il professor
Mancini ricevette molti complimenti da un collega di
veterinaria, per l’efficacia della nuova presentazione
museale. Il professore gli rispose, indicando uno di noi:
“No, è tutto merito suo: gli ho dato l’incarico, e lui ha
agito in piena libertà”. Quel professore di veterinaria
gli rispose: “è un grande merito, da parte tua, avergli
lasciato quella libertà”.
Antonmaria Mancini era così. Diceva spesso: “Se Dio
ha reso noi uomini liberi di fare anche il male, io debbo
per forza fare altrettanto coi miei collaboratori”.
Prologo sulla terra
Senza risultati pratici sulla salute del malato, la medicina non può godere di grande reputazione fra la gente.
Questo stato d’animo poco caritatevole del grande
pubblico verso i ricercatori è ben evidente sino alla
fine della seconda guerra mondiale. Le grandi scoperte
di Koch a fine Ottocento 2, per esempio, lasciavano un
senso d’amaro in bocca, perché, a causa della consistenza ancora scarsa della farmacologia, nonostante le
eccellenti conoscenze sulle malattie, la terapia aveva
ancora un’efficacia che si discostava di poco da quella
dei guaritori e dei ciarlatani. Soltanto la Seconda guerra
mondiale “fece sorgere il sole” dell’ottimismo, oramai
pronto ad affermarsi dopo un trentennio di successi terapeutici finalmente tangibili.
Ringraziamenti
I professori M. Baccarani (Bologna) e G. Bussolati (Torino) vengono ringraziati per avere letto criticamente il manoscritto.
Proprio questa lunga storia notturna ci ha sedotti a scegliere questo titolo bizzarro sulle fasi lunari. Il mondo
in cui si aggirano gli anatomopatologi, a Bologna come
altrove, è per molto tempo poco illuminato. Ciò non
tanto per la qualità delle scoperte, quanto per il loro uso
pratico, ed anche per la difficoltà a definire che cosa sia
l’anatomia patologica, e, a partire dall’Ottocento, che
cosa siano gli anatomopatologi 3.
Luna nuova: morfologia nel Cinquecento
bolognese
Studi di medicina legale sono segnalati a Bologna sin
dall’epoca di Dante (1265-1321). I medici, in tali circostanze, erano sollecitati a stabilire se la morte improvvisa
ed inaspettata di qualche personaggio illustre fosse dovuta
a cause naturali o ad avvelenamento 4. Non meraviglia che
il ricordo di queste esperienze sia conservato: si tratta di
prestazioni connesse col diritto, la scienza principe dell’antico ateneo bolognese. La medicina era considerata invece
un’arte minore. Al di fuori delle attività intellettuali superiori, ciò che facevano i medici interessava molto meno.
Fino a Giulio Cesare Aranzi nel grande fiorire degli
studi anatomici, fra cui quelli di Mondino de’ Liuzzi
(1275-1326), non si sono manifestate osservazioni di
patologia correlate con le malattie riscontrate in vita nei
defunti utilizzati per l’anatomia 5.
A Bologna sono mancati riscontri paragonabili agli
studi comparativi sistematici fra clinica ed autopsia del
fiorentino Antonio Benivieni (1430-1502) 5.
Giulio Cesare Aranzi (1530-1589)
Aranzi (Aranzio è la forma latinizzata), autentico bolognese (Fig. 1). Scoprì la circolazione fetale e la descrisse
in modo splendido, con un latino da antologia 6. L’unica
traccia che persiste di questi studi è il dotto venoso dell’Aranzio. Aranzi inoltre scoprì l’ippocampo, che lui,
Corrispondenza
prof. V. Eusebi, Sezione Anatomia, Istologia e Citologia Patologica
“M. Malpigli”, Università di Bologna, Ospedale Bellaria, via Altura
3, 40139 Bologna, Italia - E-mail: [email protected]
65
dalla luna nuova al plenilunio
Fig. 1. Giulio Cesare Aranzi (da Brambilla Giovanni Alessandro.
Storia delle scoperte fisico-medico-anatomico-chirurgiche fatte
dagli uomini illustri Italiani. Milano 1782, Edizione anastatica Bologna: Arnaldo Forni 1977, p. 188).
1605) 9. Questi era naturalista, più che medico. Aveva
tuttavia una visione così moderna della morfologia, da
studiare con cura anche gli organi interni degli animali.
I suoi studi teratologici, poi, sono di straordinario rigore.
Anche Aldrovandi non ebbe grande successo a Bologna,
nonostante la reputazione internazionale, tuttora conservata. Riuscì a dare alle stampe solo una minima parte
delle sue opere. Neppure lo volle aiutare suo cugino, il
Papa bolognese Gregorio XIII (quello della riforma del
calendario) che pure aveva tratto grandi vantaggi, anche
pratici, dall’opera scientifica aldrovandiana 10.
Non possiamo qui fare a meno di ricordare che il prossimo grande precursore bolognese dell’anatomia patologica, Marcello Malpighi, si formò come curatore delle
grandi collezioni naturalistiche di Aldrovandi.
Falce di luna crescente
più famigliarmente, chiamava ‘baco da seta’. Forse, quest’immagine, a Bologna era recepita molto più facilmente,
rispetto a quella del cavalluccio marino, dato il grande
sviluppo locale dell’industria della seta. Tale scoperta fu
una rivoluzione per le neuroscienze. Individuando l’ippocampo, Aranzi si accorse infatti dell’esistenza di un corno
in più (il corno temporale) del ventricolo laterale, ignoto
anche al suo maestro Vesalio. La scoperta è straordinaria,
anche alla luce delle gravi difficoltà che, prima dell’Ottocento, epoca dello sviluppo dei fissativi, s’incontravano
nello studio macroscopico dell’encefalo. Lo dimostra la
scarsa chiarezza delle tavole vesaliane che illustrano il
sistema nervoso nell’edizione del De humani corporis fabrica del 1543. A questo proposito, non riusciamo ancora
a capacitarci come abbiano potuto attribuire a Michelangelo (1512) la rappresentazione d’un cervello umano nel
gruppo di Dio circondato da creature volanti nella creazione di Adamo della Cappella Sistina. Ciò, si badi bene, fondandosi su confronti, non con tavole dell’epoca, ma con
quelle novecentesche di Netter 7. Oltre alla individuazione
di strutture anatomiche, Aranzi pubblicò la prima opera
anatomo-patologica Bolognese che combinava l’anatomia
con la descrizione di processi patologici.
Un’altra opera dello stesso autore, edita a Venezia nello
stesso anno, insieme con gli studi anatomici: De tumoribus secundum locos affectos 6, consiste in una raccolta
eterogenea (idrocefali, cisti, ascessi, masse solide) di tumefazioni (tumori, appunto), suddivise per sede. Sono il
frutto evidente dell’attività d’un medico pratico, dedito,
fra l’altro, anche alla chirurgia.
Oggi, quasi nessuno ricorda Aranzi a Bologna.
Nella medicina bolognese del Cinquecento c’era davvero
un buio da luna nuova, se si considera che la figura dominante nell’università era Gerolamo Cardano 8. Gli studenti preferivano, comunque, Ulisse Aldrovandi (1522-
Marcello Malpighi (1628-1694) e i suoi discepoli.
Malpighi, da Crevalcore (Bologna), fu allo stesso tempo
un grande anatomico, anatomopatologo e clinico (Fig.
2). Seppe per primo applicare la microscopia in grande
stile allo studio della struttura degli organi. Per questo,
ancora oggi si ritrova molto spesso il suo nome associato a parti della struttura del rene, della milza e della cute.
Sono di grande pregio anche i suoi studi sul polmone e
sullo sviluppo dell’embrione. Malpighi deve però anche
essere considerato un anatomopatologo perché eseguiva
accurate autopsie corredate da notizie cliniche. I referti
sono preceduti oltre che da riferimenti anagrafici anche
da dettagliate storie cliniche. Il suo metodo autoptico
era simile a quello dei nostri giorni. Si procedeva con
l’osservazione del cadavere e quindi si procedeva alFig. 2. Marcello Malpighi (quadro di Carlo Cignani, Galleria Borghese, Roma).
66
l’osservazione degli organi interni iniziando da quelli
intratoracici 11. Egli era però primariamente un medico
clinico pratico. Tutti i suoi interessi in anatomia normale
e patologica derivavano da problemi che doveva affrontare nel corso della pratica clinica. Disgraziatamente, il
suo era un lavoro troppo ante litteram, anche per i nostri
giorni. Così, nonostante gli indubbi successi, ancora riscontrabili nella quantità di riferimenti al nome di Malpighi nei testi contemporanei di anatomia e di embriologia, proprio un suo allievo, Giovanbattista Morgagni,
negò attendibilità alla microscopia, rimandandone così
la definitiva affermazione ed il trionfo alla seconda metà
dell’Ottocento 12.
Il talento di Malpighi anatomopatologo è stato ripetutamente dimostrato. Rimandiamo, per chi lo volesse, ad
uno studio del Salfi 13 sulla brillante diagnosi malpighiana ante litteram di morbo di Paget dell’osso, purtroppo
fraintesa da tanti paleopatologi d’oggi.
Numerosi cartoni di manoscritti aldrovandiani e malpighiani giacciono ancora inesplorati negli archivi
bolognesi.
Antonmaria Valsalva (1666-1723) fu l’allievo maggiore
di Malpighi. Proveniva da Imola (Bologna), e, come
il maestro, dovette sempre vivere ai margini dell’ambiente accademico cittadino. Ciononostante, nel 2004, è
trascorso trionfalmente (non a Bologna) il secondo centenario del suo splendido trattato sull’orecchio umano,
monumento alla sua meticolosità di morfologo, davvero
unica. Esso è paragonabile al trattato sulla circolazione
fetale dell’Aranzi. L’allievo prediletto Giovanbattista
Morgagni, che descrisse la morte di Valsalva con una
straordinaria commistione di affetto e di rigore clinico,
esalta la grande passione per la morfologia posseduta
dal grande Imolese. Egli viveva l’autopsia in modo veramente ‘totale’, arrivando a verificare anche il sapore
di quello che gli capitava sotto gli occhi. A dispetto delle
mille paure dei patologi d’oggi, non morì d’infezione.
Faremmo un torto a Giovanbattista Morgagni (16821771), da Forlì, il dio dell’anatomia patologica autoptica, considerandolo della scuola bolognese. Bologna lo
rigettò, e lo trattò sempre in modo malevolo, nonostante
egli provasse affetto per la città, grazie al legame con
Valsalva.
Verso la luna piena: da Napoleone
alla Repubblica romana
Quando, nel 1888, si celebrò il discusso ottavo centenario della nostra Università, l’anatomia patologica
bolognese era nata da pochi anni, nel 1859, in concomitanza col riordinamento degli studi conseguente
alla cessazione dell’amministrazione pontificia 1 14. Tale
evento, purtroppo per Bologna, non era un primato
italiano; infatti in questo la nostra città fu nettamente
preceduta da Firenze, dove il Granduca Leopoldo II
istituì la cattedra di anatomia patologica nell’autunno
p. scarani, v. eusebi
del 1840 ed anche da Genova 5 15. L’istituzione della
cattedra bolognese fu invece quasi contemporanea a
quella dell’università di Modena 16. Tuttavia, l’anatomia
patologica bolognese, indipendentemente dalla cattedra,
aveva già iniziato una rigogliosa fioritura dall’inizio
del secolo. Un Museo Universitario di Patologia fu
fondato da Napoleone (allora presidente della neonata
Repubblica Italiana) nel 1804 17. In esso erano raccolti
preparati essiccati o modelli di cera di organi affetti da
svariate malattie. A parte i materiali tuttora conservati
nel museo di anatomia, rimangono poche testimonianze di quel museo, se si eccettua una serie di memorie
in latino, nelle quali sono descritti numerosi preparati
in esso raccolti. Quelle memorie furono pubblicate
sugli Opuscoli Scientifici dell’accademia delle scienze
dell’Istituto di Bologna fra gli anni 1818 e 1823 18-21.
L’autore è Luigi Rodati, responsabile del museo di patologia dal 1815 al 1832. Le dissertazioni del Rodati si
limitano ai preparati originali a secco. Già a quell’epoca, però, il museo, uno dei più grandi d’Europa, conteneva modelli di cera, come quello, molto bello ed ancor
oggi molto famoso, del busto dell’acromegalico (1811).
La ceroplastica anatomica era in piena fioritura, in quel
periodo, ed i suoi cultori, come a Firenze, col consolidarsi della dottrina anatomopatologica, cominciarono
a modellare esempi di patologia di varia natura 22.
Numerose cere della prima metà dell’Ottocento si
trovano ancora raccolte nel museo (oggi collocato nell’Istituto di Anatomia Normale, col nome di “Museo
delle cere anatomiche Luigi Cattaneo”). Ne fu autore
Giuseppe Astorri, degno continuatore della ceroplastica
anatomica bolognese del Settecento, la cui vastissima
attività è documentata da un interessante catalogo autografo conservato all’Archivio di Stato di Bologna.
Dopo la caduta di Napoleone, le istituzioni bolognesi
furono affidate al Cardinale Carlo Oppizzoni, uomo di
perspicacia e levatura morale veramente straordinarie.
Estremamente esplicativa, a questo proposito, è la sua
critica, dura e profondamente motivata dal punto di vista
teologico, della scomunica lanciata da Pio IX contro la
Repubblica romana 23.
Oppizzoni curò con particolare passione la crescita della
facoltà medica bolognese, dotandola d’un regolamento
che è stato preso a modello anche dagli ultimi Presidi
di Medicina. Promosse, in particolare, la pratica delle
autopsie, istituendo, fra l’altro, un premio, destinato al
medico che eseguisse più autopsie nel corso di un anno.
In ciò particolarmente si distinse Antonio Alessandrini
(1786-1861) 24, figura leggendaria della scuola medica
bolognese. Di origini poverissime, contrariamente alla
maggior parte dei professori bolognesi, è soprattutto
ricordato come fondatore dei musei di anatomia patologica veterinaria (da lui denominato di “patologia comparata”) e di paleontologia. Luigi Calori, autore d’una
splendida biografia di Alessandrini, è probabilmente
l’unico morfologo che regge il confronto con questo
straordinario studioso 25-27. Uno studio sistematico dell’immensa attività di Antonio Alessandrini, non è mai
stato condotto. Anche oggi la mole di pubblicazioni
67
dalla luna nuova al plenilunio
da lui lasciata appare impressionante. Tanti scheletri di
animali esotici svariatissimi, oggi conservati nei musei
zoologico e di anatomia comparata, appaiono corrispondere alle descrizioni di tante sue pubblicazioni originali.
Egli appartiene alla generazione di transito dalla morfologia macroscopica all’istologia ed all’istopatologia. Si
tratta, comunque di un uomo con spinte potenti verso il
futuro. Ciò è, per esempio, dimostrato dalla sua stretta
relazione col grande fisico e naturalista Giovanbattista
Amici (1786-1863), fra l’altro, inventore dell’obiettivo
ad immersione. L’attività di Alessandrini era così intensa da lasciargli pochi spazi per la vita privata, e gli costò
fra l’altro una ferita infetta alla mano destra, che Francesco Rizzoli gli dovette amputare. I colleghi avrebbero
voluto conservare nel museo di patologia quella mano
straordinaria. Non dobbiamo meravigliarcene: a Torino
si conserva ancora lo scheletro di Cesare Lombroso.
Sorprendentemente, Antonio Alessandrini trovò pure il
tempo per dedicarsi alla politica: fece infatti parte del
triumvirato che organizzò la resistenza bolognese agli
Austriaci, terminata il 17 maggio 1849, dopo quattro
giorni di bombardamenti 23.
Grande importanza per l’anatomia patologica ebbe
anche la fondazione della Società medica chirurgica
bolognese (1823), la quale si fece promotrice della presentazione di casi autoptici nelle proprie sessioni 17 28. I
casi dovevano essere pubblicati, e gli organi prelevati
erano destinati, insieme con un’accurata descrizione, al
museo di patologia, che ne diveniva il custode perpetuo
(in molti casi così è stato fino ad oggi!).
La luna nell’emblema: Cesare Taruffi
Nel 1844 fu nominato settore anatomico temporaneo e
curatore del museo il giovane chirurgo Cesare Taruffi,
destinato a divenire entro breve tempo il primo professore di anatomia patologica dell’Ateneo bolognese (Fig.
3). Taruffi, discendente da un’antichissima famiglia,
cui appartennero numerosi illustri personaggi vissuti
sia a Bologna che in Toscana, nacque a Bologna il
23 marzo 1821 1. Curiosamente per la nostra storia,
l’emblema dei Taruffi porta un crescente in capo.
Esso è riprodotto nella sede della società medica chirurgica di Bologna, in quanto il Nostro ne fu a lungo
presidente, oltre che preside della facoltà medica.
Si dedicò inizialmente alla chirurgia e fu allievo di
Francesco Rizzoli, il fondatore dell’omonimo Istituto
ortopedico. Già dagli esordi, però, si curava anche dell’anatomia patologica, come è dimostrato dalla sua qualifica di settore anatomico. Ben presto si trovò coinvolto
nella politica 17. Da documenti raccolti nell’archivio del
Museo del Risorgimento di Bologna, risulta infatti nominato, il 6 novembre 1847, sottotenente del terzo battaglione della guardia civica, da poco istituita da Pio IX.
Le notizie successive da noi reperite sono frammentarie, e non fanno intendere bene il preciso ruolo avuto dal Taruffi nelle guerre del 1848-’49.
Fig. 3. Cesare Taruffi.
Una lettera del 30 aprile 1848, firmata da Carlo Bignami, uno dei difensori di Venezia dopo la
caduta di Vicenza e la resa dei volontari pontifici dell’11 giugno, lo nomina medico chirurgo del
primo battaglione mobile civico, destinato alle operazioni militari nel Veneto, contro gli Austriaci.
Un’altra lettera ufficiale, datata 1 giugno, ce lo fa trovare a
Padova, poco lontano, quindi, dai teatri dei combattimenti
dei volontari bolognesi contro gli Austriaci provenienti
dalla Carnia, che tentavano di congiungersi al Radetzky.
Lettere successive testimoniano un’intensa attività del
Taruffi negli ospedali di Venezia, dove già si trova il 30
giugno, fino al gennaio del ’49, allorché è richiamato a
Bologna per la progettazione di un ospedale militare.
Queste
notizie,
pur
frammentarie,
fanno pensare che il Taruffi si sia unito ai volontari del Bignami, dopo le resa dell’11 giugno.
Le notizie successive sono ancora più scarse. Una
lettera del Ministero della Guerra della Repubblica Romana, datata 1 giugno 1849, lo nomina chirurgo maggiore della legione bolognese.
Non è chiaro però quale sia stato il suo ruolo preciso nella difesa di quella Repubblica.
Da un foglio di via, che gli rilasciò il comando dell’esercito di occupazione francese il 7 luglio, risulta evidente
che egli si trovava a Roma fino a dopo la caduta della
Repubblica (4 luglio 1849). Evidentemente il Taruffi
non si era però segnalato come individuo particolarmente pericoloso, perché poté uscire dalla città arma-
68
to e in divisa, quantunque ciò possa anche essere in
rapporto con l’atteggiamento conciliante inizialmente
adottato dai Francesi. I numerosi timbri applicati al
foglio dimostrano poi che durante il lungo viaggio verso Bologna egli fu lasciato transitare apparentemente
indisturbato sia dai Repubblicani, in marcia verso la
Romagna con Garibaldi, che dalle Autorità Pontificie.
