World Health Organization

The series International Histological Classification of Tumours consists of the following

volumes. Each of these volumes - apart from volumes 1 and 2, which have already
been revised - will appear in a revised edition within the next few years. Volumes of
the current editions can be ordered through WHO, Distribution and Sales, Avenue
Appia, CH-1211 Geneva 27.
1. Histological typing of lung tumours (1967, second edition 1981)
2. Histological typing of breast tumours (1968, second edition 1981)
3. Histological typing of soft tissue tumours (1969)
4. Histological typing of oral and oropharyngeal tumours (1971)
5. Histological typing of odontogenic tumours, jaw cysts, and allied lesions (1971)
6. Histological typing of bone tumours (1972)
7. Histological typing of salivary gland tumours (1972)
8. Cytology of the female genital tract (1973)
9. Histological typing of ovarian tumours (1973)
10. Histological typing of urinary bladder tumours (1973)
12. Histological typing of skin tumours (1974)
13. Histological typing of female genital tract tumours (1975)
14. Histological and cytological typing of neoplastic diseases of haematopoietic and
lymphoid tissues (1976)
16. Histological typing of testis tumours (1977)
17. Cytology of non-gynaecological sites (1977)
19. Histological typing of upper respiratory tract tumours (1978)
20. Histological typing of tumours of the liver, biliary tract and pancreas (1978)
21. Histological typing of tumours of the central nervous system (1979)
22. Histological typing of prostate tumours (1980)
23. Histological typing of endocrine tumours (1980)
24. Histological typing of tumours of the eye and its adnexa (1980)
25. Histological typing of kidney tumours (1981)
A coded compendium of the International Histological Classification of Tumours
(1978).

The following volumes have already appeared in a revised edition with Springer- Verlag:
Histological Typing of Thyroid Tumours, 2nd edn. Hedinger/Williams/Sobin (1988)
Histological Typing of Intestinal Tumours, 2nd edn. lass/Sobin (1989)
Histological Typing of Oesophageal and Gastric Tumours, 2nd edn. Watanabe/lass/
Sobin (1990)
Histological Typing of Tumours of the Gallbladder and Extrahepatic Bile Ducts, 2nd edn.
Albores-Saavedra/Henson/Sobin (1991)

In this series, colour illustrations will be limited in number in order to maintain a rea-
sonable sales price.

A set of 80 colour slides (35 mm), corresponding to the photomicrographs in the book,
is available from the American Registry of Pathology, 14th Street and Alaska Ave. NW,
Washington, DC 20306, USA. For further information please see p. 77.
Histological Typing
of Tumours of the Gallbladder
and Extrahepatic Bile Ducts
1.Albores-Saavedra, D.E. Henson,
and L.H. Sobin
In Collaboration with Pathologists in 5 Countries

Second Edition

With 80 Figures

Springer-Verlag
Berlin Heidelberg New York
London Paris Tokyo
Hong Kong Barcelona
J. Albores-Saavedra
Department of Pathology, University of Miami School of Medicine
Miami, Florida, USA
Present address: Department of Pathology, University of Texas
Southwestern Medical Center, DaIIas, Texas, USA

D. E. Henson
Division of Cancer Prevention and Control
National Cancer Institute, Bethesda, Maryland, USA

L. H.Sobin
Department of Gastrointestinal Pathology
and WHO CoIIaborating Centre
for the International Histological Classification of Tumours
Armed Forces Institute of Pathology, Washington, DC, USA

First edition published by WHO in 1978 in No. 20 in the International Histological Classification of Tumours series

ISBN·13: 978·3·540·52838·8 e·ISBN·13: 978·3·642·84241·2

001: 10.1007/978·3·642·84241·2

Library of Congress Cataloging·in·Publication Data:

Albores·Saavedra, Jorge. Histological typing of tumours of the gallbladder and extrahepatic bile ducts 1 J. Albores·
Saavedra, D. E. Henson, and L. H. Sobin; in collaboration with pathologists in 5 countries. - 2nd ed. p. em. - (In-
ternational histological classification of tumours) Rev. ed. of: Histological typing of tumours of the liver, biliary
tract, and pancreas 1 J. B. Gibson, in collaboration with L. n. Sobin and pathologists in 13 countries. 1978. Includes
index.
ISBN-13: 978-3-540-52838-8
1. Gallbladder - Tumors - Classification. I. Henson, Donald EarL II. Sobin, L. H. III. Gibson, J. B. (James
Blackburn) Histological typing of the liver, biliary tract, and pancreas. IV. Title.
[DNLM: W1 IN764G 1 WI 15 A339h] [RC258.145] [RC280.G3] 616.99'207583 s - dc20 [616.99'23607583]
DNLM/DLC for Library of Congress 90-10361 CIP

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Participants

Albores-Saavedra, J., Dr.

