Table Of ContentSELECTED TOPICS IN CLINICAL ONCOLOGY
SELECTED TOPICS
IN CLINIC AL ONCOLOGY
An in-depth Study of 18 Cancers
Usually Neglected in Classical Textbooks
by
J.M. Debois
SPRINGER SCIENCE+BUSINESS MEDIA, B.V.
Library of Congress Cataloging-in-Publication Data
ISBN 978-94-010-5797-4 ISBN 978-94-011-4100-0 (eBook)
DOI 10.1007/978-94-011-4100-0
Printed an acid-free paper
AII Rights Reserved
© 2000 Springer Science+Business Media Dordrecht
Originally published by Kluwer Academic Publishers in 2000
Softcovcr rcprint of the hardcovcr 1s t cdition 2000
No part of the material protected by this copyright notice may be reproduced or
utilized in any form or by any means, electronic or mechanical,
including photocopying, record ing or by any information storage and
retrieval system, without written permission from the copyright owner.
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FOREWORD
By Prof.Dr.A.T.Van Oosterom
Head of the Department of Oncology at
the Catholic University of Leuven, Belgium
The word cancer defines over 180 different diseases. Some occurring quite often
and are well known, others are very rare and sometimes so unknown that the
diagnosis is not even suspected at operation.
In this book, Dr.Debois, a retired radiation oncologist, describes a selected group
of cancer types, some of which are difficult to find in the standard textbooks, in a
logical format starting with their bibliography, history, incidence, anatomy,
clinical presentation, diagnosis and staging, treatment and follow-up.
For the general oncologist in the community it gives the appropriate data to
understand the described diseases and to familiarize him with the peculiar patient
he has identified. The many tables and figures in every chapter contain an
enormous amount of data difficult to collect without extensive searches. The mix
of historical and new (genetic) data makes reading attractive.
In my opinion this book will find his place in the library of every oncologist who
wants to know more about the rarer tumors he or she encounters.
We know a lot about the common tumors but too little about the diseases
described here.
Dr.Debois has to be congratulated and thanked for his zeal to collect all the data
and to share them with us.
TABLE OF CONTENTS
SCOPE OF THE WORK xi
Chapter 1 Carcinoma of the Parathyroid 1
Chapter 2 Paraganglioma (Glomus Tumors) 11
Chapter 3 Thymoma and Thymic Carcinoma 37
Chapter 4 Endocrine Tumors of the GIT 65
Chapter 5 Carcinoids 121
Chapter 6 Primary Tumors of the Heart 184
Chapter 7 Tumors of the Adrenal Cortex 214
Chapter 8 Pheochromocytoma 241
Chapter 9 Carcinoma of the Fallopian Tube 281
Chapter 10 Gestational Trophoblastic Diseases 295
Chapter 11 Cancer of the Salivary Gland 345
Chapter 12 Hepatocellular Carcinoma 392
Chapter 13 Cancer of the Gallbladder 476
Chapter 14 Cancer of the Extrahepatic Bile Duct 503
Chapter 15 Cancer of the Small Intestine 527
Chapter 16 Malignant Tumors of the Appendix 547
Chapter 17 Malignant Tumors of the Cecum 555
Chapter 18 Malignant Tumors of the Anus 562
Illustration credits 587
Index 591
Experience is not what happens to a man; it is what a man does with
what happens to him (Aldous Huxley)
What is experience to an expert?
An expert is a man who has made all mistakes which can be made in
a very narrow field (Niels Bohr)
SCOPE of the WORK tumors are discussed only over a few paragraphs.
So the plan grew up to bring this together in a book
where the so-called 'neglected' tumors would be discus
~alignant tumors, commonly entitled or named cancer, is
sed to in depth. I brought together the vast literature that
thought by the public to be only one fearfull disease. The
has been accumulated over the last decades concerning
name cancer is however a collection name for about 250
eigthteen different tumors. The reader will remark, as the
distinct diseases, while each can be divided in 4 stages,
alert clinician already knows, the extreme variability of the
resulting in 'thousand' different clinical situations. They
presenting symptoms of these tumors. The commonplace
all require a unique approach and each patient requires an
of the tumors discussed on this work is the fact that they
individualized treatment.
mainly present with symptoms at first not referrable to the
Malignant tumors can manifest themselves in all organs
site of the tumor, so that really masquerades at the largest
or systems within the body. Epidemiologic and statistical
diversity present even for the same type of tumor. Several
studies have convincely demonstrated that, peculiarly, not
are very small but nevertheless can result in life
all organs are even frequently concerned.
threatening situations. Some present with 'abscopal'
There are many excellent textbooks on General Oncology.