Momentaneamente non vi sono prove sicure sull’attività
patriottica del Taruffi in Venezia ed in Roma. Neppure
vi sono conferme degli ostacoli alla carriera del Taruffi,
creati dall’Autorità Pontificia dopo la restaurazione,
e sulle relazioni da lui mantenute col gruppo liberale
di Bologna, ed in particolare con Marco Minghetti.
Certamente, i numerosi incarichi sanitari conferiti al
Taruffi da parte del governo provvisorio di Bologna e
della Romagna nell’autunno del 1859, dei quali ancora
rimane la documentazione originaria, dimostrano che
l’uomo godeva già di profonda fiducia da parte dei liberali: ciò è chiaramente in accordo con un atteggiamento
moderato del Taruffi nel corso della rivolta del 18 48’49, ed in sintonia, certamente, con le dure critiche ai
Repubblicani da parte di Luigi Carlo Farini, il medico
e politico romagnolo che attuò con grande determinazione l’annessione dell’Emilia e delle Romagne al
Piemonte, ed istituì la cattedra di Anatomia Patologica.
A dispetto di quanto appena asserito, non ci sembra
molto felice attribuire la carriera accademica del Taruffi
a puri meriti patriottici. L’enorme lavoro svolto dal Taruffi da quella data sino alla morte, nel 1902, dimostra
che egli doveva avere fin dall’inizio basi anatomopatologiche non improvvisate. Oltre a creare praticamente
dal nulla un’istituzione nuova 29, egli si dedicò con grande alacrità alla teratologia. In questo campo operò con
tenacia incredibile, raccogliendo una quantità enorme di
materiale, che accumulò progressivamente nel museo, il
quale dal 1859 era stato denominato Museo di Anatomia
Patologica. In alcuni casi conservava in alcole i feti ed
i bambini malformati. In altri, invece, dapprima faceva
eseguire una riproduzione, con cera o altri materiali.
Molto del materiale teratologico fu tuttavia ereditato da
altri studiosi. Dopo il 1863, infatti, i preparati anatomopatologici umani conservati dai veterinari, principalmente dal grande morfologo e patriota Antonio Alessandrini, furono acquisiti dal museo di anatomia patologica.
Contemporaneamente, Francesco Rizzoli donò a Taruffi
numerosi preparati ginecologici, derivati dalla sua lunga
direzione della clinica ostetrica, e svariati esempi d’interventi anche particolarmente audaci, testimonianza
della grande versatilità del Rizzoli 30.
Le più accurate preparazioni teratologiche bolognesi
sono il frutto degli studi dell’anatomico Luigi Calori 25.
Furono allestite da Cesare Bettini, famoso ceroplasta e
disegnatore anatomico suo contemporaneo; esaminati
gli organi interni e descrittene le malformazioni, Calori
ne conservava gli scheletri, e gli organi interni, essiccati
ed iniettati con una tecnica mirabile.
Calori ci fornisce un esempio tipico delle tecniche d’uno
studioso di scienze naturali, soprattutto morfologiche,
dell’Ottocento 25-27. Egli aveva la capacità di raccogliere
p. scarani, v. eusebi
preparati (naturali o in copia) con grande efficienza.
L’efficienza è evidenziata dal fatto che molti di quei
preparati resistono ancora alla distanza di quasi due
secoli. Il fatto di maggior rilevanza è tuttavia costituito
dalle pubblicazioni scientifiche, sempre illustrate con
numerose tavole che rappresentano con grande precisione i temi trattati. Per la teratologia, anzi, le tavole sono
state di estrema importanza nel riordino del museo. Di
solito, infatti, Cesare Bettini allestiva sia i preparati che
le tavole illustrative con tale rigorosità, che, non vi erano differenze fra il preparato e l’illustrazione. Sin dall’inizio del riordino del museo di anatomia patologica,
molti esperti rimasero sbalorditi per questa spettacolare
corrispondenza fra preparati e pubblicazioni scientifiche, già evidenti nelle pubblicazioni del Rodati. Nella
successiva riorganizzazione del museo di anatomia (di
cui ora fa parte anche il museo di anatomia patologica),
evidenziammo come questa relazione tra museo e pubblicazioni è diffusa nei musei universitari bolognesi, e
che le pubblicazioni ottocentesche permettono spesso
di recuperare preparati il cui significato era andato del
tutto perduto 22.
Oltre a varie memorie e pubblicazioni su singoli reperti
teratologici, Taruffi lasciò un’opera monumentale, la
Storia della teratologia 31. Essa corrisponde senz’altro
al titolo, perché è ricchissima di nozioni storiche e di
erudizione; è anche però di notevole rilievo lo sforzo
gigantesco che l’autore ha compiuto per dare organicità
e sistematicità a questa materia complessa. Questa grande opera di Taruffi vive ancora all’estero, nonostante
che in Italia ed a Bologna sia stata dimenticata 32 33.
Taruffi non raggiunse gli scopi che si era prefissato: la
pubblicazione della Storia della teratologia fu iniziata nel
1881 e terminata nel 1894, quando egli era oramai vecchio
e di salute cagionevole; il suo intento era però quello di
portare a compimento un’opera ben più vasta e sistematica, rimasta incompiuta con la sua morte, nel 1902.
Nulla possiamo dire del Taruffi insegnante. Egli fu
autore di un trattato di anatomia patologica del 1870 34,
un’opera asciutta ed essenziale. In essa l’autore dimostra di conoscere già bene i grandi temi dell’anatomia
patologica europea: quelli del Virchow, per intenderci.
Ciò depone nettamente a suo favore: da appena 10 anni
era tramontato il Governo Pontificio e Taruffi già respirava “aria più europea”.
Cesare Taruffi morì nel luglio del 1902. Frank Gonzalez-Crussi gli dedicò un’ampia parte del suo famoso
saggio 32, e di un’altra opera sulla conservazione del
corpo umano, in parte ispirata dal museo d’anatomia
patologica di Bologna 33.
La fama di Taruffi, come accurato classificatore delle
malformazioni, è meritata. Per anni rimase invece circondata da un alone di mistero la notizia, dell’esistenza
di un’opera in tedesco del Taruffi, presso la biblioteca
dell’Università di Heidelberg 35. Essa costituisce la terza
ed ultima parte d’una serie (incompleta) di saggi, riguardante l’ordinamento della teratologia. I progressi delle
69
dalla luna nuova al plenilunio
scienze morfologiche, e le sue continue ed imponenti
acquisizioni di dati epidemiologici, indussero Taruffi
ad ampliare enormemente il piano originale della Storia
della teratologia, ed a scrivere successivamente i citati
articoli sull’ordinamento 36-39.
Nonostante l’età, Taruffi appare, in queste ultime
pubblicazioni, estremamente lucido ed accurato, dimostrando inoltre d’essere tormentato da un problema che
turba l’Occidente fin dal Settecento, ma particolarmente
acuito alla fine del diciannovesimo secolo: la determinazione del sesso e l’esistenza o no d’un reale confine
fra il sesso maschile ed il femminile 40. Proprio la psicologia dei portatori di malformazioni sessuali induce
Taruffi ad occuparsi anche dei temi che più turbano la
comunità occidentale di fine Ottocento: l’omosessualità,
la bisessualità e la pedofilia.
La rivoluzione francese comportò una forte esaltazione
della virilità, in contrasto con l’attribuzione di un ruolo
materno-familiare alle donne, e l’Ottocento si trasformò
in un campo di battaglia fra questo concetto patriarcale ed i nascenti movimenti per l’emancipazione delle
donne. Un esempio tipico di questa conflittualità è in
Italia costituito dalla vita di Giuseppina Cattani 41. Tale
conflittualità, insieme con le scoperte sulla complessa
determinazione del sesso, da parte degli embriologi, e
delle reali dimensioni della presenza degli omosessuali
nella società occidentale, indussero un vivissimo interesse per gli studi sulla sessuologia.
Proprio in questo contesto debbono essere considerati
i saggi di Taruffi tradotti in tedesco. Egli si dimostra,
nonostante l’età, particolarmente aggiornato sul problema e sui più noti specialisti del tempo. La Germania del
primo Novecento è probabilmente il centro culturale più
aperto e vivace del mondo, ed è la culla della sessuologia. Non sorprende, quindi, la traduzione in tedesco
di un’opera così ricca d’informazioni come quella del
Taruffi. Neppure sorprende che Sigmund Freud (18561939) se ne interessi 42. All’inizio del Novecento, Freud
si è oramai reso conto degli stretti legami fra tante affezioni della psiche da lui studiate e varie “anomalie” della vita sessuale. La ricerca di una spiegazione fisica dei
comportamenti sessuali “anomali” lo porta al saggio in
Tedesco di Taruffi. Questo è infatti citato all’inizio dei
suoi tre saggi sulla dottrina sessuale 43-44. La morfologia
è, per Freud, d’importanza critica. Essa infatti dimostra
l’ambiguità dello sviluppo embriologico del sesso, e
contribuisce, alla “rivoluzione freudiana”. Il dinamismo
della determinazione del sesso, porta infatti Freud a
vedere anche nello sviluppo della psiche una specie di
embriogenesi, di preistoria. Si è attuata, insomma, la
scoperta della sessualità infantile e del suo sviluppo.
Taruffi fu, seppure involontariamente, una specie di detonatore, capace d’avviare quell’esplosione dell’attività
di ricerca e speculativa di Freud, la quale caratterizzò gli
anni fra il 1905 ed il 1910. Un’esplosione che cambiò
radicalmente il nostro modo di pensare 1.
Sappiamo poco della vita privata di quest’uomo. Rimase
vedovo in giovane età e non si risposò. Era un polemista
sanguigno. Nulla, però, nei suoi scritti, fa pensare alla
bizzarria. L’enigma è stato recentemente risolto con la
scoperta che molti a Bologna confondono Taruffi con
l’oculista Tartuferi (con l’accento sulla u – curiosamente, Taruffi è noto in Austria come Tartuffi), ideatore della sede della clinica oculistica al S. Orsola ai tempi della
guerra di Libia. Tartuferi era in effetti un po’ peculiare:
temendo moltissimo i ladri ed i grassatori, aveva trasformato la propria villa localizzata presso l’Osservanza,
una collina di Bologna, in una sorta di fortezza con finestre in grado di aprirsi all’improvviso, consentendo di
sparare a sorpresa su eventuali assalitori. Il modello fu
poi adottato per le fortificazioni della linea Maginot.
La luna cresce … e il lavoro aumenta
Quando, nel 1893, Taruffi si ritirò dall’insegnamento, gli subentrò Giovanni Martinotti (1857-1928), piemontese, il quale giunse a Bologna quando oramai si trovava all’apice della propria carriera accademica, iniziata a Torino (Fig. 4).
Dal 1889 al 1891 tenne la cattedra di anatomia patologica dell’Università di Modena, dove si manifestò la sua propensione per la microbiologia, allora una branca dell’anatomia patologica.
Dal 1891 sino alla chiamata a Bologna, fu a Siena.
A Bologna si dedicò soprattutto alla didattica. A questo proposito, fu un appassionato sostenitore della
creazione del nuovo Istituto di anatomia patologica,
l’attuale Istituto anatomico di via Irnerio, ultimato
nel 1907. In esso erano accolti sia l’Istituto di anatomia patologica che quello di anatomia normale.
La sede precedente era ormai fatiscente: si trattava infatti ancora di quella di Palazzo Malvezzi Lupari, a un passo dal Rettorato. Anche il Mu-
Fig. 4. Giovanni Martinotti.
70
seo, ricevette colà una sistemazione più adeguata.
Dell’epoca del Martinotti rimangono ancora alcuni
registri delle autopsie, ora in Anatomia normale. Negli
ultimi anni della direzione martinottiana, le autopsie
cliniche divennero ufficialmente e definitivamente compito esclusivo dei patologi 3 45-48, prerogativa, fra l’altro,
appassionatamente rivendicata dallo stesso Martinotti 49.
Ciò coincise con un incremento notevolissimo delle autopsie (da 100 a quasi mille per anno).
A quel periodo risalgono anche le prime testimonianze
di diagnosi istologiche su materiale bioptico e chirurgico. Le tecniche istopatologiche erano un tema d’interesse per Martinotti, probabilmente in quanto ai suoi tempi
la diagnosi bioptica di neoplasia maligna cominciava
ad assumere rilevanza pratica. Riteniamo anzi che proprio col Martinotti cominci a delinearsi a Bologna una
proficua collaborazione fra clinici, patologi e radiologi
per uno studio sistematico delle neoplasie maligne: ciò
è dimostrato dagli accurati studi statistici iniziati dal Vigi 50 51, e continuati sino al termine dell’era businchiana.
La scuola martinottiana fu molto numerosa, il che è
tuttora dimostrato dai volumi di pubblicazioni raccolti. I lavori specificamente anatomopatologici di
questa scuola non sono quasi mai, comunque, particolarmente esaltanti (con una sola eccezione, come
vedremo): ciò forse perché Martinotti era più sollecitato dalla microbiologia, e, in modo particolare, dalla ricerca di un vaccino antitubercolare, cui
dedicò numerosi lavori, anche ad impronta clinica.
Egli sosteneva 52 53 di aver ottenuto risultati lusinghieri,
col suo vaccino, ma in casi non gravi, e di non essere
in grado di escludere recidive della malattia. Risultati a
parte, i suoi lavori dimostrano una notevole padronanza
del problema della tubercolosi. Curiosamente, proprio ai
giorni nostri, essi stanno suscitando nuova curiosità, forse
a causa della disperazione in cui nuovamente ci si ritrova
nella lotta alla tubercolosi, a causa delle chemioresistenze e della scarsa efficacia del Bacillo Calmette-Guerin.
Grazie agli scritti di Bindo De Vecchi, si è aperta la
discussione che Giovanni Martinotti, contrariamente a
quanto scritto con estrema superficialità da tante parti,
non fosse lo scopritore dei neuroni corticali chiamati
“cellule del Martinotti” che invece sono state descritte
da un allievo di Camillo Golgi, Carlo Martinotti, l’autentico scopritore 54. Per contro un fratello di Giovanni
Martinotti, rinomato enologo, produsse un eccellente
metodo per produrre vini spumanti, adottato, fra l’altro,
dai Francesi.
Martinotti morì improvvisamente e tragicamente, e la chiamata a Bologna di Giulio Tarozzi, Torinese (1868-1948), fu piuttosto repentina.
Prima di passare al Tarozzi, dobbiamo però parlare di
un evento straordinario, che potremmo paragonare al
passaggio di una cometa: il periodo bolognese di Bindo
De Vecchi.
p. scarani, v. eusebi
Gli anni della cometa di Halley:
Bindo De Vecchi (Fig. 5)
Fig. 5. Bindo De Vecchi.
De Vecchi, giovane, brillante studente di medicina,
impressionò profondamente il grande clinico Augusto
Murri. Questi, con notevole perspicacia, lo indirizzò
all’anatomia patologica, presentandolo al Martinotti.
Pur non essendo destinato a raggiungere, come vedremo, l’apice della carriera a Bologna, De Vecchi
conservò sempre un saldo legame col Martinotti,
tanto da essere destinato a scriverne l’elogio funebre.
Quest’opera fu molto importante in quanto si tratta
dell’unica pubblicazione che non considera Giovanni
Martinotti scopritore dei neuroni corticali chiamati
“cellule del Martinotti”, contrariamente a tanti malaccorti storici successivi 54.
De Vecchi fu un morfologo di grande talento. Già nel
1903 formulò una diagnosi d’infarto del miocardio in
un suo verbale autoptico d’archivio (ora in Anatomia
normale). Non si tratta di cosa di poco conto. È credenza
diffusa che il concetto clinico ed anatomico d’infarto
del miocardio siano stati elaborati negli Stati Uniti dopo
la Prima guerra mondiale. In realtà, la correlazione fra
necrosi miocardica ed occlusione di un vaso coronarico
è già stabilita con chiarezza nella seconda metà dell’Ottocento, da Cohnheim 14 il cui lavoro fa parte della ricca
biblioteca di Giovanni Martinotti. Le qualità di morfologo da lui possedute sono ben evidenti nel campo della
patologia neoplastica. De Vecchi dimostra una prospettiva molto attuale, da surgical pathologist. A testimonianza del fatto che il Nostro sia uomo da tempi nuovi si
può citare il fatto che uno di questi lavori oncologici, in
lingua inglese, sia stato pubblicato in una rivista medica
di New York 55. Sia l’uso dell’inglese che l’interesse
per la cultura americana sono insoliti nei medici italiani
del primo Novecento 47: lo stesso De Vecchi, nel 1908,
preferirà la scuola di Schmorl a Dresda, per l’approfondimento della propria preparazione.
71
dalla luna nuova al plenilunio
La vicinanza alla cultura statunitense ce lo presenta,
quindi, come uomo dotato di notevole lungimiranza.
Simile a lui fu Vittorio Putti, il grande ortopedico bolognese, che seppe dare rinomanza genuinamente mondiale all’Istituto Rizzoli di Bologna.
De Vecchi era figlio di un ufficiale dell’esercito. A
ciò è attribuito il suo particolare senso patriottico, che
lo fece assurgere ad una dignità politica di grande rilevanza. Non sappiamo se questa sia una spiegazione
adeguata di tutta la sua inquieta esistenza. A noi sembra
che De Vecchi fosse un generoso, sia nel lavoro, dove
era molto amato dagli allievi, che nella vita pubblica.
A questo proposito, a parte il volontariato nella prima
guerra mondiale, bisogna ricordare il soccorso prestato
ai terremotati di Messina e Reggio Calabria del 1909, e
l’impegno profuso per la lotta al colera nel siracusano
(1911). Il periodo bellico fu molto celebrato, per l’eroismo dimostrato dal De Vecchi, che gli valse la croce di
guerra ed il conseguimento del grado di ufficiale medico
superiore. Non si può tuttavia dimenticare la sua professionalità di patologo, anche in guerra. Possiamo, a
questo proposito, citare una sua pubblicazione del 1919,
in cui presenta una statistica delle morti fra militari di
leva nel periodo attorno alla cessazione del conflitto
(autunno 1918) 56. Si tratta della grave epidemia influenzale di quell’epoca, la famosa ‘spagnola’. De Vecchi ed
i suoi collaboratori sono sorpresi dalla gravità della malattia polmonare riscontrata in gran parte delle vittime.
Si accorgono inoltre di trovarsi di fronte ad un quadro
polmonitico molto esteso, e con morfologia insolita.
Se non arrivano a caratterizzarlo come una polmonite
interstiziale acuta, si discostano tuttavia dal pregiudizio
comune che per lungo tempo volle come esclusivamente
da cause batteriche le polmoniti che portano a morte i
malati più gravi nel corso di pandemie influenzali particolarmente severe.
De Vecchi è anche considerato un patologo sperimentale di grande abilità. Particolarmente celebrati furono gli
studi sulla malattia di Addison secondaria a tubercolosi
dei surreni, pubblicati in varie riviste, ed ancora una
volta nelle Medical News 57.