Department of Pathology, University of Miami School of Medicine,
Miami, Florida, USA

Angeles-Angeles, A., Dr.

Departamento de Patologia, Instituto Nacional de la Nutrici6n "Sal-
vador Zubiran", Mexico, D. F.

Enjoji, M., Dr.

Second Department of Pathology, Faculty of Medicine, Kyushu Uni-
versity, Fukuoka, Japan

Henson, D. E., Dr.

Division of Cancer Prevention and Control, National Cancer Insti-
tute, Bethesda, Maryland, USA

Laitio, M., Dr.

Department of Pathology, Central Hospital, Seinojoki, Finland

Sobin, L. H., Dr.

Department of Gastrointestinal Pathology, Armed Forces Institute of
Pathology, Washington, DC, USA (WHO Collaborating Centre for
the International Histological Classification of Tumours)

Urban, A., Dr.

Zmiany Patom orfologiczne, W Pecherzyku Zolciowym, Z Zakldadu
Patomorfologii Instytutu, Patologii AM w Krakowie, Poland

Weedon, D., Dr.

Brisbane, Australia
General Preface to the Series

Among the prerequisites for comparative studies of cancer are inter-

national agreement on histological criteria for the definition and clas-
sification of cancer types and a standardized nomenclature. An inter-
nationally agreed classification of tumours, acceptable alike to
physicians, surgeons, radiologists, pathologists and statisticians,
would enable cancer workers in all parts of the world to compare
their findings and would facilitate collaboration among them.
In a report published in 1952,1 a subcommittee of the World
Health Organization (WHO) Expert Committee on Health Statistics
discussed the general principles that should govern the statistical clas-
sification of tumours and agreed that, to ensure the necessary flexibil-
ity and ease of coding, three separate classifications were needed ac-
cording to (1) anatomical site, (2) histological type, and (3) degree of
malignancy. A classification according to anatomical site is available
in the International Classification of Diseases. 2
In 1956, the WHO Executive Board passed a resolution 3 request-
ing the Director-General to explore the possibility that WHO might
organize centres in various parts of the world and arrange for the col-
lection of human tissues and their histological classification. The
main purpose of such centres would be to develop histological defini-
tions of cancer types and to facilitate the wide adoption of a uniform
nomenclature. The resolution was endorsed by the Tenth World
Health Assembly in May 1957.4
Since 1958, WHO has established a number of centres concerned
with this subject. The result of this endeavour has been the Interna-
tional Histological Classification of Tumours, a multivolumed series

1 WHO (1952) WHO Technical Report Series. No. 53,1952, P 45

2 WHO (1977) Manual of the international statistical classification of diseases, in-
juries, and causes of death. 1975 version. Geneva
3 WHO (1956) WHO Official Records. No. 68, p 14 (resolution EB 17.R40)
4 WHO (1957) WHO Official Records. No. 79, p 467 (resolution WHA 10.18)
VIII General Preface to the Series

whose first edition was published between 1967 and 1981. The pre-
sent revised second edition aims to update the classification, re-
flecting progress in diagnosis and the relevance of tumour types to
clinical and epidemiological features.
Preface to Histological Typing of Tumours
of the Gallbladder and Extrahepatic Bile Ducts,
Second Edition