symptoms, completely different with the site of the
The volume however of the scientific and clinical know
concerned primary, making the diagnosis sometimes very
ledge on Oncology is tremendous. It encompass patho
difficult. These masquerades make the study of these
logy of the cell, medical aspects, imaging and diagnosis,
tumors very interesting and demonstrate the multifaceted
surgical and radiotherapy techniques and many other
aspect of oncology in daily practice once again. Other
aspects as well, but also the pathology of every organ and
tumors have a double clinical presentation, either by their
organ system, so that this 'knowledge' must be mastered
remote 'hormonal' symptoms or by their local growth, or
and squeezed in an acceptable number of pages. Never
theless the textbooks as anyone will have observed have even both.
be.en growing up to several thousands pages. Even when
Anyone who has compiled literature data will have
pnnted on fine (thin) paper, the volume of the book is
remarked the strong heterogenity in the reporting of the
rather large and becomes heavy and cumbersome. The
tumors that are much less frequent will then occupy only different aspect of a tumor, so as for symptoms, laboratory
a small place in it. Nevertheless some of these tumors are data and treatment results. It is however not uncommon
sometimes even more dreathfull and dangerous if that data are reported many times in a rather abridged
diagnosis is postponed. manner, lessening considerably the documentary nature of
the publication. Overall we have tried to bring together as
much as relevant data in table or figure form, but are
The result is that several unusual or rare tumors are only
succinctly adressed and discussed in these books. When I conscious that we are not complete. We have redrawn
consulted such encyclopedial works to document cases I most of the survival and other curves to one standard
was disenchanted with the few paragraphs alloted ;0. layout in order to bring some uniformity in the
Consulting the vast periodical literature, one is then presentation. The follow-up of the literature was closed
confronted with a mass of extensive publications and data half september 1999
diluted in almost all the different disciplines and subdis~
cipline$ of medicine. We .tried to follow the same pattern within each chapter,
The subject brought has to be differentiated from what can but In some we had to modify the order to enhance under
be called rare or uncommon tumors, as ri. osteosarcoma standiblity.
of the larynx or a sarcoma of the esophagus. This should The book should then be considered as a addendum to the
be another task, but has in fact already been fulfilled in the classical textbooks.
Textbook of Uncommon Cancer': Ed.Williams C.1. et
al. 1988), of whom recently an updated edition appeared DrJ.M.Debois
(Raghavan et al.1999). But even in this book some Radiotherapist Oncologist (retired)
1
CARCINOMA of the PARATHYROID
mes to lie largely in the thorax. The parathyroid III
Anatomy-Structure
attached to it develops then more in a caudad po
sition, while parathyroid IV acquires its adult posi
1849 Discovery of gland by sir Richard Owen tion as the upper gland, near the intersection of the
1880 First full description by I.Sandstrom
recurrent laryngeal nerve and the medial thyroid artery.
This parathyroid IV, the superior one, has a more
The parathyroid glands arise as diverticula of the en constant location than III, this last one having a
doderm of the third and fourth branchial pouches. longer migration in embryonic life (Abu-Jawdeh et
They appear during the fifth week of gestation as bila a\.).
teral localize proliferations along the anterior-dorsal In about 95% of the patients there are four parathyroid
surface of pouch III and the lateral extremity of pouch glands as described above. The number varies how
IV. ever between 2 and twelve glands, so the incidence of
The inferior gland, referred as parathyroid III, along supernumerary glands in adults varies from 2 to 6.5%.
with the thymus, forms as the third pouch separates These supernumerary glands are most commonly
from the pharynx. At this stage parathyroid III lies intrathymic and are thought to result from embryonic
cephalad and lateral to parathyroid IV and the two are division. Some surgeons found indeed an extra num
separated by the medial thyroid. As the thymus grows ber in about 5% of their patients (Hooghe et a\.).
faster and becomes attached to the pericardium it co-
Thyroglossal cyst G-
Accessory
.. Ihymic
Foramen cecum ~~ tissue
I
I
Pyromidal lobe --'4"'----::-H'f..'
of thyroid
Persistent
larynx card of
thymic tissue
Parathyroid glands
Manubrium
of sternum
Thymus (pouch 31
Fig. 1. I -Left: the embryonic pathway of primordia of glands derived from the pharyngeal pouches. The parathyroid
glands descend normally to the level of the thyroid gland. Right: locations where abnormally positioned pharyngeal
glands, esp. the parathyroids can be found, e.g. high in the neck or in the anterior mediastinum. (Carlson, with
permission)
2 CHAPTER I
Parathyroid gland IV lies in 77% at the cricothyroid This is a rare hereditary disorder. It presents with
junction posteriorly, in 22% behind the upper pole of hypercalcemia earlier than MEN-I patients. Incidence
the thyroid, even often within the surgical capsule of of carcinoma is about 15 % (Yoshimoto et al.)