Teniamo per ultima la spettacolare carriera accademica
di De Vecchi. Ebbe la prima cattedra a Perugia nel 1920
(fu una sorta di ripresa, dopo la partenza volontaria per
la guerra, nel 1915), poi a Palermo, e infine, ebbe dalla
Facoltà Medica di Firenze l’onore di succedere a Guido
Banti (1925). A Firenze, De Vecchi raggiunse l’apice
della celebrità, divenendo Rettore e Podestà di Firenze,
e, alla morte, nel 1936, fu celebrato come un eroe nazionale. Tutto questo lo diciamo alla fine, per dimostrare
che De Vecchi meritò gli onori di fine carriera. Era un
fascista convinto, figlio di quei tempi, che oggi conosciamo per sentito dire e non siamo in grado di rivivere.
Una cosa, però, è certa: De Vecchi non era una nullità
consenziente, ma un fiore all’occhiello, per Mussolini,
come Guglielmo Marconi.
Luna quasi piena: Giulio Tarozzi
Mentre del Taruffi, grazie al Museo, e del Martinotti, grazie ad una lapide nell’anticamera dell’Aula Magna dell’oramai decrepito Istituto, un pallido ricordo esiste ancora, Tarozzi è quasi dimenticato.
Abbiamo soltanto rinvenuto uno scritto commemorativo, opera del suo allievo (da studente a Cagliari) e successore a Bologna: Armando Businco 58.
Questa commemorazione è molto bella e precisa nella
critica della vasta attività scientifica del Tarozzi, coi suoi
numerosi lavori in lingua italiana e tedesca, pubblicati soprattutto nel lungo periodo anteriore a Bologna, trascorso
in Pisa, Siena, Cagliari e Modena. Essa non ci permette
tuttavia di scorgere bene l’uomo del periodo più attivo,
il quale, da quanto almeno traspare nelle ultime pubblicazioni 59, doveva essere dotato d’intelligenza molto
sensibile e dedita alla speculazione. Il Tarozzi doveva
comunque essere un morfologo solido, conforme ai canoni della scuola tedesca: ciò è dimostrato specialmente
dai suoi ultimi studi sul parkinsonismo postencefalitico 60.
Negli ultimi anni il Tarozzi sembrava spesso affascinato
da problemi profondi, coinvolgenti il significato della
vita e del mondo misterioso che ci circonda. Sapevamo
che un fratello di Tarozzi era stato professore di filosofia,
e che aveva avuto molta influenza su di lui, soprattutto
introducendolo alle speculazioni dei filosofi della scienza
dell’epoca. Evidentemente, però, Giulio Tarozzi aveva
una vita autonoma molto vivace, in questa attività speculativa. Recentemente, infatti, Sandra Linguerri e Raffaella
Simili hanno dimostrato che egli faceva parte del gruppo
di studiosi bolognesi che sostenevano Einstein, e l’invitarono anche per alcune conferenze nella nostra città 61. Essi
poi si distinsero per essere tra i pochi Italiani ancora in
rapporto con lui, dopo che Einstein ebbe pubblicamente
osteggiato l’Italia per l’adesione alla politica razziale di
Hitler.
Come Martinotti, anche Tarozzi compì studi microbiologici, interessandosi, in particolare di terreni di coltura per
anaerobi 62. Col trasferimento, all’inizio del millennio, del
museo di anatomia patologica nell’antico Istituto martinottiano di via Irnerio, dove anche Tarozzi operò, sono
stati ritrovati per puro caso alcuni preparati istologici
autoptici della sua epoca. Forse non è un caso che questi
preparati riguardassero patologia neoplastica, oggetto di
accurate revisioni anatomocliniche da parte dei collaboratori del Tarozzi 63 64, le quali, come molti studi analoghi
compiuti dai patologi bolognesi in altre epoche, hanno
permesso di interpretare con maggior precisione diversi
verbali dell’archivio autoptico di quel periodo.
Una serie di strisci senza coprioggetto ha costituito poi
una sorpresa del tutto inattesa. Ripristinatili per la visione al microscopio, abbiamo visto che si tratta di bacilli
del carbonchio e del tetano, fra l’altro, ancora in ottimo
stato di conservazione. Si tratta sicuramente degli ultimi
resti della collezione microbiologica di Giulio Tarozzi.
Secondo il professor Mario Alberto Dina, oramai l’unico patologo vivente che conobbe Tarozzi, egli si occupò
proprio anche di questi patogeni.
72
p. scarani, v. eusebi
Plenilunio o alba? Armando Businco (Fig. 6)
Fig. 6. Armando Businco.
Il Tarozzi si ritirò dall’insegnamento nel 1938, e gli subentrò Armando Businco (1886-1967), di Ierzu (Nuoro),
il padre dell’anatomia patologica bolognese contemporanea e di una generazione di patologi alcuni ancora viventi.
Iniziò la sua attività accademica a Cagliari, ma presto l’interruppe, partendo volontario, nel 1916, per la guerra (sottotenente medico).
Estremamente attivo, in quel periodo compì una revisione dei preparati istopatologici ottenuti da una sperimentazione, disposta dal ministero della guerra italiano,
sugli effetti di varie sostanze tossiche su animali da
esperimento. Lo studio era anteriore all’impiego massivo di molte di quelle sostanze nel corso della prima
guerra mondiale. Businco compì la revisione istopatologica quando già era iniziato l’impiego d’alcuni di
quei prodotti chimici, potendo così confrontare i dati
sperimentali con quelli riscontrati su vittime umane.
Sull’argomento esistono alcune pubblicazioni del 1920
(di cui una in inglese) 65-67, le quali evidenziano, fra
l’altro, l’attenzione dello studioso per i danni indotti
dalle sostanze inalate sulla membrana alveolocapillare
del polmone.
Dopo la guerra, Businco ricoprì l’insegnamento dell’Anatomia Patologica presso diverse Università: nell’ordine, Perugia, Cagliari, Palermo, e di nuovo Cagliari, finché, nel 1938, non fu chiamato a Bologna, dove
rimase fino al collocamento fuori ruolo, nel 1956.
L’arrivo a Bologna corrispose con l’apice della fama
nazionale del Businco. Egli si era in quegli anni particolarmente distinto per gli studi sull’endemia malarica in
Sardegna. Egli teneva molto all’educazione dei medici
sul problema della malaria, tanto da scrivere una monografia “L’infezione malarica” 68, che, col volumetto di
tecnica delle autopsie, rivisitato negli anni novanta da
Antonmaria Mancini 69, costituiva un supporto obbligatorio al testo di anatomia patologica sistematica per
la preparazione dell’esame a Bologna. Prima e dopo la
seconda guerra mondiale, Businco contribuì con grande
passione alla lotta antimalarica in Italia. Oggi, questa
grandiosa operazione è considerata con grande ammirazione dagli storici, tanto da essere suggerita come
modello per i tanti paesi che ancora aspirano all’eradica-
zione di questo flagello. Dispiace che Businco, anche in
opere recenti sull’argomento, non sia stato ricordato 70.
Al periodo bolognese è collegato un episodio drammatico e misterioso: nel 1944, Businco fu arrestato dai
nazisti e deportato, ma riuscì a fuggire ed a nascondersi
fino al termine della guerra. Prima della guerra, Businco non appariva in dissonanza col regime fascista.
Ai tempi dell’occupazione tedesca, qualcosa doveva
essere cambiato. Egli si era infatti opposto al tentativo
degli occupanti di appropriarsi delle apparecchiature
dell’Istituto del Radio; inoltre, era in contatto con un
gruppo di studenti e giovani medici partigiani, molti dei
quali furono barbaramente massacrati, e da lui ricordati
nel 1948, in una lapide collocata nel nuovo Istituto,
al Policlinico S. Orsola, che fu proprio inaugurato nel
1948. Il discorso pronunciato dal Businco in quella
circostanza fu pubblicato e si tratta d’uno scritto capace
d’emozionare ancora oggi, ed una dimostrazione dei
sentimenti che poté suscitare allora è data dalla lettera
autografa di complimenti inviata all’autore da Bartolo
Nigrisoli, un professore di chirurgia dell’università di
Bologna che era stato allontanato dall’insegnamento per
non aver voluto pronunciare il giuramento di fedeltà al
regime fascista.
Dopo tanti anni, evidentemente, le acque non si sono
ancora placate a sufficienza per spiegare con chiarezza
che cosa fosse successo ad Armando Businco. Probabilmente, una spiegazione di tutto questo si trova nel
ruolo ambiguo che la sanità bolognese venne a giocare
fra il 1943 ed il 1945. L’Istituto Ortopedico Rizzoli e
l’Istituto Traumatologico, diretti dal Professor Oscar
Scaglietti, costituivano il più importante ed efficiente
ospedale militare delle retrovie per le forze armate
tedesche. Gli ufficiali italiani della croce rossa erano
tuttavia anche in contatto con la Resistenza e con gli
Alleati, sicuramente con una sorta di tacito consenso
da parte dei Tedeschi. La tragedia di Businco e degli
studenti di medicina fu forse “un’anomalia”, come
asserisce il linguaggio diplomatico. Ciò spiega come
Businco, pur essendo stato nominato presidente del
comitato per l’epurazione, dopo la liberazione, di
fatto, non riuscì ad andare oltre un ruolo puramente simbolico. Inoltre, gli strascichi giudiziari che
ebbe il supposto collaborazionismo dei medici di
Bologna, si chiuse con un “non luogo a procedere”
(conservato nel gigantesco archivio di Armando Businco), che purtroppo non porta alcuna luce nuova.
Businco era un deciso assertore della pratica delle autopsie 71, e riteneva che i clinici dovessero assistere personalmente al riscontro, per poter avere sempre un franco e non
sterile scambio di idee col patologo. Gli stessi direttori
degli altri Istituti erano invitati a presenziare alle autopsie.
La completa ricostruzione dell’archivio autoptico universitario, dal 1838 al 1999, ha presentato qualche
incongruenza col mito creatosi fra gli allievi del grande
patologo sardo. Sino agli anni 20 del Novecento, le autopsie universitarie erano quasi puramente didattiche. Se
dalla luna nuova al plenilunio
ne eseguivano soltanto da ottobre a giugno, e, all’epoca
del Taruffi, i verbali autoptici, in fogli protocollo, erano
scritti e firmati dagli studenti, con revisione del Taruffi e dei collaboratori. Ciò costituiva un preliminare
d’ammissione all’esame vero e proprio. Abbiamo documentato il fatto che, conformemente alla tradizione di
Malpighi e di Morgagni, i clinici del passato eseguivano
personalmente l’autopsia sui propri malati 72, realizzando in tal modo quella che Juan Rosai vorrebbe rivitalizzare come “posthumous analysis” 73. Dopo la nascita
dell’istopatologia moderna, il patologo era coinvolto
dal clinico soltanto quando era necessario compiere uno
studio istopatologico, a causa della necessità di conoscenze specifiche non alla portata di tutti i medici, e,
soprattutto, dei costi d’un laboratorio istologico. Come
abbiamo più volte sottolineato, fu la decisione di Virchow d’attribuire la gestione delle autopsie ai patologi,
la causa del grande aumento dei riscontri autoptici nel
Novecento, che a Bologna si manifestò negli anni venti,
nell’ultimo periodo della direzione di Martinotti 3 28. Dopo, si ebbe una stabilizzazione, fino agli anni sessanta,
quando iniziò un quasi inarrestabile declino, pur con
pregevolissime eccezioni 74. Il dato veramente sconcertante è che l’introduzione della “dittatura” virchowiana
introdusse un incredibile scadimento della qualità dei
verbali autoptici, con una lenta, progressiva crescita di
verbali inevasi. Ancora più sorprendente è lo scarso uso
dell’istopatologia per la diagnosi, spesso con risultati
perniciosi, come nella diagnosi di broncopolmonite 75.
Questa situazione deludente, in un settore che è sempre
stato considerato così vitale per i patologi, fu causa di
ripetute prese di posizione da parte dei professori di
anatomia patologica, a cominciare dal Martinotti, le
quali, curiosamente, fanno riferimento ad una supposta
‘età dell’oro’ dell’autopsia, forse mai esistita 45 46 48 49 71,
con l’eccezione dell’esclusiva scuola viennese 76 e delle
università da essa influenzate.
Crisi dell’autopsia a parte, già prima della guerra,
contemporaneamente agli americani e forse indipendentemente da essi, data la barriera culturale che
allora ce ne separava, il Businco aveva compreso i
grandi cambiamenti cui andava incontro l’Anatomia
Patologica: il miglioramento delle tecniche chirurgiche
consentiva infatti un numero d’interventi sempre più
elevato ed un crescente ricorso alla biopsia su organi
prima inaccessibili. Ciò comportava per il patologo
una diagnosi istopatologica di tipo nuovo e più difficile, la quale richiede una precisa conoscenza delle
notizie cliniche e quindi uno stretto rapporto col clinico.
Questo profondo travaglio dell’anatomia patologica
moderna era particolarmente sentito dal Businco, e gli
ispirò l’idea della necessità di un nuovo approccio, da
lui denominato “approccio anatomoclinico all’anatomia
patologica”, che già aveva discusso nella sua prolusione
del 1938 71. Il suo insistere su ciò fu fondamentale per
il rilancio dell’Istituto nei dopoguerra, quando le Scuole
73
anatomopatologiche europee furono pervase dal nuovo
concetto americano della Surgical Pathology.
In Businco troviamo i pregi ed i difetti dell’anatomia patologica, alla radice, probabilmente, della crisi
d’identità che da tempo affligge questa disciplina. Dalla
seconda metà dell’Ottocento sino agli anni Cinquanta, il
patologo deteneva saldamente il controllo dei laboratori
di medicina, esercitando in tal modo un’influenza sui
clinici non proprio ben accetta 3 77. La rivendicazione di
questo ruolo egemone è ben evidente in molti scritti del
Businco, specialmente tra le due guerre mondiali. Egli
auspica l’affidamento al patologo della direzione e del
coordinamento di ogni grande clinica.
Come molti altri patologi, Businco percepì subito la
grande importanza della radiologia, e la sua potenziale
pericolosità per il controllo sulla medicina esercitato dal
patologo. Proprio per questo egli riteneva che, trattandosi di scienza morfologica, la radiodiagnostica dovesse
appartenere all’anatomia patologica. Analogamente, auspicava il controllo della nascente radioterapia da parte
dei patologi, a causa dell’impegno da essi profuso nella
diagnostica oncologica.
Businco ebbe la fortuna di non vivere la crisi dell’anatomia patologica odierna. Riteniamo tuttavia che, forse,
se fosse vissuto più a lungo, avrebbe compreso i nuovi
orientamenti necessari alla rinascita della disciplina.
Secondo noi, era un uomo di grande intuito, anche negli
ultimi anni della sua lunga carriera. Proprio all’inizio
del periodo bolognese, si accorse infatti del dilagare di
una malattia poco frequente e, fino a quel momento,
proprio per la sua relativa rarità, ancora mal conosciuta:
il cancro polmonare. Negli ultimi anni della sua carriera,
Businco s’interessò di altre patologie ‘alla moda’, come
l’aterosclerosi e le malattie del sistema degli istiociti. Il
cancro polmonare appare tuttavia per lui una fonte di autentica preoccupazione. In un decennio di pubblicazioni
egli evidenzia il drammatico incremento del numero di
queste neoplasie, e, negli anni Cinquanta, cerca di crearne una classificazione razionale, basata, come sempre,
su rilievi anatomoclinici molto accurati. Da tutto questo
deriva una pubblicazione molto articolata, poi tradotta
in varie lingue, con accurati rilievi macroscopici ed istopatologici 78. Riteniamo che, se si eccettua la scoperta
del microcitoma da parte di Azzopardi , ben poco sia
stato aggiunto ai rilievi del Businco, sino allo sviluppo
della patologia molecolare.
Un uomo così sensibile ai momenti di crisi della medicina sarebbe forse stato capace di guidare i patologi italiani ad una necessaria autocritica, attuando, nella teoria
e nell’insegnamento dell’anatomia patologica, quelle
modificazioni già verificatesi nell’attività professionale:
la necessità di trasformare l’anatomia patologica in una
materia che, come tutta la medicina di laboratorio, non
è più il primo motore della medicina, ma una disciplina
fedelmente al servizio della clinica.
74
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pathologica 2009;101:76-79
Original
article
Cervical cancer screening programs in low-income
communities. Experiences from Ecuador. Low cost
detection of HPV infection in a developing country
G. Cecchini, G. Paganini, M. D’Amico*, M. Cannone*, C. Bertuletti, M.C.P. Barberis**
Amici Fundation Terra Nueva Onlus, Ferrara; * Pathology Unit, Multimedica Group, Milan; ** Department of Pathology,
Ospedali Riuniti di Bergamo, Italy
Key words
Ecuador • HPV screening • Archive smear • PCR
Summary
Objectives. With the support of the independent humanitarian
organization “Amici Fundation Terra Nueva” in Quito, Ecuador,
we evaluated the feasibility of a cytologic screening program
sustained by volunteers on the field and in Italy.
Methods. 250 women underwent a cervical Pap-test. The
women with a positive Pap-smear were re-called for visual inspection with acetic acid (VIA), whereas those with a negative
smear were invited for a new Pap-test after 3 years. To obtain
samples for molecular assays, cytologic material was removed
from slides, submitted to DNA extraction and amplified by nested PCR of the L1 region of HPV DNA. PCR-positive samples
were sequenced.
Results. Six (2.6%) samples showed squamous intra-epithelial
lesions (SILs): 4 low grade and 2 high grade SILs were present in
women more than 40 years old. The overall rate of successful DNA
recovery on a per-slide basis was 96.5%. High grade SILs were
characterized by HPV 16 and 18 co-infection. HPV 16 was detected in one low grade SIL. HPV-DNA was detected in 11 smears
(4.95%): in all 6 SILS and in 5 of the 216 negative smears.
Conclusion. Independent humanitarian organizations could play
a role in supporting national screening programs offering skilled
field professionals and technical support by scientists operating
in their countries. Our molecular technique has the potential to
provide important epidemiological information in many resourcepoor areas of developing countries.
Cervical cancer is the second most common cancer
among women worldwide, with about 500,000 cases
diagnosed annually 1. It reflects the global health inequity: there are dramatic differences between countries
with efficient public health assistance and screening
programs compared to developing countries in Africa,
Latin America and Caribbean area where cervical cancer is the most common cause of death for cancer in
women 2-4.
Human papilloma viruses (HPVs) cause virtually all
cervical cancers with HPV genotypes 16 and 18 responsible for approximately 70% 5. Since recent studies on
bivalent (HPV 16, 18) and quadrivalent (HPV 6, 11, 16,
18) vaccines showed a significantly lower incidence of
high grade cervical intraepithelial neoplasia (CIN) in
young women who had not been previously infected and
received the vaccine 6, it is necessary to determine the
distribution of oncogenic HPVs in different populations
and geographic areas in order to estimate the potential
benefits of the implementation and diffusion of vaccines. Little is known about the molecular epidemiology
of HPV in Ecuador. The most cited epidemiologic study
about the HPV–related cancers in Latin America, was
published by the International Agency for Research on
Cancer and it did not contain data on Ecuador 7. However, in Ecuador women with lower socio-economic
status and less education have few chances to obtain
a Pap smear as in most instances they do not have the
financial resources.