This is a revision of the WHO classification published in 1978 1. In or-

der to keep the classification up to date, revision proposals were cir-
culated to the participants listed on page V. Their responses were dis-
cussed at a meeting in 1989, at which time a new draft was
elaborated. After further communication among the participants, the
present classification, definitions and explanatory notes were recom-
mended for publication.
The histological classification of tumours of the gallbladder and
extrahepatic bile ducts, which appears on pages 5 and 6, contains the
morphology code numbers of the International Classification of Dis-
eases for Oncology (lCD-Of and the Systematized Nomenclature of
Medicine (SNOMEDf
It will, of course, be appreciated that the classification reflects the
present stage of knowledge, and modifications are almost certain to
be needed as experience accumulates. Although the present classifi-
cation has been adopted by the members of the group, it necessarily
represents a view from which some pathologists may wish to dissent.
It is nevertheless hoped that, in the interests of international coop-
eration, all pathologists will use the classification as put forward.
Criticism and suggestions for its improvement will be welcomed;
these should be sent to the World Health Organization, Geneva, Swit-
zerland.

1 Gibson lB, Sobin LH (1978) Histological Typing of Tumours of the Liver, Bil-
iary Tract and Pancreas. Geneva. World Health Organization (International
Histological Classification of Tumours, No. 20)
2 World Health Organization (1990) International Classification of Diseases for
Oncology. Geneva
3 College of American Pathologists (1982) Systematized Nomenclature of Medi-
cine. Chicago
X Preface to Histological Typing of Tumours of the Gallbladder

The publications in the series International Histological Classifi-

cation of Tumours are not intended to serve as textbooks but rather to
promote the adoption of a uniform terminology that will facilitate
communication among cancer workers. For this reason the literature
references have intentionally been omitted, and readers should refer
to standard works for bibliographies.
Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1

Histological Classification of Tumours of the Gallbladder and

Extrahepatic Bile Ducts . . . . . . . . . . . . . . . . . . . . . . 5

Definitions and Explanatory Notes . 7

Epithelial Tumours . . . 7
Endocrine Tumours . . . 13
Non-epithelial Tumours 14
Miscellaneous Tumours 16
Tumour-like Lesions " 17

TNM Classification of Tumours of the Gallbladder

and Extrahepatic Bile Ducts 23

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Introduction

This is a classification of tumours and tumour-like lesions of the gall-

bladder and extrahepatic bile ducts, including the ampulla of Vater.
Although most of the lesions are found in all three sites, variations in
frequency of the histological types occur and will be noted.
The incidence of carcinoma of the gallbladder varies in different
parts of the world. Variation is also found in different ethnic groups
within the same country. In the United States, for example, carcino-
ma of the gallbladder is more common in American Indians than in
Caucasians or in Blacks; the rate among female American Indians is
21 per 100000 compared with 1.4 per 100000 among Caucasian fe-
males. In Latin American countries, the highest rates are found in
Chile, Mexico and Bolivia. In other countries, such as Japan, the inci-
dence rates are intermediate between those of American Indians and
those of Caucasians.
Despite certain features in common, carcinomas of the gallblad-
der and carcinomas of the extrahepatic bile ducts show a number of
differences. Gallbladder carcinomas are usually associated with
cholelithiasis and have a strong female predominance. In contrast,
extrahepatic bile duct carcinomas are seen less often, occur in both
sexes with equal frequency, are usually not associated with choledo-
cholithiasis, produce early biliary obstruction, and are better differen-
tiated histologically as a group. Moreover, they are seen in patients
with primary sclerosing cholangitis and ulcerative colitis.
The classification is based primarily on the microscopic character-
istics of tumours. It is therefore concerned with the identification of
cell types and histological patterns as seen by conventional light mi-
croscopy. Immunocytochemistry can play an important adjunctive
role in the identification of certain lesions. When appropriate, we
have included such information. In general, traditional terms have
been retained. Synonyms are listed only if they are widely used or if
they are considered to be important for understanding the disease
process. In such cases, the preferred term is listed first, followed by
the synonym in parentheses.
2 Introduction

Histological Typing

Typing divides tumours according to their direction of differentiation.

Although typing may frequently indicate the underlying histogenesis,
it may be difficult or impossible to identify the cell of origin. Note is
taken of the structure and function of cell types as well as overall
growth patterns with the aim of comparing these features to those of
the corresponding normal tissue.

Histological Grading

Histological grading of tumours provides some indication of their ag-

gressiveness, which may relate to prognosis or treatment. In grading,
the cytological and architectural features are compared to the pre-
sumed tissue of origin. Cellular anaplasia, nuclear pleomorphism,
and mitotic activity are the most important parameters. Three catego-
ries are defined:

1. Well differentiated
2. Moderately differentiated
3. Poorly differentiated

When a tumour shows different grades of differentiation, the less dif-

ferentiated areas should determine the final categorization.