the thyroid. Other uncommon locations are a more -- in patients on chronic renal dialysis
Remarkable in this rare situation is that hypercalcemia
caudal position by the inferior thyroid artery, a retro
is almost never encountered. This is most preponderate
pharyngeal or retro-esophageal position or rarely
in female patients. The prognosis appears to be better
within the thyroid parenchyma. The gland III have a
than for sporadic cases. (Review by Miki et al.)
more variable distribution, but are most commonly
-- within some glands with adenoma or hyperplasia
(42 to 61%) located between the lower pole of the
--after irradiation of the head and neck (Cohen et al.).
thyroid and the thymus. In a prospective study in a cohort of 4300 children
They can however occur as high as the hyoid bone or having received irradiation for tonsillitis before the age
as low as the pericardium. Another not so uncommon of 16, they found a 2.9-fold increase in the incidence of
location is the thymic tongue or cervical extension of BPT. Even 30% of the patients with BPT developed
the thymus. Uncommon locations are the anterior me also thyroid cancer.
diastinum or the mediastinal thymus.
Each gland measures 3 to 6mm in length, 2 to 4 mm It should be stressed that these instances account only
in width and 0.5 to 2.0mm in thickness. Its shape for a very small part of the parathyroid carcinomas.
varies but is oval, bean shaped or spherical in 83% of
the cases. They can show a more elongated form in Cytogenetics
about 11%. (Akerstrom).
The upper or superior pair is supplied by the inferior Inactivation of the Retinoblastoma Gene is common
thyroid artery or rarely by the superior artery, while in parathyroid carcinoma and is likely to be an im
the inferior pair is supplied by the inferior artery. portant contributor to its molecular pathogenesis
The normal parathyroid gland contains stromal fat (Crynn et a1.). This has been confirmed by Dotzenrath
cells, fibroblasts, capillaries and collagen and paren et a!. who stated that RB or 13q loss is specific for
chymal cells. The parenchymal cells are separated each parathyroid tumors with increased aggressiveness and
from the stroma by a prominent basement membrane, might be of clinical significance. In parathyroid ade
are arranged in irregular sheets. In children there is nomas there is probably an inversion between the
only one type of cell present, the chief cell. In the short and long arms of chromosome II, leading to the
adult the parenchymal cells are arranged in solid nests, juxtaposition of the parathyroid hormone regulatory
rounded or lobulated masses and trabeculae or both. element and the PRAD 1 putative oncogene, resulting
The follicle formation in the parathyroid is the result in dramatic PRADI overexpression (Solomon). Fur
of proliferation. ther studies led Cryns et a!. to the conclusion that p53
Aditionally to the chief cell in its active and inactive allelic loss and abnormal p53 protein expression in
forms, there are oxyphil or clear cells. The chief cell is parathyroid carcinoma should implicate p53 in the
the basic functional unit and is responsible for the pathogenesis of at least a subset of these tumors.
production and secretion of PTH and in tum for the Nevertheless Hakim et al. remarked that p53 point
maintenance of the homeostasis of ionized calcium in mutations do not appear to be a primary event res
the serum. ponsible for neoplastic growth in parathyroid tissue.
The oxyphil cell is felt to be derived from the chief
cell. They are distributed among the chief cells as Incidence
individual cells, sheets and small or large nodules. So
there is probably a continual transformation from the Parathyroid carcinoma is a rare disease.
chief cells and clonal proliferation of the oxyphil cells. Due to the increased use of multichannel analyser,
many more patients with hypercalcemia are detected.
Parathyroid carcinoma is however rarely asymptomatic
The definition of normal parathyroid weight is much
or discovered by routine serum calcium determination.
debated. The total weight ranges from 3 to 78 mg
Previously the incidence was reported varying between
with a mean of 35-40mg. It was less than 50mg in
0.1% to 5% of the patients with hyperparathyroidism
99% of autopsy cases. According to Akerstrom et al.
(HPT). The incidence is probably at the lowest value,
the parenchymal weight is 74% of the total weight.
I to 2%, as their has not been an elevation of carci
noma patients compared with the higher number of
Etiology
HPT in the last decades.
Of309 patients operated for hyperparathyroidism, only
The etiology of parathyroid carcinoma is unknown, as
16 cases of carcinoma were detected or 5.2% (Favia et
risk factors have not been found.
a!.).