With the support of the humanitarian organization “Associazione Amici Fundation Terra Nueva” in Quito, Ecuador, we studied the prevalence of HPV infection and
HPV genotypes in women living in two different areas
of this country: the town of Tosagua (region of Manabi)
and the suburbs of Quito. The goal of the study was
to determine the feasibility of a cytological screening
Correspondence
Massimo C.P. Barberis, Department of Pathology, Ospedali
Riuniti Bergamo, largo Barozzi 1, 24128 Bergamo, Italy - Tel.
+39 035 269054 - Fax +39 035 266176 - E-mail: mbarberis@
ospedaliriuniti.bergamo.it
77
cervical cancer screening programs in low-income communities
program sustained by field volunteers and cytotechnologists, molecular biologists and pathologists operating
in Italy, offering their cooperation free of charge. A
‘home-brew’ molecular technique was used in order to
reduce the costs and obtain information from the same
stained smear used for cytological evaluation.
Patients and methods
We studied 250 women seeking a cervical Pap-test and
attending two private health centers sustained by the
Italian independent “Associazione Amici Terra Nueva
Onlus” connected with Terra Nueva Hospital in Quito.
The first group of women was enrolled in Tosagua, a rural community in the region of Manabi, not far from the
Pacific coast. The population consisted of women living
in poor hygienic conditions, usually with at least three
or four pregnancies in their life beginning from 14-16
years. The second group was women attending a mobile
screening service operating in the outskirts of the south
of Quito City, the poorest quarters of the capital. Here,
extremely low socio-economical conditions are associated with sexual promiscuity.
One hundred and twenty nine women from Tosagua and
141 from the outskirts of Quito were included in the
study. All 270 participants were consecutively enrolled
from September 2005 to October 2005.
Exfoliated cervical cells using an Ayre spatula were
collected by two expert gynecologists (GC and GP),
smeared and fixed with polyethylene glycol. All the
smears were sent by post to the Department of Pathology of Multimedica Hospitals, Milan, Italy, at a cost
of 50 Euros. They were routinely stained and read
by trained cytologists, and classified according to the
Bethesda system 8. All abnormal smears and 20% of
the negatives were re-examined by pathologists at the
Pathology Unit of Ospedali Riuniti, Bergamo, Italy.
The women with a positive Pap-smear were re-called
at the Terra Nueva Hospital for visual inspection with
acetic acid (VIA) and further therapy, if necessary,
whereas the women with a negative smear were invited
to perform another Pap-test after 3 years. The patients
sustained only the costs for travelling from Tosagua to
Quito.
To obtain samples for molecular assays, we used a
previously described technique 9. Briefly, slides were
immersed in acetone overnight to remove cover slips
and then rinsed in xylene for 30 minutes and twice in
ethanol; they were then air dried and the cytologic material removed by gentle scraping with a disposable blade
and placed in a tube containing 300 μg/mL proteinase
K in digestion buffer (50mM Tris-HCl, pH 7.5; 10 mM
EDTA in 0.5% SDS; 50 mM NaCl). The samples were
incubated overnight at 56°C and the DNA extracted using the phenol/chloroform method followed by ethanol
precipitation. The amount of DNA was quanified by
spectrophotometric determination (GeneQuant II, Pharmacia, Uppsala, Sweden). DNA integrity and absence
of tissue amplification inhibitors was evaluated by PCR
for HLA-DQα, as previously reported 10. Nested PCR
was performed for the L1 region (open reading frame)
of HPV DNA. Consensus primers (MY09, MY11) were
used for outer amplification (450 base pair fragment).
After the first round of the reaction, 3 μl of the amplified product underwent a second round of PCR using
the inner primers GP5+ and GP6+, which amplify a 150
base pair fragment. Ten μl of the final product were
electrophoresed on 2% agarose gel stained with ethidium bromide. The DNA extracted from HPV positive
cervical biopsies was used as a positive control. Primers
sequences are reported below:
MY09 5’-CGT CCM ARR GGA WAC TGA TC-3’
MY11 5’-GCM CAG GGW CAT AAY AAT GG-3’
GP5+ 5’-TTT GTT ACT GTG GTA GAT ACT AC-3’
GP6+ 5’-GAA AAA TAA ACT GTA AATCAT ATT
C-3’
Amplification controls and detection limits were chosen and verified according to the methods described by
Puranen et al. 11. Briefly, amplification included positive (CaSki cells) and negative (sterile water) controls.
The detection limit of the amplified sequence using gel
electrophoresis and ethidium bromide staining alone was
20 SiHa cells. This represented approximately 20 copies
of HPV DNA (20 fg HPV16 DNA). PCR-positive samples were purified with QIAquick PCR purification kit,
according to the manufacturer’s instructions (Quiagen,
Valencia, CA, USA). DNA sequencing was performed
using an automatic DNA sequencer (ABI PRISM 3100,
Applied Biosystems, Foster City, CA, USA). Sequence
homology was determined by BLAST and ClustalW programs. HPV types considered “high risk” (HR) included
all those described by Munoz et al.: 16, 18, 26, 31, 33, 35,
39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 82 12.
Results
There were 20 inadequate cytological samples (11 from
Tosagua and 9 from Quito). Therefore, the study evaluated 250 specimens (118 and 132, respectively).
The age of the women from Tosagua ranged from 24 to
68 years (mean 43), whereas the mean age of the Quito
series was 49 years (range 21-72).
Six (2.4%) of the 250 samples showed squamous intraepithelial lesions in the Papanicolaou stained smear.
Table I shows the results of the Pap smear in women at
the two health centers. Four high grade squamous intraepithelial lesions (SIL) were present in women more
than 40 years old. All the SILs were characterized by
HPV 16 and 18 co-infection. The same genotypes were
also present in the four low grade SILs that occurred
in women older than forty years. The incidence of Pap
smear alterations was the same in the two series.
The overall rate of successful DNA recovery on a perslide basis was 88.8% (222 of 250 specimens). HPV-
78
g. cecchini et al.
Tab. I. Overall prevalence of cervical lesions in women of the two health centers.
Cytological diagnoses
Quito
Tosagua
N
%
N
%
LSIL
2
1.5
2
1.7
HSIL
1
0.7
1
0.8
Total
3
2.2
3
2.5
Tab. II. Results of PCR for stained cervical smears.
Cytological diagnoses
HPV-DNA positive
HPV genotype
N
%
N
%
244
97.6
5
2.3
42, 16, 66, 81
LSIL
4
1.6
4
1.8
16,18, 81
HSIL
2
0.8
2
0.9
16, 18, 81
Negative
Low risk: 42, 66, 81
High risk: 16, 18
DNA was detected in 11 smears (4.95%): in all 6 squamous intra-epithelial lesions and in 5 of the 216 negative
smears. The PCR results are reported in Table II.
Discussion
Cancer of the uterine cervix is a major public health
problem in Latin America. In most resource-poor settings, cytological screening has proven difficult to
implement and sustain, in large part because this form
of screening relies on highly trained cytotechnologists,
high quality laboratories and a logistic organization to
support screening, colposcopy and treatment. In Ecuador, additional issues are the jeopardization of resources
and the exclusion of a number of citizens from public
health facilities both in the metropolitan area of Quito
and in rural areas simply because they cannot sustain
costs.
Our study showed the feasibility of a small screening
program proposed by a humanitarian organization operating for many years in Ecuador with limited resources,
but sustained by volunteer professionals who devote a
small part of their time. Only the direct health care costs
are be covered by the organization (screening test, clinic
visit, laboratory tests, specimen transport, subsequent
visits for treatment). The direct non-health care costs
such as child care costs for a mother in treatment and
transport costs for treatment were covered by families.
In this study, we found an HPV infection rate of 4.95%
in women seeking a Pap test in two different areas of
Ecuador. This prevalence is somewhat lower than those
reported in other countries in Latin America, such as
Mexico (14%) 13, Chile (14%) 14, Colombia (16.8%) 2
and Argentina (15.5%) 2. The prevalence found in
this study is quite similar to those observed in Bolivia
(5,2%) 15 and in the state of Durango, Mexico (4.8%) 16.
These two studies considered women living in rural vil-
lages and in a metropolitan area, but all were characterized by a very low socio-economical status and with a
mean age higher than the one reported in other studies.
These findings may agree with the observation that
the prevalence of the infection decreases with age 17,
whereas the incidence of high grade SILS and cancer
increases with age. However, the low incidence of infection cannot be solely explained by the higher age of
the women. It probably reflects different sexual behavior and a different prevalence of infection in areas that
cannot epidemiologically be assimilated to a generic
“Latin America and Caribbean area”. Only in one of the
244 cytologically negative smears a high-risk HPV 16
genotype was detected (a 28 year-old woman). Other
low risk HPVs were found in four other smears (women
age ranging from 23 to 51 years). In all the cytologically
positive smears (low and high grade SILs), high risk
HPV 16 and 18 were always present. If confirmed on a
large series, and a significant prevalence of other high
risk genotypes is excluded, a presumptive opportunity
for vaccination could be considered. Disease simulation models based on epidemiologic data could provide
information on the cost effectiveness of HPV vaccine
in this setting. However, it is likely that HPV vaccination together with at least a single lifetime cytological
screening could represent a cost effective compromise
in many developing countries 4.
Our technique could provide important epidemiological
informations in many resource-poor areas of Ecuador
and other developing countries: Papanicolaou stained
smears could be used for cytological screening, HPVDNA detection and genotyping, thus favoring data collection. In other words, a reflex HPV testing can be obtained from a conventional smear in a low cost setting.
A source of possible bias leading to unsuccessful
amplification must be considered: removing material
from the slides by unskilled personnel, the relatively
small amount of DNA available for testing, and deg-
cervical cancer screening programs in low-income communities
79
radation of DNA caused by fixation and staining.
This last point has been exhaustively discussed by
Canfell et al. 18. The high recovery rate of DNA that
we obtained was due to the use of reagents and dyes
without acetic acid in order to avoid hydrolysation
of glycosidic bonds and subsequent generation of
basic DNA sites, which may adversely impact Taq
polymerase activity during the extension phase of the
PCR 18-20. Similar results were obtained in a previous
study in Netherlands, which reported a DNA recovery
rate of 98% 21.
The technique is robust and inexpensive: DNA extraction and amplification is available at a direct cost of
less than 10 Euros per sample, and HPV genotyping by
sequence analysis has similar costs. Commercial kits for
high and low risk HPV detection cost 5-10 times more.
Independent humanitarian organizations can play a role
in supporting national screening programs by offering
skilled field professionals and technical support by scientists operating in their countries. The poorest part of
population that are excluded from any form of screening
can be reached at least in part by these organizations and
obtain benefits in terms of early detection of cervical
cancer. A continuous education project in cytology and
molecular techniques for local technicians and biologists is pending economic support.
References
chain reaction amplification of Human Papilloma virus DNA
from archival, Papanicolaou-stained cervical smears. Acta Cytol
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12
Munoz N, Bosch FX, de Sanjosè S, Herrero R, Castellsaguè X,
Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancers. N Engl J Med
2003;348:518-27.
13
Gonzales Loza M del R, Lavada Mier y Teran MA, Puerto Solis
M, Garcia Carranca A. Molecular variants of HPV type 16 E6
among Mexican women with LSIL and invasive cancer. J Clin
Virol 2004;29:95-8.
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Ferreccio C, Prado RB, Luzoro AV, Ampuero SLI, Snijders PJF,
Meijer CJ, et al. Population based prevalence and age distribution
of human papillomavirus among women in Santiago, Chile. Cancer Epidemiol Biomarkers Prev 2004;13:2271-6.
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Cervantes J, Lema C, Hurtado L, Andrade R, Quiroga G, Garcia G, et al. Prevalence of human papillomavirus infection in
rural villages of Bolivian Amazon. Rev Inst Med Trop S Paulo
2003;45:1-9.
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Sanchez-Anguiano LF, Alvarado-Esquimel C, Reyes-Romero
MA, Carrera-Rodriguez M. Human papillomavirus infection
in women seeking cervical Papanicolaou cytology of Durango,
Mexico:prevalence and genotypes. BMC Infectious Diseases
2006;6:27.
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Sahebali S, Depuydt CE, Segers K, Vereecken AJ, Begers JJ.
Cervical cytological screening and human papillomavirus DNA
testing in Flanderes. Acta Clin Belg 2003;58:211-9.
18
Canfell K, Gray W, Snijders P, Murray C, Tipper S, Drinkwater K,
et al. Factors predicting successful DNA recovery from archival
cervical smears samples. Cytopathology 2004;15:276-82.
19
Bonin S, Petrera F, Rosai J, Stanta G. DNA and RNA obtained
from Bouin fixed tissues. J Clin Pathl 2005;58:313-6.
20
Gree CE, Wheeler CM, Manos MM. Sample preparation and PCR
amplification from paraffin-embedded tissues. PCR Methods Appl
1994;3:S113-122.
21
de Roda H, Snijders PJ, Stel HV, Van Den Brule AJ, Meijer CJ,
Walboomers JM. Processing of long stored archival cervical
smears for human papillomavirus detection by the polymerase
chain reaction. Br J Cancer 1995;72:412-7.
Russell AH, Seiden MV, Duska LR, Goodman AK, Lee SI, Digumarthy SR, et al. Cancers of the cervix, vagina and vulva. In:
Abeloff MD, ed. Clinical Oncology. Third edition. Philadelphia:
Churchill Livingstone 2004, pp. 2217-2271.
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Clifford GM, Gallus S, Herrera R, Munoz N, Snijders S, Vaccarella S, et al. Worldwide distribution of human papillomavirus types
in cytologicaly normal women in the International Agency for
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Lancet 2005;366:991-8.
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National Institute of Health Consensus Development Conference
Statement: Cervical Cancer. April 13,1996. J Natl Cancer Inst
Monogr 1996;22:vii.
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Agosti J, Goldie SJ. Introducing HPV vaccine in developing countries - key challenges and issues. N Engl J Med 2007;356:1908-10.
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Bosch FX, Lorinecz A, MuNoz N, Meijer Cj, Shah KV. The causal relation between papillomavirus and cervical cancer. J Clin
Pathol 2002;55:244-65.
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The Future II Study Group. Quadrivalent vaccine agains human
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Ferlay J, Maxwell Parkin D, Pisani P. GLOBOCAN: Cancer
Incidence and Mortality Worldwide. Lyon, France: International
Agency for Research on Cancer, Globocan I Database, World
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Solomon D, Davey D, Kurman R. Moriarty A, O’Connor D, Prey
M, et al. The 2001 Bethesda System: terminology for reporting
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Vago L, Zerbi P, Caldarelli Stefano R, Cannone M, D’Amico M,
Bonetto S, et al. Polymerase Chain Reaction for Mycobacterium
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Puranen M, Saarikoski, Syrianen K, Syrianen S. Polymerase
1
pathologica 2009;101:80-84
Original
article
Liquid-based endometrial cytology:
the Florence and Bari experience
A.M. Buccoliero, L. Resta*, A. Napoli*, G.L. Taddei
Department of Human Pathology and Oncology, University of Florence, Italy; * Department of Pathology, University of Bari, Italy
Key words
Thin-layer • Liquid-based • Endometrial cytology • Endometrial adenocarcinoma • Endometrial hyperplasia
Summary
Several diagnostic procedures are available to investigate the
endometrium, i.e. sonography, hysteroscopy, biopsy, endometrial
curettage and cytology. Among these, endometrial cytology is
less commonly utilized. Although the use of cytology in the diagnosis of endometrial adenocarcinoma has already been proposed
due to its low cost and simple execution, a general consensus has
not been reached. The improvement of the diagnostic capacity
of endometrial cytology following the introduction of a liquidbased method suggests that this test should be routinely used in
endometrial diagnosis. The main advantages of this method are
the reduction in confounding factors, the distribution of cells on a
thin layer and the possibility to obtain more slides from the same
sample. The aim of this article is to focus on the methodological
procedures and diagnostic criteria in liquid-based endometrial
cytology based on the experience in two Italian centres: Department of Pathology, University of Bari and Department of Human
Pathology and Oncology, University of Florence. The sampling
method used by the Bari authors consists in the collection of
liquid for uterine distension during hysteroscopy, while the Florence group used an endometrial brush. The sensitivity and specificity at Bari were 75% and 83%, respectively, and were 94-100%
and 95-100% at Florence, respectively. Endometrial cytology
provided sufficient diagnostic material significantly more often
than biopsy. We thus propose that endometrial cytology can be
used in routine diagnosis either alone or in association with other
diagnostic procedures in order to improve diagnostic accuracy.
Introduction
men. Indeed, endometrial atrophy may determine a high
inadequacy rate of endometrial biopsies. In this context,
endometrial cytological samples have been shown to be
diagnostic in a significantly higher percentage of cases
with respect to biopsy samples (82% vs. 24%) 1. Moreover, thin layer endometrial cytology appears to fill a
large diagnostic gap in endometrial pathology, namely
recognition of a small cancer arising in atrophic mucosa
and characterization of tamoxifen-induced changes that
are not easily detectable with biopsy, hysteroscopy or
sonography.
The use of the thin layer endometrial cytology is encouraged by its excellent diagnostic accuracy, particularly
in cases of endometrial carcinoma and atypical hyperplasia, in which the method may be compared with the
secular experience of endometrial biopsy 2-10.
The aim of this article is to focus the methodological
procedures and diagnostic criteria in liquid-based endometrial cytology based on the experience in two Italian
centres (Department of Pathology, University of Bari
and Department of Human pathology and Oncology,
University of Florence).
Several diagnostic procedures are available to investigate the endometrium, i.e. sonography, hysteroscopy,
biopsy, endometrial curettage and cytology. Among
these, endometrial cytology is less commonly utilized.
Although the use of cytology in the diagnosis of endometrial adenocarcinoma has already been proposed due
to its low cost and simple execution, a general consensus has not been reached. The diffusion of conventional
endometrial cytology has been hampered by difficulty
in its interpretation due to the presence of excess blood,
mucus and overlapping cells.
Improvements in the diagnostic accuracy of endometrial
cytology related to the introduction of the liquid-based
methodology suggest that the test could be routinely
used in endometrial diagnosis. The main advantages of
the method are the reduction in confounding factors, the
distribution of cells on a thin layer and the possibility to
obtain more slides from the same sample.
The possibility of cytological examination of the endometrium is particularly useful in post-menopausal wo-
Correspondence
Anna Maria Buccoliero, Department of Human Pathology and
Oncology, University of Florence, v.le G.B. Morgagni 85, 50134
Florence, Italy.
81
liquid-based endometrial cytology
Methodological procedures and patients
Diagnostic criteria
Bari
This method is proposed for women who undergo
hysteroscopy using physiological solution for uterine
corpus distension. As a cytological sample, the first 20
ml of liquid used in uterine distension is collected and
promptly processed in the cytology laboratory as follows:
- centrifugation at 1,200 rpm/10 min;
- suspension of the pellet in 50 ml of Cytolyt® (Hologic), saline solution with a low part of ethanol for
lysis of erythrocytes, granulocytes and mucus;
- lysis for 20-30 min;
- centrifugation at 1,200 rpm/10 min;
- the pellet is suspended in PreservCyt® (Hologic), a
methanol-based solution used as a bactericide and
fixative;
- preparation of slides with “Thin-prep 2000” (Hologic);
- post-fixation with 95% ethanol /30 min;
- Papanicolau staining;
- observation by standard light microscopy.