Staging

The prognosis of tumours of the extrahepatic biliary tract depends

primarily on the extent of disease. For example, tumours that only
extend into the lamina propria have a much better prognosis than
those that infiltrate the serosa or invade the liver. The TNM system,l, 2
which appears on pages 23-28, provides a uniform classification for

1 Hermanek P, Sobin LH (eds) (1987) TNM Classification of Malignant Tumours,

4th edn. International Union Against Cancer. Springer-Verlag, Berlin Heidelberg
New York
2 Beahrs 0, Henson DE, Hutter RVP, Myers M (eds) (1988) Manual for Staging
of Cancer, 3rd edn. Lippincott, Philadelphia
 Fixation 3

the extent of disease. In cholecystectomy specimens and surgical re-

sections of extrahepatic bile duct tumours pathological staging
should be included in the pathologist's report.

Fixation

Because of the susceptibility of the biliary mucosa to autolysis from

the action of bile, prompt fixation without prior washing is necessary
for optimal histological sections. This is especially important for the
assessment of dysplasia, carcinoma in situ and the grossly inapparent
carcinomas.
Histological Classification of Tumours
of the Ga"bladder and Extrahepatic Bile Ducts

1 Epithelial Tumours
1.1 Benign
1.1.1 Adenoma 814010 a
1.1.1.1 Tubular 8211/0
1.1.1.2 Papillary 826010
1.1.1.3 Tubulopapillary 8263/0
1.1.2 Cystadenoma 844010
1.1.3 Papillomatosis (adenomatosis) 806010
1.2 Dysplasia 74000
1.3 Malignant
1.3.1 Carcinoma in situ 814012
1.3.2 Adenocarcinoma 8140/3
1.3.3 Papillary adenocarcinoma 8260/3
1.3.4 Adenocarcinoma, intestinal type 8144/3
1.3.5 Mucinous adenocarcinoma 8480/3
1.3.6 Clear cell adenocarcinoma 8310/3
1.3.7 Signet-ring cell carcinoma 8490/3
1.3.8 Adenosquamous carcinoma 8560/3
1.3.9 Squamous cell carcinoma 8070/3
1.3.10 Small cell carcinoma (oat cell carcinoma) 8041/3
1.3.11 Undifferentiated carcinoma 8020/3

2 Endocrine Tumours
2.1 Carcinoid tumour 8240/3
2.2 Mixed carcinoid-adenocarcinoma 8244/3
2.3 Paraganglioma 868010

a Morphology code of the International Classification of Diseases for Oncology

(lCD-O) and the Systematized Nomenclature of Medicine (SNOMED)
6 Histological Classification of Tumours

3 Non-epithelial Tumours
3.1 Benign
3.1.1 Granular cell tumour 9580/0
3.1.2 Ganglioneurofibromatosis 9491/0
3.1.3 Leiomyoma 8890/0
3.1.4 Lipoma 8850/0
3.1.5 Haemangioma 9120/0
3.1.6 Lymphangioma 9170/0
3.1.7 Neurofibroma 9540/0
3.2 Malignant
3.2.1 Rhabdomyosarcoma 8900/3
3.2.2 Kaposi sarcoma 9140/3
3.2.3 Leiomyosarcoma 8890/3
3.2.4 Malignant fibrous histiocytoma 8830/3
3.2.5 Angiosarcoma 9120/3
4 Miscellaneous Tumours
4.1 Carcinosarcoma 8980/3
4.2 Malignant melanoma 8720/3
4.3 Malignant lymphomas

5 Unclassified Tumours

6 Secondary Tumours

7 Tumour-like Lesions
7.1 Regenerative epithelial atypia
7.2 Papillary hyperplasia 72050
7.3 Adenomyomatous hyperplasia 72440
7.4 Intestinal metaplasia 73320
7.5 Pyloric gland metaplasia 73330
7.6 Squamous metaplasia 73220
7.7 Heterotopias 26000
7.8 Xanthogranulomatous cholecystitis
7.9 Cholecystitis with lymphoid hyperplasia
7.10 Inflammatory polyp 76820
7.11 Cholesterol polyp 76870
7.12 Malacoplakia 43180
7.13 Congenital cyst 26500
7.14 Amputation neuroma 49770
7.15 Primary sclerosing cholangitis 45000
Definitions and Explanatory Notes