It is recognized however that parathyroid carcinoma
According to' the SEER data (Correa), there were
can occur
between 1973 and 1987 15. 186 cases of cancers of the
- in Multiple Endocrine Neoplasia I (MEN I).
endocrine glands. Of these 0.4% or 65 cases were
The incidence of parathyroid carcinoma is only 1%.
parathyroid carcinoma.
---in families with hyperparathyroidism (HPT)
A very low number of non-functioning parathyroid
(Kassem et al.)
CARCINOMA of the PARATHYROID 3
carcinoma s have been reported. splitting the parenchyma in a nodular fashion
(Bondeson).
Patient characteristics Half or more of the cancers consist almost entirely of
chief cells, whereas oxyphil cells predominated in
Compared with HPT where there is a l~rge majorit~, only II %. About 20% have a mixture of both ele
up to two or three times, of female patients, th~re IS ments. The malignant tumor is usually widely inva
almost no difference between genders, or only slightly sive, with cells arranged intrabeculae, lobes or in
in favor of women. sheets.
Suggestive features for diagnosis on histology were
40 proposed by Schantz & Castleman:
1. The tumor is adherent to surrounding structures of
the neck and cannot easily be enucleated;
2. The tumor is clinically palpable;
30
3. The gland has a thick capsule with bands offi-
brous trabeculae coursing through the tumor;
4. Invasion of tumor through the capsule;
20 5. Invasion of venous blood vessels;
6. The presence of mitoses.
10 No one single factor may be entirely reliable however.
Suspicion for malignancy increases with the number of
criteria. There is ample discussion in the literature
........ concerning the impact of the number of mitosis and of
o~- the other factors.
-10 -20 -30 -40 -50 -60 -70 -80 -90
After a carefull review of 95 cases collected from 37
hospitals, Bondeson et al. could distinguish two tu
Fig.1.2 - Age distribution of 108 patients. (drawn
mor categories:
from literature data ofMurie 1973)
1. A carcinoma demonstrating extraglandular invasi
veness or tumor recurrence, to be classified as
Reviewing I 08 patients, Murie clearly outlined that
definitive carcinomas (56/95 or 59%), and
the main age group of the patients with parathyroid
2. Tumors lacking these criteria and classified as
carcinoma are between 20 and 60 years (Fig. 1.2).
equivocal cases. .
Patients are usualy in the fourth and fifth decade, while
The classic triad macronucleoli, more than five mi
adenoma patients are generally 10 to 20 years older
tosis per 50 hpf and necrosis were associated with ~n
and mostly female (Palnaes-Hansen et aL). Only 5
aggressive behavior andlor recurrence ..S ~me fi?roSIS,
cases have been reported in children, all between 13
necrosis and mitotic activity were of limited diagno
and 16yrs (Meier et al.).
stic significance.
Fibrosis, necrosis, nuclear atypia (especially macro
Pathology Histology nuclei), and mitotic figures were significantly more
frequent in the carcinoma group. These showed also a
positive correlation with aberrant DNA
MACROSCOPY
In patients with a demonstrated cancer, DNA flow
Most are firm or hard tumors with adherence to the
cytometry may help to differentiate the patients who
surrounding tissue because of fibrosis or even infil
are likely to behave indolently (diploid tumors) from
tration. The tumor itself is often irregularly delineated,
those (aneuploid) more likely to behave aggressively
with a grayish or white tone. There are however also
by recurring locally or even metastasize (Obara et al. -
tumor that are encapsulated and with more yelow or
August et al.).
pink color, making a distinction from adenoma diffi
Immunocytochemistry to identity parathyroid tissue,
cult (Grimelius). Intra-operative diagnosis is simpli
proliferation markers and monoclo.nal ant~-par~thyro~d
fied when gross muscle invasion is seen. A number of
antibodies can be helpful in the differential diagnOSIs
macroscopic features suggest malignancy as hard con
(Grimelius) .
sistency, a thick fibrous capsule, gray-white color or
The microscopic features of non-functioning para
adherence of the parathyroid gland to adjacent
thyroid carcinoma are identical to those of the func
structures.
tioning carcinoma (Aldinger et al.).
Recently Vargas et al. have reported that the deter
MICROSCOPY
mination of the 'mean tumor proliferation fraction',
A parathyroid carcinoma presents mostly as a ma
could be useful in the diagnosis of malignity, as it
lignant tumor with a solid growth pattern, with cells
strongly correlates: a value above 40 was positive in
arranged in diffuse masses or closely packed nests.
carcinoma in 9111 or 82%.
About 20% should occur with a focally trabecular
pattern. A large majority (80%) shows areas of fibrosis