This methodology was used preliminarily in 97 patients
with a history of abnormal uterine bleeding, often in
menopause, under tamoxifen treatment or infertility.
Statement on specimen adequacy
Specimens are considered inadequate for diagnostic
evaluation when they contain less than 6 epithelial
endometrial cell clusters. Moreover, specimens are considered unsatisfactory for diagnosis when insufficient
clinical information (i.e. age, menopausal state, menstrual state, hormonal therapy, risk factors, symptoms)
is provided.
Florence technique
Cytological sampling is performed by endometrial
brushing using the Endoflower device (RI-MOS). After
endometrial sampling, the device tip is immersed in the
Cytolyt® vial where it is vigorously rotated to facilitate
cell release, the sample is sent to the cytology laboratory
where it is processed as follows:
- centrifugation at 1,200 rpm/10 min;
- removal of the supernatant
- suspension of the pellet in 50 ml of Cytolyt® for
erythro- mucolysis;
- lysis in 20-30 min;
- centrifugation at 1,200 rpm/10 min;
- removal of the supernatant;
- (in case of persistence of blood and mucus, additional centrifugation, supernatant removal and suspension in Cytolyt® may be performed)
- the pellet is suspended in PreservCyt;
- preparation of slides with “Thin-prep 2000”;
- post-fixation with 95% ethanol/30 min;
- Papanicolau staining;
- observation by standard light microscopy.
Since 2001, liquid-based endometrial cytology has been
routinely used at the Department of Human Pathology
and Oncology of Florence Italy. During this period, we
assessed the diagnostic accuracy of the liquid-based
method in endometrial diagnosis through several cytohistological concordance studies. We ascertained its effectiveness in different aspects of endometrial pathology:
asymptomatic women (320 patients) 10, thickened endometrium as evaluated by trans-vaginal sonography (670
patients) 5, and women on tamoxifen (168 patients) 4.
Diagnostic criteria
Diagnostic criteria are based on cyto-architectural evaluations and consider the epithelial and stromal (Fig.
1) endometrial cells as well as the background 11. Proliferative endometrium (Fig. 2) is characterized by the
presence of three-dimensional cylindrical epithelial
endometrial clusters. Cytoplasm is scant. Nuclei are
isomorphic with finely granular chromatin. Nucleoli are
small or absent. Cellular polarity is preserved. Stromal
Fig. 1. Sheet of stromal endometrial cells. (PAP-stain; original
magnification 10X).
Fig. 2. Proliferative endometrium: three-dimensional cylindrical
epithelial endometrial cluster (scant cytoplasm, isomorphic nuclei, preserved cellular polarity) and spindle-shaped stromal cells.
(PAP-stain; original magnification 10X).
82
A.M. buccoliero et al.
Fig. 3. Secretory endometrium: wide, three-dimensional cylindrical epithelial cluster (clear and obvious cytoplasm, isomorphic
nuclei, preserved cellular polarity). (PAP-stain; original magnification 5X).
Fig. 5. Progestin effects: secretory endometrial gland and
decidualized stroma (wide cytoplasm, round-oval nuclei, finely
granulated chromatin, micro-nucleoli). (PAP-stain; original magnification 20X).
cells are abundant and spindle-shaped. The background
is clean. Secretory endometrium (Fig. 3) shows wide,
three-dimensional cylindrical epithelial clusters. Bi-dimensional placards may be present in the late secretory
phase. Cytoplasm is clear and obvious. Nuclei are isomorphic with dispersed chromatin and small or absent
nucleoli. Cellular polarity is preserved. Stromal cells
are abundant and decidualized (wide cytoplasm, round
nuclei, finely granulated chromatin, micro-nucleoli).
The background is clean or in the late secretory phase
is moderately inflammatory. Endometrial atrophy (Fig.
4) is characterized by the presence of small cylindrical
three-dimensional epithelial clusters. Epithelial clusters
may appear swollen in cystic atrophy. Cytoplasm is
scant. Nuclei are isomorphic with dense chromatin and
small or absent nucleoli. Cellular polarity is preserved.
Stromal cells are abundant and spindle-shaped. The
background is clean. Multinucleated histiocytes are
often recognizable. Hormonal administration (Fig. 5)
Fig. 4. Atrophic endometrium: small cylindrical three-dimensional epithelial cluster (scant cytoplasm, isomorphic nuclei, dense
chromatin, preserved cellular polarity) and multinucleated histiocyte. (PAP-stain; original magnification 10X).
Figs. 6a-6b. Endometrial hyperplasia: wide three-dimensional
epithelial endometrial clusters with cellular crowding and architectural disorder. (PAP-stain; original magnification: 6a, 20X; 6b, 10X).
liquid-based endometrial cytology
leads to endometrial morphological modifications that
depend on the type of hormone administrated, dosage, regimen (combined or sequential estro-progestin
administration) and duration and in fertile women the
menstrual phase in which the hormone is administrated.
Oestrogens, when unopposed by progestins, produce
a proliferative input on the endometrium determining
possible hyperplastic and even neoplastic progression.
In contrast, progestins are responsible for proliferative
arrest, glandular secretion and decidualization of stromal cells. Prolonged progesterone treatment induces
progressive arrest of secretions and glandular atrophy.
Cytological features in endometrial specimens reflect
these hormonal induced modifications. Endometrial
Hyperplasia (Figs. 6a-6b) appears in cytological samples as numerous, wide, three-dimensional epithelial
endometrial clusters with variable cellular crowding and
architectural disorder. In typical endometrial hyperplasia, the cytoplasm is commonly scant and the nuclei are
isomorphic with finely granular chromatin and small
or absent nucleoli nucleoli. In atypical endometrial
hyperplasia, the cytoplasm becomes evident and nuclei
may show a moderate-grade of pleomorphism. Spindleshaped stromal cells are abundant in typical hyperplasia,
while they are less represented in atypical hyperplasia.
The background may enclose inflammatory cells. The
83
Fig. 8. Endometrial adenocarcinoma: cellular cannibalism. (PAPstain; original magnification 20X).
Fig. 9. Micropapilla from a serous carcinoma. (PAP-stain; original
magnification 40X).
Figs. 7a-7b. Endometrial adenocarcinoma: the medium size
aggregates of neoplastic cells with overlapped nuclei; cellular
polarity is lost. (PAP-stain; original magnification 20X).
main diagnostic criteria for endometrial carcinoma
(Figs. 7-10) are: 1. architectural (loss of polarity, papillary cell clusters, dyshesive cells); 2. cellular (high nucleo/cytoplasmatic ratio, anisonucleosis, coarse and/or
marginated chromatin, nucleolar prominence, nuclear
membrane incisures, cell cannibalism): 3. background
(scarcity of stromal cells, inflammation, necrosis). In the
case of well differentiated (G1) endometrioid adenocarcinoma, epithelial endometrial clusters are medium in
size and show cellular overlapping. Cellular polarity is
lost, at least in part. Cytological atypia is unremarkable
and tumour diathesis is not a constant feature. In case
of poorly differentiated (G3) endometrioid adenocarcinoma, epithelial endometrial clusters are small and less
crowded with respect to endometrial hyperplasia and
well differentiated adenocarcinoma. Cytological atypia
is prominent. Cell cannibalism is observed more often in
poorly differentiated tumours. Specimens obtained from
patients affected by serous carcinomas are hypercellular (small cellular clusters with inconspicuous cellular
84
A.M. buccoliero et al.
Tab. I. Results of the Bari experience.
Cytology
Histology
Positive
33
20
Negative
39
36
Inadequate
15
False
positive
False
negative
6
4
crowding, single cells, bare nuclei). Psammoma bodies
can sometimes be seen.
Results
Bari results
The number of inadequate specimens was 6/29 in the
group of endometrial cancer; 6/20 in the group of tamoxifen-treated and 3/48 in patients with infertility,
abnormal uterine bleeding or endometritis. The correlation between cytology and histology (when performed)
revealed a sensibility of 75% and a specificity of 83%.
Most inadequate cases and false positive or negative
samples were seen in the initial experience before the
technique was improved upon (Tab. I).
Florence results
For all samples 4 5 10, endometrial cytology provided
sufficient material more often than biopsy (P < 0.01).
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The sensitivity and specificity were estimated, respectively, at 94-100% and 95-100%; the positive
and negative predictive values were estimated, respectively, at 80-100% and 99-100% (100% values
were obtained in 33 women on tamoxifen in which
both endometrial cytology and biopsy gave adequate
specimens 4).
Conclusions
The improvement of the diagnostic capacity of endometrial cytology by introduction of a liquid-based method
should persuade both clinicians and pathologists to
definitively introduce this test in routine endometrial
diagnosis. Indeed, the characteristics of the thin layer
method, namely reduction of confounding factors, distribution of cells in a thin layer, and the possibility to
obtain more than one slide that can be used for further
investigation, i.e. immunohistochemistry and molecular
biology, are all useful for endometrial diagnosis. The
low percentage of unsatisfactory specimens, and the
high sensibility, specificity, and positive and negative predictive values from both the Bari and Florence
experience, as well as in a number of recently published
studies, support this belief.
In conclusion, we consider endometrial cytology an efficacious diagnostic procedure. It can be applied either
alone or in association with other diagnostic procedures
to improve diagnostic accuracy.
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2008;36:216-23.
8
Norimatsu Y, Kouda H, Kobayashi TK, Moriya T, Yanoh K,
Tsukayama C, et al. Utility of thin-layer preparations in the endometrial cytology: evaluation of benign endometrial lesions. Ann
Diagn Pathol 2008;12:103-11.
9
Kipp BR, Medeiros F, Campion MB, Distad TJ, Peterson LM,
Keeney GL, et al. Direct uterine sampling with the Tao brush sampler using a liquid-based preparation method for the detection of
endometrial cancer and atypical hyperplasia: a feasibility study.
Cancer 2008;114:228-35.
10
Buccoliero AM, Castiglione F, Gheri CF, Garbini F, Fambrini M,
Bargelli G, et al. Liquid-based endometrial cytology: its possible
value in postmenopausal asymptomatic women. Int J Gynecol
Cancer 2007;17:182-7.
11
Taddei GL, Buccoliero AM. Atlante di citologia endometriale.
L’endometrio normale, iperplastico e neoplastico nella citologia
in fase liquida. Florence, Italy: SEE Editrice 2005.
pathologica 2009;101:85-88
Case
report
Primary linitis plastica of the right colon
M. ONORATI, M.R. AMBROSIO, V. MOURMOURAS, M.G. MASTROGIULIO, B.J. ROCCA
Department of Human Pathology and Oncology, Section of Anatomic Pathology, University of Siena, Italy
Key words
Linitis plastica • Right colon
Summary
A case of primary linitis plastica of the colon is presented. This
case is of interest for three reasons: the site of origin in the right
colon (80% of cases reported develop distally to the splenic flexure), a biopsy previously taken from the mucosa demonstrated the
presence of a signet ring cell carcinoma (endoscopic biopsies do
not provide a conclusive diagnosis in the majority of cases reported) and hyaline with sparse amyloid nodules were detected in the
extensive, dense fibrous tissue intermingled with tumour cells.
Introduction
The only remarkable event in his medical history was
a prostatic adenocarcinoma treated with radical surgery
and radiotherapy. The abdomen was tense and painful,
with lower right dullness and hyperperistalsis. Haemoglobin was 12.4% and haematocrit 32.9%. Colonoscopy
showed a stricture involving the caecum and the proximal portion of the ascending colon; a biopsy revealed a
signet ring cell carcinoma. Computerized tomography
revealed a neoplasm of the caecum and ascending colon,
located cranially to the ileo-caecal valve, and appearedmainly extrinsic. Lymph nodes were enlarged and there
were peritoneal implants.
Apart from the ileum no other abdominal or pelvic organs were involved. Gastroscopy and gastric biopsies
were negative for neoplasia. At laparotomy, ascites and
diffuse peritoneal and omental carcinomatous implants
were seen, without liver metastases. The carcinoma
extended transmurally through the wall of the caecum
and terminal ileum, which appeared rigid and thickened.
The adjacent soft tissues were hardened. A right hemicolectomy (12 cm) and a terminal ileum resection (30
cm) were performed. Pericolic and peri-ileal tissues and
several lymph nodes were removed. The intestinal loops
were conglomerated, rigid and thickened due to a mass
encircling them and considerably reducing their lumen.
However, only a part of the mucosa appeared to be involved, where it was eroded and haemorrhagic. Tissues
taken from all involved areas were included in paraffin.
Sections were stained with haematoxylin and eosin,
Alcian blue and Congo red, while others were prepared
for immunohistochemistry and stained for the following
The term “linitis plastica” was introduced by Lietaud
in 1779, followed by Andran in 1829 and Brinton in
1859, and is considered as a gastric inflammatory-like
neoplastic lesion (sicut retis ex lino facta) that produces
abundant fibrous tissue (plastica = desmoplastic) in the
stomach wall. It is interesting to note how Antonio Benivieni described this lesion in 1507 “stomachum fere
totum obcaluisse repertum est”.
Primary linitis plastica of the colon was first described
by David in 1931 1 2 and was defined by Laufman and
Saphir in 1951 3 as a neoplastic lesion characterized by
a conspicuous, prevalently submucosal, desmoplastic
reaction to various histotypes of infiltrating carcinoma.
The colon wall is considerably thickened, but in many
cases the mucosa has a normal appearance. Based on
previous knowledge and a higher frequency of gastric
linitis plastica, it is always necessary to exclude secondary colon involvement by a gastric carcinoma,
which has been recognized as a possibility since its first
description by Coe (1931) 4. To our knowledge, only
about 60 cases of linitis plastica of the colon have been
described 1 5-15. Herein, we report a case originating in
the right colon in the absence of gastric lesions.
Case report
A 69-year-old man was admitted to the Surgery Unit of
Nottola Hospital (Siena) with severe abdominal pain.
Correspondence
dott.ssa Monica Onorati, Dipartimento di Patologia Umana e
Oncologia, Sezione di Anatomia Patologica, Policlinico Universitario “Le Scotte”, via delle Scotte 6, 53100 Siena, Italia - Tel. +39
0577 233236 - E-mail: [email protected]
86
m. onorati et al.
Fig. 1. Clusters of cuboidal basophilic cells, occasionally forming abortive glands, are encircled by dense connective tissue (a, b). Nests of
signet ring cells are visible in the lower part of the mucosa (c, d). (haematoxylin and eosin x100, x100, x100, x400, respectively).
antibodies: cytokeratin AE1/AE3, 7 and 20, CDX2,
chromogranin, synaptophysin and PSA. Histologically,
at low magnification, the carcinoma was composed of
nests and clusters of small, low cuboidal cells with basophilic cytoplasm and vesicular nuclei that sometimes
formed abortive glandular structures (Fig. 1a). Some of
these glands showed a mucinous content in their small
luminal spaces and the ability to produce an intracytoplasmic mucinous secretion. Clusters of neoplastic cells
were distorted and dislocated by dense collagenous tissue that was occasionally structured in concentric bands
to form discrete hyalinized nodules (Fig. 1b). At higher
magnification, nests of signet ring cells were visible in
the lower part of the mucosa (Fig. 1c, d). In the sections
stained with Alcian blue, isolated or small clusters of
signet ring cells were intermingled with small, cuboidal
cells (Fig. 2a) and scattered throughout the wall and in
the stromal tissues. Under polarized light, a moderate
green birefringence was visible inside these nodules in
the sections stained with Congo red (Fig. 2b). Both the
cuboidal cells and the signet ring cells were positive for
CDX2 (Fig. 2c), CK AE1/AE3. They were also positive
for CK20 (although not diffusely) and for CK7 (only
focally), while they were negative for chromogranin and
synaptophysin.
Infiltration by prostatic adenocarcinoma was excluded
based on the morphology and negativity for PSA. Vascular and perineural invasion was detected. Lymph
node metastases were observed. The diagnosis was
“poorly differentiated adenocarcinoma with extracellular mucinous and signet ring cell carcinoma components, pT4N2Mx C2/III G3”.
Discussion
There are several reasons for describing this case of
linitis plastica of the colon. To date, only about 60 cases
have been reported in the literature1. Our case originated
in the right colon, which is unusual as 80% of primary
linitis plastica of the colon develops distally to the
splenic flexure 6. An endoscopic biopsy taken from an
area of eroded and haemorrhagic mucosa demonstrated
the presence of a signet ring cell carcinoma. This was
also unusual since the mucosa was mainly spared in the
majority of cases reported, meaning that endoscopical-
87
primary linitis plastica of the right colon
Fig. 2. Numerous signet ring cells are intermingled with basophilic cells (a). In the connective tissue, there are hyaline nodules showing
green birefringence under polarized light in the sections stained with Congo red (b). Positivity for CDX2 in the two population of neoplastic
cells (c). (Alcian blue x400, Congo polarized light x50, CDX2 x50).
ly directed biopsies not including the submucosa can
rarely provide a conclusive diagnosis 1 6 16. The tumour
histotype consisted of two cell populations. The first
was small, low cuboidal cells with basophilic cytoplasm and vesicular nuclei, which formed abortive glands
with luminal and cytoplasmatic mucin content or were
aggregated in cords and clusters. The second population
consisted of nests of signet ring cells in the deep part of
the mucosa, which were easily visible with Alcian blue,
CDX2, CK20 and CK7 and were scattered throughout
the colon wall, even inside the aggregates of cuboidal
cells. The positivity of both these components for CDX2
and for CK20 (although not diffusely) favours a large
bowel origin of the tumour and constitutes a histogenic
link between the two populations of neoplastic cells. As
in the majority of cases reported 1 3 16, extensive dense
fibrous tissue intermingled with clusters of tumour cells
was evident and especially notable within the submucosa and muscolaris propria. Discrete hyalinized nodules
were present in the fibrous tissue, and a moderate green
birefringence was visible within them under polarized
light in the sections stained with Congo red.
Similarly to previous reports 6, the tumour showed aggressiveness since it invaded vessels in the colon wall as
well as soft tissues, the ileum and lymph nodes, although evident visceral metastases were absent.
References
4
1
2
3
Stevens WR, Ruiz P. Primary linitis plastica carcinoma of the
colon and rectum. Modern Pathology 1989;2:265-9.
David VC. Malignancy in linitis plastica. Surg Clin North Am
1981;11:47-52.
Laufman H, Saphir O. Primary linitis plastica type of carcinoma
of the colon. Arch Surg 1951;62:79-91.
5
6
7
Coe FO. Linitis plastica. South Med J 1931;24:477-82.
Almagro UA. Primary signet ring carcinoma of the colon. Cancer
1983;52:1453-7.
Amorn Y, Knight WA. Primary linitis plastica: report of two
cases and review of literature. Cancer 1978;41:2420-5.
Andersen JA, Hansen BF. Primary linitis plastica of the colon and
rectum: report of two cases. Dis Colon Rectum 1972;15:217-21.
88
8
9
10
11
12
m. onorati et al.
Andersen JA. Primary linitis plastica of the colon and rectum.
Acta Pathol Microbiol Scand 1970;78:277-83.
Balthazar EJ, Rosenberg HD, Davidan MM. Primary and metastatic scirrhous carcinoma of the rectum. AJR 1979;132:711-5.
Bashour T, Goldman ML, Geber L, Danovitch SH. Primary linitis plastica carcinoma of the colon. Med Ann DC
1974;43:549-52.