1 Epithelial Tumours

1.1 Benign

1.1.1 Adenoma
A benign neoplasm of glandular epithelium which is typically polypoid
and well demarcated.
Microscopically, adenomas are divided into three types: tubular,
papillary and tubulopapillary. The epithelium is cuboidal or colum-
nar, mucus-secreting and with at least mild dysplasia. Rarely, adeno-
mas consist of glands lined by colonic-like epithelium and small
groups of Paneth cells. In these adenomas a variable number of en-
docrine cells can be demonstrated by silver stains and immunocyto-
chemistry. These cells contain serotonin and/or peptide hormones.
Adenomas of the gallbladder and extrahepatic bile ducts are usually
solitary, measuring less than 2 em in diameter. Approximately one-
third, however, are multiple. Rarely, they are so numerous that they
fill the lumen of the gallbladder. In the gallbladder they are usually
asymptomatic whereas in the extrahepatic bile ducts they often cause
obstruction. Adenomas are either pedunculated or sessile. Fewer than
50% are associated with cholelithiasis. Occasionally, adenomas occur
in association with Gardner syndrome or with Peutz-Jeghers syn-
drome.
1.1.1.1 Tubular Adenoma (Figs. 1-4)
A well-demarcated benign tumour composed predominantly of closely
packed, short tubular glands lined by cuboidal or columnar epithelial
cells most of which are mucus-secreting.
The majority of glands are small, although some may be dilated
or cystic. In some adenomas the glands are similar to the metaplastic
pyloric glands often seen in cases of chronic cholecystitis. Foci of
squamoid spindle cells are occasionally noted. Less frequently there
8 Definitions and Explanatory Notes

is unequivocal squamous metaplasia. Tubular adenomas composed

of glands similar to metaplastic pyloric glands are the most common
type of adenoma in the gallbladder. A few tubular adenomas are in-
distinguishable from tubular adenomas of the colon. In these colonic-
like adenomas, severe dysplasia and carcinoma in situ are more fre-
quent than in the adenomas composed of pyloric-like glands.

1.1.1.2 Papillary Adenoma (Figs. 5-8)

A benign tumour composed predominantly of papillary structures lined
by cuboidal or columnar epithelial cells.
In most tumours the lining cells contain more mucin than normal
biliary epithelium. In others, however, the lining cells show minimal
variation from normal epithelium. A few papillary adenomas are com-
posed of colonic-like epithelium, Paneth cells and endocrine cells. Se-
vere dysplasia and carcinoma in situ are more frequent than in tubular
adenomas. Papillary adenomas appear to be more common in the am-
pulla of Vater than in other parts of the extrahepatic bile ducts.

1.1.1.3 Tubulopapillary Adenoma

An adenoma composed of tubular glands and papillary structures, each
contributing to more than 20% of the tumour.

1.1.2 Cystadenoma (Fig. 9)

A multiloculated thin-walled tumour that contains mucinous or serous
fluid. The locules are lined by a single layer of cuboidal or columnar
cells that stain for mucin.
Occasionally endocrine cells may be present. The wall is com-
posed of cellular connective tissue that resembles ovarian stroma.
Areas of fibrosis are usually present. This rare and distinctive neo-
plasm is more common in the extrahepatic bile ducts than in the gall-
bladder. Malignant transformation (cystadenocarcinoma) can occur.

1.1.3 Papillomatosis (Adenomatosis) (Figs. 10, 11)

A clinical pathological condition characterized by multiple recurring pap-
illary adenomas that may involve extensive areas of the extrahepatic
bile ducts and even extend into the gallbladder and intrahepatic bile
ducts.
The adenomas consists of numerous papillary structures as well
as complex glandular formations. Because severe dysplasia is often
present, papillomatosis is difficult to distinguish from papillary carci-
noma. Papillomatosis has a greater potential for malignant transfor-
mation than solitary adenomas.
 Epithelial Tumours 9

1.2 Dysplasia and Carcinoma in Situ (Fig. 12)

Since dysplasia and carcinoma in situ are biologically related and

cause similar problems in diagnosis, they are discussed together. Dys-
plasia is defined as epithelial atypia with an increased risk of becom-
ing cancer compared to normal epithelium. It is characterized by co-
lumnar, cuboidal or elongated cells showing variable degrees of
pseudostratification, nuclear atypia, loss of polarity, and mitotic fig-
ures. Carcinoma in situ is epithelium with the histological features of
carcinoma but without evidence of invasion into the lamina propria.
The mucosa adjacent to invasive carcinomas of the gallbladder
and extrahepatic bile ducts often shows dysplasia and carcinoma in
situ. Likewise, dysplasia and carcinoma in situ are found in a small
percentage of gallbladders removed for cholelithiasis, especially in
geographic areas in which there is a high incidence of carcinoma of
the gallbladder. Because of these observations it is believed that dys-
plasia - carcinoma in situ is the usual sequence for the development
of carcinoma of the extrahepatic biliary tract. Only a small number of
carcinomas arise from pre-existing adenomas.
Dysplasia and carcinoma in situ are usually not recognized on
gross examination. However, a papillary form of dysplasia and carci-
noma in situ may appear as small cauliflower-like excrescences that
are visible grossly.
Since dysplasia and carcinoma in situ are often seen in associa-
tion with cholelithiasis, they usually arise in an abnormal mucosa
showing pyloric gland or intestinal metaplasia. Dysplasia usually be-
gins on the surface and extends laterally and downward even into
Rokitansky-Aschoff sinuses and metaplastic pyloric glands. Rarely,
dysplasia and carcinoma in situ may arise in Rokitansky-Aschoff si-
nuses or in adenomyomatous hyperplasia. Two types of growth pat-
terns of dysplasia and carcinoma in situ have been described: papil-
lary and flat. Both types are characterized by columnar, cuboidal or
elongated cells showing variable degrees of pseudostratification, nu-
clear atypia, loss of polarity, and occasional mitotic figures.
Less commonly, dysplasia and carcinoma in situ are composed
predominantly of goblet cells and/or colonic-like columnar cells with
or without small groups of Paneth and endocrine cells. It is assumed
that this lesion is the precursor of the intestinal-type adenocarcinoma.
Squamous cell dysplasia and squamous cell carcinoma in situ are
often seen in the vicinity of invasive squamous cell carcinomas. This
suggests that the latter follows the same pathological sequence in its
development as those arising in other sites.
10 Definitions and Explanatory Notes

It should be noted that the morphological type of the in situ carci-

noma does not always correspond with that of the invasive carcinoma.
Differentiation of dysplasia or carcinoma in situ from regenera-
tive epithelial atypia may be difficult. This distinction is of clinical
significance because regenerative epithelial atypia is not precancer-
ous (see Sect. 7.1).
Dysplasia is usually graded as mild, moderate or severe based on
the extent of cytological atypia and loss of polarity. The distinction
between severe dysplasia and carcinoma in situ may be difficult or
impossible. In cases of dysplasia and carcinoma in situ multiple sec-
tions are needed to exclude invasive carcinoma.

1.3 Malignant

1.3.1 Carcinoma in Situ (Figs. 13-18)

(See Sect. 1.2)

1.3.2 Adenocarcinoma (Figs. 19-26)

A malignant epithelial tumour composed of short or long tubular glands
lined by cells that vary in height from low cuboidal to tall columnar.
Mucin is frequently present in the cells and glands. Adenocarci-
nomas can be divided into well, moderately or poorly differentiated
types. About one-third of the well-differentiated tumours contain en-
docrine cells. Their presence does not warrant a diagnosis of carci-
noid. Paneth cells may rarely be seen. In poorly differentiated adeno-
carcinomas the neoplastic cuboidal or columnar cells are arranged in
sheets and cords although some gland formation is maintained.
Another form of poorly differentiated adenocarcinoma is com-
posed of small round cells arranged in sheets, nodules, cords and
poorly defined glandular structures. Some of these tumours contain
cells having vesicular nuclei, prominent nucleoli and scant cytoplasm.
Because of these cytological features they may be confused with large
cell lymphomas. However, the more common form of poorly differ-
entiated adenocarcinoma contains cells with hyperchromatic nuclei
and vacuolated cytoplasm. Mucin can usually be demonstrated in
both forms although it is more abundant in the latter. Immunocyto-
chemical stains for cytokeratin and other epithelial markers are
usually positive in these tumours and negative in lymphomas.
Adenocarcinoma is the most common malignant tumour of the
gallbladder and extrahepatic bile ducts. An adenocarcinoma showing
both well and poorly differentiated areas should be classified as
poorly differentiated.
 Epithelial Tumours 11