Bonello JC, Quan SHQ, Sternberg SS. Primary linitis plastica of
rectum. Dis Colon Rectum 1980;23:337-42.
Chowdhury JR, Das K, Das KM. Primary linitis plastica of the
13
14
15
16
colon: report of a case and review of literature. Dis Colon Rectum
1975;18:332-8.
D’Abadie FA, Goodman ML. Primary linitis plastica carcinoma
of the colon: report of a case. Arch Surg 1962;84:686-91.
Dailey TH, Garret R. Primary linitis plastica of the rectum: report
of two cases. Dis Colon Rectum 1971;14:218-21.
Nadel L, Mori K, Shinya H. Primary linitis plastica of the colon
and rectum. Dis Colon Rectum 1983;26:736-40.
Fenoglio-Preiser CM. Gastointestinal Pathology. Wolters Kluver/
Lippincott Williams & Wilkins 2008, pp. 976-979.
pathologica 2009;101:89-92
Case
report
Renal hilus paraganglioma:
a case report and brief review
F. Pagni, E. Galbiati*, F. Bono, C. Di Bella
University Milan “Bicocca”, Desio Hospital, Italy; * University Milan “Bicocca”, Nephrology Department, Monza San Gerardo Hospital, Italy
Key words
Paraganglioma • Renal hilus • Extraadrenal paraganglioma • Extraadrenal pheochromocytoma
Summary
Paraganglioma is a rare tumour that originates from any paraganglia.
Among extra-adrenal paraganglioma, renal hilus is a rare location.
The authors report a case of a 43-year-old female who was admitted
for evaluation of a renal mass detected incidentally by ultrasound
imaging. Suspecting malignancy, the patient underwent radical
nephrectomy. Upon macroscopic examination, the lesion was located into the renal hilus. Histological study revealed a neoplasm
Case report
A 43-year-old woman was submitted to renal ultrasonography for a 1 month history of abdominal pain.
The patient was normotensive; all laboratory data, including endocrinologic tests, were within normal ranges
and there were no pathologic signs in conventional urine
tests. During an ultrasound exam, a mass was detected
close to the right kidney. Abdominal and pelvic CT
showed no abnormalities in the bilateral adrenal glands,
but a large, partially cystic and encapsulated mass (9
cm in maximum diameter) was localized near the renal
hilus. There were no nodal or distant metastases. The
initial radiological differential diagnosis included renal
cell carcinoma and pelvis transitional cell carcinoma.
Based on this, the patient underwent right radical nephrectomy. Frozen sections were not performed. By
macroscopic examination, the kidney showed a red to
brownish mass, solid and cystic, partially haemorrhagic,
with a central white scar, located in the renal hilus and
detachable from the contiguous renal tissue (Fig. 1).
Histology revealed a neoplastic mass arising from the
kidney, in the adipose tissue of the hilus (Fig. 2), which
consisted of nests of cuboidal, monomorphic cells with
basophilic granular cytoplasm and round to oval nuclei
without severe nuclear atypia (Fig. 3). A prominent
fibro-vascular stroma was present. Neoplastic cells
constituted of nests of monomorphic cuboidal cells with basophilic
granular cytoplasm and round to oval nuclei. Necrosis was absent.
The proliferative index (Mib-1) was very low (< 5%). Immunohistochemical examination revealed reactivity for neuron specific enolase
(NSE), chromogranin A and synaptophysin. The final diagnosis was
renal hilus paraganglioma. The paper shows the difficulty in diagnostic approaches to paraganglioma in this atypical site.
Fig. 1. Mass in radical nephrectomy: an encapsulated lesion with
central haemorrhagic features without connection to adjacent
renal tissue and adrenal gland.
were positive for neuron specific enolase (Fig. 4a),
chromogranin A (Fig. 4b) and synaptophysin (Fig. 4c),
and were negative for AE1-AE3 cytokeratins (Fig. 4d).
Only a small number of S-100 protein positive spindle
shaped cells (sustentacular cells) were detectable around
the tumour nests. Mitotic figures were virtually absent;
proliferative index, evaluated by Mib-1, was < 5%.
Correspondence
Dr Fabio Pagni, University Milan Bicocca, Pathology Department, via Cantore 8, 20052 Monza, Italy - E-mail: petala.83@
tiscali.it
90
Fig. 2. The neoplasm (lower left) was separated from the normal
kidney (upper right) and was situated in the adipose tissue of the
renal hilus (H&E;1x).
f. pagni et al.
Fig. 3. “Zellballen” characteristic pattern of growth with classic
fibrovascular stroma of paraganglioma (haematoxylin and eosin;
20x).
Fig. 4. Immunohistochemical staining for enolase neurone specific (Fig. 4a), chromogranin A (Fig. 4b), synaptophysin (Fig. 4c); no immunoreactivity for keratin AE1/AE3 was observed (Fig. 4d).
91
renal hilus paraganglioma
There was no evidence of capsular or vascular invasion.
Accordingly, a final diagnosis of paragaglioma of the
renal hilus was made.
Materials and methods
Immunohistochemical analysis was performed using
the following antibodies: S-100 protein (polyclonal,
Dako), NSE (BBS/NC, Dako), synaptophysin (polyclonal, Zymed), chromogranin A (polyclonal, Zymed), Ki67 (Mib-1, monoclonal, Dako), cytokeratin (AE1-AE3
monoclonal, Dako).
Discussion
Regardless of location, paraganglioma is defined as
a tumour arising from any paraganglia. Historically
paraganglioma that arise from adrenal medulla is defined
“pheochromocytoma”, and extra-adrenal paragangliomas
that are associated with clinical evidence of epinephrine
secretion are defined as “extra-adrenal pheochromocytomas”. However, there are no histological criteria to distinguish between functioning or non-functioning tumours 1.
The functioning form of this tumour can lead to clinical
manifestations: in this case, diagnosis may be easier but
prognosis is more difficult since surgical manipulation
of the neoplastic mass can produce a hypertensive crisis.
Paraganglioma may develop in the context of type IIA
and IIB MEN syndrome, neurofibromatosis, von Hippel-Lindau syndrome or Carney syndrome, but most
frequently it arises spontaneously 2. The most common
site is the carotid body at the bifurcation of the common
carotid artery1. In other cases, the tumour arises from the
retroperitoneal paravertebral chain, which is why the term
Zuckerkandl’s body paraganglioma is used.
This entity is usually found next to the angle formed
by the aorta and the origin of the inferior mesenteric
artery 2. A search of the literature revealed 5 reported
cases of renal paraganglioma and 6 reported cases
of renal pheochromocytoma up to 2005 3. In 2007,
Yamamoto 3 described a new malignant case arising
in the kidney of a 34-year-old man. Table I shows the
previous 12 case reports and details the characteristic
clinical findings. The patient-age ranged from 27 to 68
years old with a clear predominance in males. Interesting variants included cystic paragangliomas 4, giant
cystic paraganglioma 5 and malignant pheochromocytoma 3. Relevant clinical findings included association
with carotid paraganglioma, appendiceal mucocele 6 and
renal pheochromocytoma with renal artery stenosis 7. In
one case, in a 27-year-old man, only cDNA microarray
analysis assisted in diagnosis of malignant intrarenal
pheochromocytoma that was originally masquerading as
a renal cell carcinoma 8. Because of its rarity, especially
in non-functioning cases, paraganglioma can create
problems in preoperative differential diagnosis.
In our case, radiological examination demonstrated the
connection of the tumour with the kidney, but it was not
possible to better define the lesion. In fact, the absence
of clinical secretions and the anatomical independence
of the mass from the adrenal gland persuaded the surgeons to surmise a renal malignant tumour. Therefore,
only histology could define the lesion. Histological differential diagnosis included many entities. First of all, it
was important to rule out the possibility of a neuroendocrine carcinomas: keratins were negative as in all extraadrenal paragangliomas, with exception of those arisen
from filum terminale. We next excluded a primitive
neuroectodermal tumour (PNET) of the kidney based on
morphological and phenotypic criteria. This is a rare and
highly aggressive malignancy that can also present with
inferior vena caval thrombus 9. Immunohistochemistry
Tab. I. Review of literature about paraganglioma in kidney with clinical features.
Authors
Journal
Prager, 1976
J Urol
Clinical findings
Simon, 1979
J Urol
Hypertensive patient
ipsilateral renal artery stenosis
Bezirdjian, 1981
Urol Radiol
Alcini, 1981
Minerva Urol
el Ouakdi, 1990
Ann Urol (Paris)
Takahashi, 2005
J Med Genet
first diagnosis:RCC, suspected based on microarray analysis
Guate Ortiz, 2000
Arch Esp Urol
associated with carotid paraganglioma and appendicular
mucocele
Rossi, 2001
J Urol
Melegh, 2002
Pathol Res Pract
giant cystic variant
Rafique, 2003
Int Urol Nephrol
cystic variant
Elder, 2003
Eur J Surg Oncol
Yamamoto, 2007
Int J Clin Oncol
Pagni, 2009
Pathologica
malignant variant
92
f. pagni et al.
revealed strong positivity for CD99 and weak positivity
for vimentin. Neuron-specific enolase (NSE), chromogranin and cytokeratin were negative. Finally, we considered the possibility of a schwannoma of the kidney.
This is a rare condition with only a few reported cases 10.
Schwannoma is totally or partially encapsulated; it is
diffusely positive for S100 protein and neuron-specific
enolase. Immunostaining for neurofilament, HMB45,
microphthalmia transcription factor, smooth muscle actin, CD34, cytokeratin AE1/3, cytokeratin 7, and CD10
were negative.
In adrenal paraganglioma, the literature proposes the
“rule of 10s” because about 10% of paragangliomas has
familiar incidence, 10% present as multiple tumours,
10% have childhood onset, 10% recur after surgery
and 10% are malignant 11. Although extra-adrenal paragangliomas are very similar to adrenal ones, malignant
paragangliomas in extra-adrenal sites are more frequent:
29-40% versus 2-11% 12. According to the literature, the
clinical and histological features predictors of malignancy are male sex, size over 5 cm, high mitotic activity, presence of confluent necrosis, vascular or capsular
invasion, secreting tumours and decreased immunoreactivity for neuropeptides 13. On the contrary a high representation of S-100 protein positive sustentacular cells
in the histological specimen should be associated with a
better clinical course 14. Nonetheless, differentiation between malignant and benign cases may be very difficult
and only the clinical behaviour (such as the evidence
of metastases) could be a definitive criterion. As in our
case, the treatment of choice and the best predictor of
no recurrence is the surgical complete removal of the
mass. In fact, in the absence of guidelines for management of these neoplasms, patients undergo clinical and
ultrasound examination every 6 months for the first 5
years after surgical treatment.
References
sis assists in diagnosis of malignant intrarenal pheochromocytoma originally masquerading as a renal cell carcinoma (electronic
letter). J Med Genet 2005;42:e48
9
Kourda N, El Atat R, Derouiche A, Zeddini A, Chebil M, Baltagi
S, et al. Primitive neuroectodermal tumor of the kidney with vena
caval tumor thrombus: diagnosis and management. Pathologica.
2007;99:57-60.
10
Gobbo S, Eble JN, Huang J, Grignon D, Wang M, Martignoni G, et
al. Schwannoma of the kidney. Modern Pathology 2008;21:779-83.
11
Lack EE, Cubilla AL, Woodruff JM, Lieberman PH. Extra-adrenal paragangliomas of the retroperitoneum. A clinicopathologic
study of 12 tumors. Am J Surg Pathol 1980;4:109-20.
12
O’Riordain DS, Young WF, Grant CS, Carney JA, Heerden JA.
Clinical spectrum and outcome of functional paraganglioma.
World J Surg 1996;20:916-22.
13
Kliewer KE, Wen DR, Cancilla PA, Chochrane AJ. Paragangliomas: assessment of prognosis by histologic, immunohistochemical
and ultrastructural techniques. Hum Pathol 1989;20:29-39.
14
Achilles E, Padberg BC, Holl K, Kloppel G, Schroder S. Immunocytochemistry of paragangliomas –value of staining for S-100
protein and glial fibrillary acid protein in diagnosis and prognosis. Histopathology 1991;18:453-8.
Rosai J. Adrenal gland and other paraganglia. Rosai and Ackerman’s Surgical Pathology. 9th edition. USA: Mosby 2004,
pp.1142-1146.
2
Goldstein RE, O’Neill JA, Holcomb GW. Clinical experience over
48 years with pheochromocytoma. Ann Surg 1999;6:755-64.
3
Yamamoto N, Maeda S, Mizoguchi Y. Malignant paraganglioma
arising from the kidney. Int J Clin Oncol 2007;12:160-2.
4
Rafique M, Bhutta RA, Muzzafar S. Case report: intra-renal
paraganglioma masquerading as a renal cyst. Int Urol Nephrol
2003,35:475-8.
5
Melegh Z, Renyi-Vamos F, Tanyay Z. Giant cystic pheochromocytoma located in the renal hilus. Pathol Res Pract
2002;198:103-6.
6
Guate Ortiz JL, Alvarez Pérez JA, Velasco Alonso J, González
Tuero J, Baldonedo Cernuda R, Lanzas Prieto JM, et al. Non-functional renal paraganglioma associated with carotid paraganglioma and appendicular mucocele. Arch Esp Urol 2000;53:845-8.
7
Bezirdjian DR, Tegtmeyer CJ, Leef JL. Intrarenal pheochromocytoma and renal artery stenosis. Urol Radiol 1981;3:121-2.
8
Takahashi M, Yang XJ, McWhinney S. cDNA microarray analy1
pathologica 2009;101:93-96
Case
report
Endometrial stromal sarcoma presenting
as a cystic abdominal mass
R. Doghri, K. Mrad, M. Driss, S. Sassi, I. Abbes, R. Dhouib, M. Hechiche*, K. Ben Romdhane
Pathology Department of Salah Azaiez Institute, Bab Saadoun, Tunis, Tunisia
Key words
Endometrial stromal sarcoma • Abdominal tumour • Hormonal receptors
Summary
Endometrial stromal sarcoma (ESS) is rarely localized in extrauterine sites if metastasis or local extension of the primary uterine tumour are excluded, and diagnosis can be delayed because
of the unusual site. We report a case of abdominal ESS in a 45year-old woman who presented with an abdominal complaint.
Ultrasound of the abdomen showed a large multiloculated cystic
mass. The complete excision of the tumour revealed ESS arising
in endometriosis. The tumour expressed hormonal receptors
and the patient was administered hormonal therapy. ESS has
a better prognosis than the sarcoma that is part of differential
diagnosis, and is associated with endometriosis in about onehalf of cases.
Introduction
Gross findings
Endometrial stromal sarcoma (ESS) is an uncommon
neoplasm of low grade of malignancy according to the
WHO classification. The occurrence of ESS outside the
uterus is extremely rare in the absence of metastasis
or extension of a primary uterine neoplasm; it is then
easily misdiagnosed in extra-uterine sites. When ESS
occurs in an extra-uterine location, it presumably arises
from foci of endometriosis, which should be carefully
investigated.
The surgical specimen included the abdominal mass
and the omentectomy. The mass measured 35x28x18
cm. The external surface was smooth. Sections showed
a large multilocular cyst filled with haemorrhagic fluid
that occupied the major volume of the tumour. The inner lining of cysts was orange-yellow or tan-grey to
slightly yellow (Fig. 1). The solid areas were firm, with
a whorled cut surface and focal haemorrhage. Another
specimen submitted as “epiploon surrounding abdominal mass” measuring 22x20x2 cm. It consisted of fatty
tissue with no suspect nodules.
Case report
A 45-year-old woman, gravida 2/para 2, presented with
complaints of abdominal discomfort lasting 6 months.
She has no significant medical history. Physical examination revealed a large palpable abdominopelvic
mass. Ultrasound showed a large multiloculated cystic
mass measuring 29 cm in maximum dimension. The
inner lining of cysts revealed multiple papillary projections measuring up to 0.1 cm in the greatest dimension.
Uterus and adnexa were within normal size. Surgical
investigation revealed an enlarged tumour measuring
35 cm in diameter. The abdominal cystic mass was
reported as completely excised and appeared to have
no involvement with any intra-abdominal organs except
the omentum.
Microscopic findings
The abdominal mass had hypercellular zones mixed
with areas of lower cellularity, irregular infiltrating
borders and several foci of necrosis. The tumour was
arranged in a diffuse and slightly whorled pattern.
Cells were oval to spindle-shaped with a scant cytoplasm (Fig. 2). Cell nuclei were of uniform size with
smooth contours, distributed chromatin and indistinct
nucleoli. Mitotic figures were extremely rare and when
found were normal in appearance (3 mitosis/10 HPF).
No polymorphic or enlarged nuclei were found. Some
bland glands with a single epithelium were intimately
admixed with tumoural cells (Fig. 3). The large cystic
Correspondence
Karima Mrad, Institute Salah Azaiez, 1006 Bab Saadoun, Tunis,
Tunisia - Tel. +21671577848 - Fax +21671571380 - E-mail:
[email protected]
94
R. doghri et al.
Fig. 1. Large cystic mass showing yellow and brownish surface
and some solid areas.
Fig. 4a. CD10 is positive (DAB, x200).
Fig. 2. Diffuse sheet of small neoplastic cells with minimal atypia
(HE, x200).
Fig. 4b. Estrogen receptor are positive (DAB, x200).
walls were lined by a discontinuous endometrial epithelium. A prominent plexiform vasculature was noted. In
peripheral areas, extensive stromal hyalinization, sheets
of foamy cells and cholesterol deposits were present.
Fig. 3a. Neoplastic cells are intermingled with bland glands (HE, x200).
Fig. 3b. Neoplastic cells are intermingled with bland glands (cytokeratine, x200).
Immunohistochemical studies showed that the neoplastic cells were immunoreactive to CD10 (Novocastra®)
(Fig. 4a), and both oestrogen receptor and progesterone receptor antibodies (Novocastra®) showing diffuse
strong nuclear staining (Fig. 4b). Actin (Dako®) was
weakly positive, desmin (Dako®) and inhibin (Zymed®)
were negative.
All these features were compatible with a diagnosis of
low grade endometrial stromal sarcoma arising from
pelvic endometriosis.
Discussion
a
b
Low grade endometrial stromal sarcoma is an uncommon
neoplasm of uterus accounting for only 0.2% of all genital tract malignant neoplasms 1. Outside the uterus, this
tumour is extremely rare in the absence of metastasis or
extension of a primary uterine neoplasm. Several primary
extrauterine locations of EES have been reported such as
the pelvic cavity 1-3, abdominal cavity 1, ovary 1 2, fallo-
95
endometrial stromal sarcoma presenting as a cystic abdominal mass
pian tube 1, retroperitoneum 1 4 and vagina 1 5. Extrauterine primary endometrioid stromal sarcomas often
arise from endometriosis 3 6. Kondi-Pafiti reported
on a series of 14 neoplasms arising in endometriosis,
with seven cases of ESS among which one case arising in the omentum and another in the pelvis 6.
Endometrial stromal sarcomas (ESS) have been previously divided into low grade and high grade subtypes
based on mitotic count by Norris and Taylor in 1966 7.
However, in the WHO classification, the high grade
type is replaced by undifferentiated endometrial sarcoma and the distinction between the two entities is based
on nuclear pleomorphism and necrosis. Low grade ESS
affects younger women with a mean age ranging from
42-58 years, and 10-25% of patients are premenopausal 7.
On macroscopy, the tumour presents as a solitary well
delineated mass. The sectioned surface appears yellow
to tan, and the tumour has a softer consistency than a
usual leiomyoma. Cystic and myxoid degeneration as
well as necrosis and haemorrhage are seen occasionally.
In our case, cystic changes were unusually prominent.
On microscopy, low grade ESS is usually a dense tumour composed of uniform, oval to spindle-shaped cells
resembling the stromal cells of normal proliferative endometrium. Significant atypia and patent pleomorphism
are absent. Although most tumours are paucimitotic, mitotic rates of 10 or more per 10 high power fields can be
reached. This proliferation of spindle cells is intimately
associated with a delicate vasculature of small arterioles
that may undergo hyalinization, and thus resemble the
spiral arterioles of the late secretory endometrium. Cells
with foamy cytoplasm are prominent in some cases 8. In
our case, they were present and intermingled with cholesterol deposits. Sex cord-like structures may also be
found 8. Myxoid and fibrous change may occur focally
or diffusely 7 9.
ESS with endometrioid glands have been reported in
11 to 40% of published series of ESS 7 10. These benign
endometrioid glands are focally, sparsely distributed,
and their identification depends upon adequate sampling
of the tumour. Their presence can be disconcerting if
ESS diagnosis is ignored, but of substantial value if the
correct diagnosis is suspected. Moreover immunoreactivity for oestrogen and progesterone receptors in ESS
is generally seen, with the majority of cases being immunoreactive for both hormone receptors 11.
The differential diagnosis of a densely cellular spindle
cell neoplasm with only minimal cytologic atypia arising in the abdominal cavity of a woman includes all
spindle cell neoplasms at this site, but rarely ESS. The
absence of endometriosis does not preclude a diagnosis
of primary extrauterine ESS, as the largest series to date
failed to show an association with endometriosis in almost one-half of cases 12.
This pattern of hyalinization with associated uniform
spindle cells is not unique to ESS and can be seen in
smooth muscle tumours and in solitary fibrous tumours,
but differs from the thicker vessels seen in these two
latter entities. The absence of immunoreactivity for
CD34 argues strongly against solitary fibrous tumour,
while the positive staining for smooth muscle actin and
the immunoreactivity for oestrogen and progesterone
receptor does not distinguish ESS from a smooth muscle
tumour, because both are positive for these antibodies
as well as for desmin 13. CD10 is positive in ESS, while
only rare cases of leiomyomas show focal staining 14.
In extra-uterine sites, the other neoplasms included in
differential diagnosis are synovial sarcoma, peripheral
nerve sheath tumours and gastrointestinal stromal tumour. The immunoreactivity for CD117 and CD34 in
gastrointestinal stromal tumour and their absence in
ESS are especially useful in this setting. Endometriosis
is easily ruled out as it is not consistent with the formation of a distinct large mass.
Lastly, metastasis from an ESS of the uterus or a uterine
“adenosarcoma” with relatively bland features are to
be considered, and the only way to definitely rule out
these lesions is to have the entire gynaecologic tract for
pathologic review.
The diagnosis of low grade ESS is relevant because
this tumour is characterized by indolent growth and late
recurrences. The median interval to recurrence is 3-5
years but may exceed 20 years. Pulmonary metastases
occur in 10% of stage I tumuors 15. The 5-year survival
rate for low grade ESS ranges from 67% to nearly 100%
with late metastases and a relatively long-term survival
despite tumour dissemination 15.
In summary, the occurrence of extrauterine and extragonadal ESS arising in the abdominal cavity includes a
several differential diagnoses. While extremely rare,
any spindle cell neoplasm occurring in the abdominal
cavity of a female that has bland nuclear features and
scant cytoplasm should be considered as a possible ESS,
and positive myogenic markers should not exclude its
diagnosis. Diffuse strong immunostaining for CD10
confirms the diagnosis of EES in doubtful cases 14.
A panel of immunohistochemical markers combined
with a careful morphologic examination and consideration of ESS in differential diagnosis should allow the
pathologist to reach a correct diagnosis in these rare
circumstances.
metrial stromal sarcoma: Report of three cases. Pathol Int
1998;48:297-302.
References
Chang KL, Crabtree GS, Lim-Tan SK, Kempson RL, Hendrickson MR. Primary extrauterine endometrial stromal neoplasms: A
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Int J Gynecol Pathol 1993;12:282-96.
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Fukunaga M, Ishihara A, Ushigome S. Extrauterine endo1
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McCluggage WG, Bailie C, Weir P, Bharucha H. Endometrial stromal
sarcoma arising in pelvic endometriosis in a patient receiving unopposed oestrogen therapy. Br J Obstet Gynecol 1996;103:1252-4.
Morrison C, Ramirez NC, Chan J KC, Wakely Jr P. Endome-
96
trial stromal sarcoma of the retroperitoneum. Ann Diag Pathol
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Corpa M VN, Serafini EP, Bacchi CE. Low-grade endometrial
stromal sarcoma presenting as vaginal nodule. Ann Diagn Pathol
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6
Kondi-Pafiti A, Kairi-Vassilatoul E, Spanidou-Carvouni H, Kontogianni-Katsarou K, Anastassopoulos G, Papadias K, et al. Malignant neoplasms arising in endometriosis: clinicopathological
study of 14 cases. Clin Exp Obstet Gynecol 2004;31:302-4.
7
Norris HJ, Taylor HB. I. A clinical and pathological study of 53
endometrial stromal tumors. Cancer 1966;19:755-66.
8
Clement PB, Scully RE. Uterine tumors resembling ovarian sexcord tumors. A clinicopathological analysis of fourteen cases. Am
J Clin Pathol 1976;66:512-25.
9
Oliva E,Young RH, Clement PB, Scully RE. Myxoid and fibrous
endometrial stromal tumors of the uterus:a report of 10 cases. Int
J Gynecol Pathol 1999;18:310-9.
10
Clement PB, Scully RE. Endometrial stromal sarcomas of the
uterus with extensive endometrioid glandular differenciation: a
R. doghri et al.
report of three cases that caused problems in differential diagnosis. Int J Gynecol Pathol 1992;11:163-73.
11
Reich O, Regauer S, Urdl W. Expression of oestrogen and progesterone receptors in low-grade endometrial stromal sarcomas. Br
J Cancer 2000;82:1030-4.
12
Oliva E, Young RH, Scully RE. Primary endometrioid stomal
sarcomas of the ovary. A clinicopathologic analysis of 36 cases.
Mod Pathol 1998;11:110A(abstr).
13
Farhood AI, Abrahms J. Immunohistochemistry of endometrial
stromal sarcoma. Hum Pathol 1991;22:224-30.
14
Chu PG, Arber DA, Weiss LM, Chang KL. Utility of CD10 in
Distinguishing between endometrial stromal sarcoma and uterine
smooth muscle tumors: an immunohistochemical comparison of
34 Cases. Mod Pathol 2001;14:465-71.
15
Itoh T, Mochizuki M, Kumazaki S, Ishihara T, Fukayama
M. Cystic pulmonary metastases of endometrial stromal
sarcoma of the uterus, mimicking lymphangiomyomatosis : a
case report with immunohistochemistry of HMB45. Pathol Int
1997;47:725-9.
pathologica 2009;101:97-100
Case
report
Primary CD30/ALK-1 positive anaplastic large cell
lymphoma of the skeletal muscle in a child
M. Driss, I. Abbes, K. Mrad, S. Sassi, F. Oubich**, S. Barsaoui**, K.B. Romdhane
Department of Pathology, Salah Azaïz Institute, Bab Saadoun, Tunis, Tunisia, * Department of Oncology, Children’s Hospital, Bab
Saadoun, Tunis, Tunisia
Key words
CD30/ALK+ lymphoma • Anaplastic large cell lymphoma • Soft tissue • Childhood • Non-Hodgkin lymphoma
Summary
Anaplastic large cell lymphoma (ALCL) represents approximately 10 to 30% of all childhood non-Hodgkin lymphomas.
It frequently involves both lymph nodes and extranodal sites
whereas primary or secondary muscular involvements are quite
uncommon. We describe a case of an 8–year-old boy presented
with one month progressively swelling right buttock mass without association of lymphadenopathy or skin extension. Biopsy
of the lesion showed large anaplastic cells with voluminous and
abundant cytoplasm as well as folded nuclei. The tumour cells
were positive for CD30, CD3, EMA and ALK-1. Chemotherapy
resulted in durable remission status. This case emphasizes the
occurrence of anaplastic large cell lymphoma in the soft tissue
and the favourable outcome of ALK-positive anaplastic large cell
lymphoma.
Introduction
in diameter wrapping the hip, but without extension to
the proximal groin. The mass was heterogeneous with
low signal intensity on T1-weighted images and high
signal intensity on T2- weighted images (Fig. 1). On
the basis of these findings, a diagnosis of rhabdomyosarcoma was initially suspected. The patient underwent
a tumor biopsy, which revealed anaplastic large cell
lymphoma. Further staging studies, which included
computed tomography (CT) of the chest and abdomen
as well as bone scan and bone marrow aspiration did
not reveal evidence of dissemination of disease. In
addition to these findings, the patient was diagnosed as
having Ki-1 ALCL lymphoma primary in soft tissue.
Accordingly, intensive chemotherapy was prescribed
as follows: doxorubicin, ifosfamid, cyclophosphamide,
adriamycin and intrathecal methotrexate. One month
after the completion of the chemotherapy regimen, MRI
revealed the complete disappearance of the tumour. The
patient has been in complete remission for more than 7
years without further treatment.
While skeletal muscle can be involved in anaplastic cell
lymphoma as a part of disseminated disease, primary
anaplastic large cell lymphoma (ALCL) of skeletal
muscle is exceedingly rare with only a few cases reported in the English literature 1 2. We present a case of an
8-year-old boy diagnosed with a CD30/ALK+ ALCL
in skeletal muscle, with no other sites of disease; the
boy is still disease-free 7 years after completion of chemotherapy. To the best of our knowledge, this is the first
paediatric case reported in the literature.
Case report
A previously healthy 8-year-old boy presented in June
1999 with a month-long history of an enlarging painful
mass of the right buttock. Initial physical examination
was essentially non-informative except for the mass. He
had no history of fever, weight loss or other systemic
symptoms. Furthermore, neither lymphadenopathies nor
skin changes were detected. Laboratory studies showed
mild leukocytosis and an elevated erythrocyte sedimentation rate (48 mm). Magnetic resonance imaging study
of the pelvis revealed a large soft tissue mass of 8 cm
Materials and methods
Two small fragments of tissue fixed in 10% buffered
formalin were received. The specimen was embedded in
Correspondence
Maha Driss, Department of Pathology, Salah Azaïz Institute,
1006 Bab Saadoun, Tunis, Tunisia - Tel. 0021671577850 - Fax
0021671574725 - E mail: [email protected]
98
Fig. 1. A magnetic resonance imaging (MRI) of the pelvis reveals
an 8 cm tumour wrapping the hip.
m. driss et al.
Fig. 2A. A low-magnification view showing diffuse infiltration of
the striated muscle. Note atrophic striated muscle fibres at the
periphery of the tumour (H&E).
Fig. 2B. Higher magnification showing neoplastic cells with reniform nuclei and prominent nucleoli (H&E).
paraffin, and 4-µm-thick paraffin sections were stained
with haematoxylin-eosin. Immunohistochemistry was
performed using the following antibodies (Dako; 1/50):
CD3, CD20, CD15, CD30, CD45RO, CD68, CD79a,
epithelial membrane antigen (EMA), vimentin, desmin,
actin, PS100 and ALK-1.
Results
Microscopic findings
Histological sections revealed striated muscle tissue
extensively infiltrated by sheets of large neoplastic cells
with irregularly indented embryo-like nuclei, vesicular
chromatin, and prominent nucleoli (Fig. 2A). The cytoplasm was abundant amphophilic with distinct cytoplasmic membranes and pale paranuclear eosinophilic
regions (Fig. 2B). Mitotic figures were numerous and
there were occasional areas with apoptotic features. A
variable number of reactive cells such as small lymphocytes, plasma cells and neutrophils were found,
including histiocytes, which imparted a “starry-sky” appearance and occasionally showing signs of erythrophagocytosis. One striking finding, however, was the presence of tumor emboli appearing as ill-defined cellular
aggregates that showed central loss of cellular cohesion
reminiscent of alveolar areas.
Immunohistochemical findings
All tumour cells were strongly positive for CD30, ALK-1
and vimentin, and were focally positive for EMA, CD3 and
CD45RO. Tumor cells were negative for CD20, CD79a,
CD68, actin, desmin and S100 protein. CD30, EMA and
vimentin staining were localized at the paranuclar regions
and the cell membrane. ALK-1 had an obvious cytoplasmic and nuclear pattern of immunoreactivity (Fig. 2C).
Histiocytes were positive for CD68, which highlighted
imaging of erythrophagocytosis (Fig. 2D).
Discussion
Primary malignant lymphoma of soft tissues is rare, accounting for less than 2% of lymphoma of all sites and
is most often of B cell phenotype 3 4. It is characterized
by the development of a soft tissue mass in a region not
99
primary cd30/alk-1 positive anaplastic large cell lymphoma
Fig. 2C. All tumour cells are expressing the ALK protein both in
the nucleus and the cytoplasm.
Fig. 2D. Histiocytes are positive for CD68 highlighting imaging of
erythrophagocytosis.
typically considered rich in lymph nodes and without
extension from adjacent skin, lymph node or bone. Furthermore, staging studies must exclude other sites of distant metastases 3 4. About 15 to 85% of systemic ALCL
contain the translocation (2;5)(p23;q35) which fuses the
anaplastic lymphoma kinase (ALK) gene at 2p23 with
the nucleophosmin (NPM) gene at 5q35, resulting in
the production of a chimeric NPM-ALK protein 5. The
detection of ALK by reverse transcription polymerase
chain reaction and by immunohistochemistry has made
possible a new classification between ALK positive and
ALK negative ALCLs. ALK-positive ALCL occurs ear-
lier in life and accounts for 10 to 30% of all childhood
non-Hodgkin lymphoma. It frequently involves both
lymph nodes and extranodal sites including the skin,
lung, bone, soft tissue and gastrointestinal tract 6 7. In
contrast to ALK-positive ALCL, ALK-negative ALCL
are characterized by a higher age and advanced stage at
diagnosis and poor prognosis. It shows similar clinical
features to ALK-positive ALCL, but extranodal involvement is less common. Although soft tissue involvement may be seen at diagnosis or relapse in primary
systemic ALCL, the sole involvement of skeletal muscle is quite uncommon with only 2 documented cases
reported in the international literature 1 2. Ishii reported
a case of paediatric ALK-positive ALCL in a Japanese
girl who presented with an intramuscular tumour on her
upper arm. However, further investigation at diagnosis
showed an enlarged lymph node 8. In our case, diagnosis
of Ki-1 ALCL was performed by morphological and
immunological analysis of the intramuscular tumour.
Additionally, we think that the ALCL arising primarily
within muscle because the tumour was intimately admixed with muscle fibres. Furthermore, we noted that
the tumour was situated far from the proximal groin,
and staging studies showed no evidence of disease elsewhere or extension from adjacent skin, lymph node or
bone. Immunohistochemically, both cytoplasmatic and
nuclear ALK staining strongly suggested that tumour
cells contained the 2;5 translocation 7 8. Unfortunately,
cytogenetic analysis was not possible.
The main differential in both clinical and histological
diagnosis considered in this case was rhabdomyosarcoma. In fact, the patient’s age as well as the presence of
an exclusively intramuscular mass without concomitant
lymphadenopathy, associated cutaneous or osseous
change was suggestive of rhabdomyosarcoma. Furthermore, the presence of ill-defined cellular aggregates
with central loss of cellular cohesion is suggestive of
the alveolar area of rhabdomyosarcoma. Such a distinction may be achieved mainly by immunohistochemical
stains that include a panel for muscular markers which,
as in our case, was non-reactive. Reactive histiocytosis
with erythrophagocytosis, as described in our case, is
occasionally reported in ALCL and can be incorrectly
diagnosed as malignant histiocytosis 9.
In conclusion, ALCL may be present solely in soft tissue. Despite the overtly anaplastic appearance of this
lymphoma, favourable long-term survival is possible,
and in our case study the patient is still alive and well 7
years after completion of chemotherapy. The paediatric
age and ALK expression may have played an important
role in this patient’s excellent post treatment outcome.
phoma primarily infiltrating femoral muscles. Ann Hematol
2005;84:764-6.
References
Chim CS, Choy C, Liang R. Primary anaplastic large cell lymphoma of skeletal muscle presenting with compartment syndrome.
Leuk Lymphoma 1999;33:601-5.
1
2
Liao WP, Dai MS, Hsu LF, Yao NS. Anaplastic large-cell lym-
3
4
Lanham GR, Weiss SW, Enzinger FM. Malignant lymphoma.
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Salamao DR, Nascimento AG, Lloyd RV, Chen MG, Habermann
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TM, Strickler JG. Lymphoma in soft tissue: A clinicopathologic
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5
Stein H, Mason DY, Gerdes J, O’Connor N, Wainscoat J, Pallesen
G, et al. The expression of Hodgkin’s disease associated antigen
Ki-1 in reactive and neoplastic lymphoid tissue: Evidence of
Reed-Sternberg cell and histiocytic malignancies are derived from
activated lymphoid cells. Blood 1985;66:848-58.
6
Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro
DN, Saltman DL, et al. Fusion of a kinase gene, ALK, to a
nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma.
Science 1994;263:1281-4.
m. driss et al.
7
Stein H, Foss HD, Dürkop H, Marafioti T, Delsol G, Pulford
K, et al. CD30+ anaplastic large cell lymphoma: A review
of its histopathologic, genetic, and clinical features. Blood
2000;96:3681-95.
Sagaert X, De Wolf-Peeters C. Anaplastic large cell lymphoma.
Curr Diagn Pathol 2003;9:252-8.
8
Ishii E, Honda K, Nakagawa A, Urago K, Oshima K. Primary
CD30/Ki-1 positive anaplastic large cell lymphoma of skeletal
muscle with der(17)t(1;17) (q11;p11). Cancer Genet Cytogenet
2000;122:116-20.
9
pathologica 2009;101:101-104
Case
report
Small cell osteosarcoma: a case report
R. Kallel, L. Ayadi, N. Toumi*, E. Daoud**, A. Khabir, Z. Ellouze***, S. Charfi, S. Makni,
T. Sellami Boudawara
Pathology Department, * Oncology Department, ** Radiology Department, *** Orthopedic Department, H. Bourguiba Hospital, Sfax,
Tunisia
Key words
Small cell osteosarcoma • Round cell tumor • Chemotherapy
Summary
Introduction. Small cell osteosarcoma (SCO) is a rare bone
tumour representing 1.3% of all osteosarcomas. This rare variety
of osteosarcoma tends to arise in the metaphysis of long bones
and may extend secondary to epiphysis. By histopathology, the
tumour is composed of small round cells with a variable degree
of osteoid production. We report a new case of SCO in the distal
femur with epiphyseal involvement. We also present the clinical,
radiologic and therapeutic features of SCO with particular emphasis on the pathologic features that allow differentiation of this
neoplasm from other small round cell tumours.
Observation. A 14-year-old girl presented with a 6-month history of a painful tumefaction of the left knee with motor deficit.
Imaging analysis of the knee demonstrated a lytic lesion of the
metaphysis in addition to epiphysis of the distal femur with
cortical destruction and invasion of soft tissues. Histological
examination of a biopsy specimen showed sheets of neoplastic
small round cells simulating Ewing’s sarcoma. Osteoid was focally present. A diagnosis of SCO was made. The patient received
2 cycles of adjuvant chemotherapy with ifosfamide, adriamycin
and cisplatin. MRI showed no change in tumour size. An en bloc,
wide-margin resection of the lesion was performed. Histological
examination showed a viable tumour with few necrotic foci. The
patient received adjuvant chemotherapy with Holoxan and VP16.
The clinical response was favourable.
Conclusion. SCO is a rare clinical entity with a high grade of
malignancy that must be distinguished from other round cell
tumours, particularly Ewing’s sarcoma, in order to optimise treatment protocols.
Introduction
destruction and a periosteal reaction. Computed tomography (CT) and magnetic resonance imaging (MRI)
showed a large tumour in the metaphysis involving
the epiphysis of the distal femur measuring 6.5 x 5.5
x 5.5cm with cortical destruction and involvement of
soft tissues (Fig. 1). The lesion showed inhomogeneous
radiotracer uptake.
Skeletal scintigraphy showed strong hyperfixation in
the left femoral condoyle. Chest radiographs and CT
were normal. An open surgical biopsy was collected.
Histological examination showed sheets of small neoplastic round cells with scant cytoplasm, round to oval
nuclei and a fine chromatin pattern; mitotic figures were
abundant; focal areas of tumour osteoid were rarely seen
(Figs. 2, 3). By immunohistochemistry, tumour cells
were strongly positive for vimentin and neuron specific
enolase (NSE), weakly positive for CD99 (cytoplasmic
staining) and negative for epithelial membrane antigen
(EMA) and leukocyte common antigen (LCA). A diagnosis of SCO was made. The patient received 2 cycles
of adjuvant chemotherapy with ifosfamide, adriamycin
and cisplatin. MRI showed no change in tumour size
Small cell osteosarcoma (SCO) of the bone is a rare
variant of osteosarcoma that poses unique diagnosis and
treatment considerations. The tumour arises in the metaphysis of long bone. We report a new case in the distal
femur with epiphyseal involvement. We also present
the clinical, radiologic and therapeutic features of SCO
with particular emphasis on the pathologic features that
allow differentiation of this neoplasm from other small
round cell tumours.
Case report
A 14-year-old girl presented with a 6-month history
of a painful tumefaction of the left knee. Physical examination revealed a firm mass in the distal left femur
with motor deficit; no regional adenopathy was evident.
Radiographs of the knee demonstrated an aggressive
metaphyseal lytic lesion of the internal femoral condoyle with involvement of the epiphysis and cortical
Correspondence
Dr Rim Kallel, Pathology Department. H. Bourguiba Hospital,
3029 Sfax, Tunisia - Tel. 216 74240341 - Fax 216 74243427 E-mail: [email protected]
102
Fig. 1. a: Anteroposterior radiogram demonstrates a lytic lesion
of the metaphysic with involvement of the internal femoral
condoyle, cortical destruction and periosteal reaction (→). b:
Coronal T1-weighted enhanced MRI shows a large tumor in the
metaphysis involving the epiphysis of the distal femur with cortical destruction (→) and invasion of soft tissue (*).
(Fig. 4). An en bloc, wide-margin resection of the lesion was performed. The tumour was localized in the
metaphysis and extended into the femoral condoyle.
Histological examination showed a viable tumour with
few necrotic foci; surgical margins and the articular
cartilage of the epiphysis were uninvolved. The patient
received adjuvant chemotherapy with Holoxan and
VP16. The clinical response was favourable after a follow-up of 2 years.
Discussion
SCO of the bone is rare, accounting for 1.3% of all
osteosarcomas 1. It was first reported by Sim et al. 2 in
1979. It is a tumour of young adulthood, with a reported
age range from 19 to 28 years (average, 19 years) 3.
Fig. 2. Proliferation of small round cell tumor with scant cytoplasm and round to oval nuclei.
R. kallel et al.
Fig. 3. Tumor proliferation with osteoid production (*).
There is a slight predilection for females, sex ratio 1.1 4.
The anatomic distribution of SCO is similar to that of
conventional osteosarcoma: the distal femur is the most
common site, followed by the proximal tibia and proximal humerus 5. The metaphysis of long bones is most
commonly affected, followed by a diaphyseal location
accounting for 14% of cases of long bone SCO 1. It was
originally suggested that the epiphyseal plate is a barrier to the spread of tumour, as cartilage was believed to
contain a substance that inhibits angiogenesis and collagenase formation by tumour tissue 6. However, some
authors have reported invasion of the epiphyseal plate
by osteosarcoma 1 6 7. In a study of 11 cases of SCO,
Bertoni et al. 8 reported seven cases extending into the
epiphysis, and in a study by Norton et al. 6 involvement
of the epiphysis was present in 12 of 15 cases (80%).
These findings are contrast with the common misconception that the epiphyseal plate is a barrier to tumour
spread 6 7.
Fig. 4. MRI post-chemotherapy: stagnation of the tumor mass.
a: Axial T1-weighted enhanced MRI: fat sat with cortical destruction and invasion of soft tissue (*). b: sagittal T2- weighted MRI:
very low signal.
103
small cell osteosarcoma: a case report
The clinical presentation of SCO at the time of initial
diagnosis is similar to that of conventional osteosarcoma 8. Pain and swelling are common clinical manifestations, often beginning with intermittent pain, swiftly
turning into persistent pain 4. The duration of symptoms
before presentation usually ranges from a few weeks to
several months 5.
The radiographic features of SCO are nonspecific, although the tumour shows a predominantly lytic lesion
and an aggressive malignant appearance with destruction of the cortex 1 4 5. There is always a lytic component,
usually admixed with radiodense areas 4. The appearance on radiographs of mineralized matrix outside the
bone is an indication of osteosarcoma 1 9. Reactive bone
sclerosis and soft tissue mineralization may also be seen
in SCO 1. MRI is useful for evaluating infiltration of the
marrow space, soft tissues and joint spaces, and is also
used to assess the extent of transepiphyseal involvement 6. Because osteosarcomas may present as lytic
tumours that may extend into the epiphysis, they should
be included in the differential diagnosis of clear cell
chondrosarcoma, chondroblastoma, epiphyseal enchondroma and mesenchymal chondrosarcoma 10 11.
Histologically, SCO of bone is a tumour constituted
predominantly of small cells with variable osteoid
production 1. Specifically, it is composed of round cell
or short spindle cell types; the round cells are small,
may have a lymphoma-like pattern and have a scanty
cytoplasm; nuclei are round to oval and chromatin may
be fine to coarse; mitoses range from 3 to 5/high power
field. In the short spindle cell type, the tumour cells
are mainly composed of short-spindle nuclei containing fine granular chromatin with scanty amounts of
cytoplasm 1 4. Lace-like osteoid production is always
present, but in variable amounts thus requiring an
adequate sampling of the tumour. Moreover, reactive
periosteal bone formation, fibrin deposits, necrotic
debris and stromal collagen may all be misinterpreted
as areas of osteoid synthesis by tumour cells 3. It can
be critical for diagnosis if the biopsy material does not
clearly include osteoid: this is especially important
in SCO, where the small round cells may histologically simulate Ewing’s sarcoma (EWS) 1 12. EWS occur
more frequently, and although reactive new bone may
be seen, there is no malignant osteoid 8. The tumour
cells of SCO are more pleomorphic than in EWS and
may indeed show spindling of nuclei 1. A positive PAS
staining does not favour a diagnosis of EWS since it
is usually positive in SCO as well 9 12. By immunohistochemistry, there are no specific reports exploring its
use in differential diagnosis between SCO and EWS 12;
CD99, a relatively specific marker for EWS may be
positive in some cases of SCO; however, the staining
is not membranous, intense and diffuse 12. In addition,
the tumour may be difficult to distinguish from other
small round cell malignancies, such as malignant lymphoma and mesenchymal chondrosarcoma 1 12. Lymphomas of bone are predominantly composed of larger
cells with prominent nucleoli, and it rarely occurs in
the first or second decade of life 8. Furthermore, LCA
is useful for differential diagnosis 8. Primitive neuroectodermal tumour of bone (PNET), which belong
to the Ewing’s family of tumours, can be ruled out as
neither bone or cartilage is identified and neuroectodermal markers (neuron specific enolase and Leu-7)
are usually positive 8. Other small cell malignancies
can be easily ruled out by immunohistochemical staining (e.g. with keratins in the case of metastatic small
cell carcinoma) 1.
By cytogenetic analysis, the 11:22 translocation of
Ewing’s tumours is not usually seen in this neoplasm 4,
although Noguera 13 has reported this chromosomal
translocation in a case of SCO.
Some authors believe that SCO is a definite histological
entity. It seems reasonable that tumours, with spindling
small cells or when matrix production is definite, should
be treated based on a protocol for osteosarcoma. This
would include neoadjuvant chemotherapy and surgical
removal with a wide margin by amputation or a limbsalvage procedure. If tumour cells are small, round, and
uniform and matrix is questionable, it probably is best to
treat it as EWS 1. It has been suggested 2 that SCO may
be less sensitive to irradiation than EWS, and that ablative surgery and adjuvant chemotherapy offer the best
chance for control of the disease.
The SCO has a poorer prognosis than conventional
osteosarcoma (5-year survival rate of 77%) and EWS
(5-year survival rate of 50%) 1, and long-term prognosis
depends on several factors including size, location, tumour extent, marrow involvement, presence and number
of metastases at diagnosis, and response to preoperative
chemotherapy 6.
References
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1979;61A:207-15.
3
Devaney K, Vinh TN, Sweet DE. Small cell osteosarcoma of
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2
Sim FH, Unni KK, Beabout JW, Dahlin DC. Osteosarcoma with
1
Conclusion
SCO is a distinct variant of osteosarcoma with unique
histological features. This tumour must be differentiated
from other small cell malignancies because of treatment
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pathologica 2009;101:105-107
Case
report
Extraventricular neurocytoma in a child mimicking
oligodendroglioma: a diagnostic pitfall
F. Limaiem*, S. Bellil*, I. Chelly*, A. Mekni*, K. Bellil*, H. Jemel**, S. Haouet*, M. Zitouna*, N. Kchir*
Departments of * Pathology and ** Neurosurgery, La Rabta Hospital, Bab Saâdoun, Tunis, Tunisia
Key words
Extraventricular • Neurocytoma • Oligodendroglioma • Central nervous system • Immunohistochemistry
Summary
Extraventricular neurocytomas are rare neuronal tumours that
have been included in the 2007 WHO classification as a variant
of central neurocytoma. They arise outside the ventricles, usually within the cerebral hemisphere,s but also in other regions
throughout the neuraxis. The morphological overlap of these tu-
mours with oligodendroglioma often poses diagnostic difficulty.
Herein, a case of extraventricular neurocytoma in a 4-year-old
girl is reported that mimicked histologically oligodendroglioma.
The authors describe the clinicopathological features of this rare
entity with special emphasis on differential diagnosis.
Introduction
Extraventricular neurocytomas (EVN) are rare neuronal
tumours recently included in the 2007 WHO classification as a variant of central neurocytoma 1. They arise
outside the ventricles, usually within the cerebral hemispheres, but also in other regions throughout the neuraxis.
When neurocytomas occur in the cerebral hemispheres,
where oligodendrogliomas are more common and better
recognized, diagnostic confusion often arises due to the
striking morphological overlap of both tumours. In this
paper, we report a new case of EVN located in the left
parieto-temporal lobe of a 4-year-old child that mimicked histologically oligodendroglioma. Our aim was to
describe the clinicopathological features of this rare entity
with special emphasis on differential diagnosis.
Clinical history
A 4-year-old, previously healthy girl, presented with a
one-month history of headache, vomiting and progressive onset of weakness on the right side of her body.
On admission, the child was alert and oriented, with
normal speech. Neurological examination revealed right
hemiparesis with hyperactive reflexes on the right ankle
and a negative Babinski response. Pupils were reactive
to light and there were no cranial nerve deficits. CT
scan showed a hyperdense calcified lesion located in
the left parieto-temporal lobe with peri-lesional oedema,
Fig. 1. CT scan demonstrating a hyperdense calcified
lesion located in the left
parieto-temporal lobe with
central hypodense zones
consistent with cystic change, perilesional oedema and
significant mass effect on
median structures.
significant mass effect on midline structures and central
hypodense zones consistent with cystic change (Fig. 1).
The lesion did not enhance after contrast medium injection. Subtotal excision of the tumour was achieved. At
surgery, the tumour was clearly demarcated from the
surrounding brain parenchyma, had a soft consistency
and bled moderately. Histological examination of the
surgical specimen revealed a proliferation of cells with
large, clear cytoplasm and a round or ovoid nucleus
embedded in a neuropil-like background (Fig. 2). Some
areas showed greater cellularity with limited intervening matrix. Vascularization was rich and there was no
evidence of necrosis, haemorrhage, or endothelial proliferation. Mitotic figures were rare. Based on cytologic
Correspondence
Faten Limaiem, Department of Pathology, La Rabta Hospital, Bab
Saadoun (1007) Tunis, Tunisia - Tel. +216 96 55 20 57 - E-mail:
[email protected]
106
Fig. 2. Proliferation of small round monotonous cells arranged
against a neuropil-like background (haematoxylin & eosin, original magnification x100).
F. LIMAIEM et al.
additional elements. At present, the child is still on follow-up and has shown no evidence of recurrence.
Discussion
and morphological features, a differential diagnosis
including oligodendroglioma and neurocytoma was
considered. Immunohistochemical staining for synaptophysin was diffuse and highlighted the neuropil matrix
surrounding tumor cells (Fig. 3). Rare tumour cells
showed weak reactivity for glial fibrillary acidic protein.
Labeling with Ki-67 (MIB-1) yielded a tumour cell proliferation index as high as 1%. Given these morphological and immunophenotypic features, a diagnosis of extraventricular neurocytoma was rendered. No adjuvant
radiation therapy was administered post-operatively. At
the last routine follow-up visit (1 year post-operatively),
the patient complained of recurrent headaches. CT scan
demonstrated tumour recurrence and the patient underwent further tumour resection. Histological examination
of the surgical specimen showed no features suggesting
that the tumour had undergone progression or contained
Fig. 3a. Tumour cells had regular round or oval nuclei and a clear
cytoplasm. (haematoxylin & eosin, original magnification x400).
Fig. 3b. Tumour cells demonstrating synaptophysin immunoreactivity (Immunohistochemistry, original magnification x400).
Neurocytomas are rare tumours of the central nervous system constituting approximately 0.25-0.5% of
all intracranial tumours 1 2. The definition of “central
neurocytoma” is restricted to neoplasms located within
the ventricles, whereas the term “extraventricular neurocytoma” is used for neurocytomas arising at other sites
such as the cerebral hemispheres, thalamus, amygdala,
pineal gland, retina, skull base, cerebellum, pons, spinal
cord and cauda equine. To our knowledge, about 60 cases
of EVN have been reported in the literature to date, with
the frontal and parietal lobes being the most commonly
affected sites 2 3. Neurocytomas, either at ventricular or
extraventricular locations, commonly affect young adults
with no gender predilection 4. Our patient was a 4-yearold female child. Patients with EVNs usually present with
seizure or hemiparesis 4. In the presented case, the chief
complaints were right hemiparesis, headache and vomiting. On CT scan, cerebral neurocytomas have been described as hypodense or isodense relative to grey matter,
and as for intraventricular neurocytomas, coarse or punctate calcification is common 5 6. In the present case, CT
scan showed a spontaneously hyperdense, calcified lesion
located in the left parieto-temporal lobe with hypodense
zones consistent with cystic change. The radiological
finding is somewhat different from those described to
date. On MR images, cerebral neurocytomas appear hypointense on T1-weighted sequences and hyperintense on
T2-weighted studies. Contrast enhancement is mild and
occasionally rim-like 6. Extraventricular neurocytomas
often pose a diagnostic challenge because of overlap of
clinical, radiologic and histological features with those
of other primary brain tumours, particularly oligodendroglioma. Although pediatric oligodendrogliomas are rare,
they must be differentiated from neurocytic tumours. One
critical distinction between oligodendroglioma and EVN
lies in their respective interactions with adjacent brain.
Whereas oligodendroglioma is diffusely infiltrative, EVN
appear rather circumscribed 2 7. Histologically, EVNs
demonstrate pushing borders with respect to surrounding
brain. While the presence of infiltrated CNS axons can
be demonstrated in oligodendroglioma by neurofilament
immunohistochemistry, this is less evident in EVN 8. The
aforementioned properties are particularly significant because the cytological features of oligodendroglioma and
neurocytoma overlap and cannot always be relied upon
for distinction. Both EVN and oligodendrogliomas predominantly contain a clear cell population of well-differentiated cells with round, regular nuclei. Neither contains
the course fibrillarity of astrocytic differentiation, but
EVN often show a delicate neuropil background. Ganglionic differentiation, if present, strongly favors EVN 1.
EVNs are strongly positive for neuronal markers, such
as synaptophysin, and show only focal staining for glial
107
extraventricular neurocytoma
fibrillary acid protein (GFAP). Neuronal differentiation
is necessary, but not sufficient for the diagnosis of EVN,
since oligodendrogliomas, surprisingly, can also show
some neuronal differentiation by immunohistochemistry
and ultrastructural studies 9 10. The morphological overlap
between EVN and oligodendroglioma, the lack of specific oligodendroglial markers, and the co-expression of
neuronal markers in EVN and oligodendroglioma have all
provided evidence that oligodendroglial and neurocytic
lesions may form a biological and diagnostic spectrum 8.
The ends of the spectrum are anchored by classical oligodendroglioma and EVN, but rare tumours with intermediate or biphasic differentiation would be expected 8.
Recent investigations have attempted to provide genetic
markers that can distinguish classic EVN from oligodendroglioma 11. An obvious place is the status of chromosome 1p and 19q, since their combined loss is frequent in
a large subset of oligodendrogliomas and has been shown
to be prognostically significant. A recent fluorescence in
situ hybridization (FISH) analysis of oligodendroglioma
and its mimic found that 70% of oligodendrogliomas
showed losses of 1p and 19q 8. Unexpectedly, infrequent
losses of 1p and 19q (16%) were also seen in EVN, further clouding the distinction between EVN and oligodendroglioma. On the other hand, Kreiger et al reported that
paediatric oligodendrogliomas rarely demonstrate losses
of 1p and 19q, suggesting that they have a distinct molecular pathogenesis. These findings argue that 1p and
19q loss cannot be used as a molecular diagnostic marker
for oligodendrogliomas in children, and raise the challenge of identifying other genetic alterations that might
characterize these tumours 12. Like central neurocytoma,
most EVNs do not recur, especially after complete resection. Subtotal resection, high proliferation rates, atypical
histological features and older patient age appear to be
associated with an increased likelihood of recurrence 2.
Our patient developed tumour recurrence due to subtotal
excision of the primary tumour.
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