Cystadenocarcinoma refers to a uni- or multilocular glandular tu-

mour which may be the result of malignant transformation of a
cystadenoma.
1.3.3 Papillary Adenocarcinoma (Figs. 27 - 29)
A malignant tumour composed predominantly of papillary structures
lined by cuboidal or columnar epithelial cells often containing variable
amounts of mucin.
Some tumours show focal intestinal differentiation with small col-
lections of goblet, endocrine and Paneth cells. Papillary adenocarci-
nomas may fill the lumen before invading the wall. As a result they
are associated with a better prognosis than other types of carcinomas.
Papillary adenocarcinomas appear to be more frequent in the ampul-
la of Vater than in other parts of the extrahepatic biliary tree.
1.3.4 Adenocarcinoma, Intestinal Type (Figs. 30-34)
A carcinoma composed of tubular glands or papillary structures lined
predominantly by cells with an intestinal phenotype, namely goblet cells
or colonic-type epithelium or both, with or without a variable number of
endocrine and Paneth cells.
1.3.5 Mucinous Adenocarcinoma (Fig. 35)
An adenocarcinoma in which more than 50% of the tumour contains ex-
tracellular mucin.
The three growth patterns described for mucinous adenocarcino-
mas of the intestine may also occur in the gallbladder: (a) neoplastic
glands distended with mucin and lined by columnar cells; (b) small
groups or clusters of cells surrounded by abundant mucin; (c) small
groups or cords of signet-ring cells. Not infrequently, the tumour
shows all three growth patterns. The abundant mucin makes the tu-
mour appear hypocellular.
1.3.6 Clear Cell Adenocarcinoma (Figs. 36,37)
A rare malignant tumour composed predominantly of glycogen-rich
clear cells having well-defined cytoplasmic borders and hyperchromatic
nuclei.
In addition to clear cells, a variable number of cells contain eosin-
ophilic granular cytoplasm. The cells are arranged in nests, sheets,
cords, trabeculae, tubular or papillary structures. Foci of mucin-pro-
ducing neoplastic glands are usually found; these are useful in the
separation of primary from metastatic clear cell carcinomas. In some
clear cell adenocarcinomas the columnar cells contain subnuclear
vacuoles similar to those seen in secretory endometrium.
12 Definitions and Explanatory Notes

1.3.7 Signet-Ring Cell Carcinoma (Fig. 38)

A malignant tumour composed predominantly of cells containing intra-
cytoplasmic mucin which displaces the nuclei toward the periphery.
Lateral spread through the lamina propria is a common feature.

1.3.8 Adenosquamous Carcinoma (Figs. 39, 40)

A tumour that consists of two malignant components, one glandular
and the other squamous.
The extent of differentiation of the two components varies, but in
general they tend to be moderately differentiated. Keratin pearls are
present in the well-differentiated squamous component, and mucin is
usually demonstrable in the neoplastic glands, regardless of the de-
gree of differentiation. A small proportion of adenosquamous carci-
nomas contain endocrine cells.

1.3.9 Squamous Cell Carcinoma (Figs. 41,42)

A malignant epithelial tumour composed entirely of squamous cells.
The extent of differentiation varies considerably. Keratinizing and
non-keratinizing types exist. Spindle cells predominate in some poor-
ly differentiated tumours which may be confused with sarcomas, es-
pecially malignant fibrous histiocytomas or carcinosarcomas. Im-
munocytochemical stains for cytokeratin may clarify the diagnosis in
these spindle cell cases. The tumour may arise from areas of squa-
mous metaplasia. Dysplastic and in situ carcinomatous changes can
be found in the metaplastic squamous mucosa.

1.3.10 Small Cell Carcinoma (Oat Cell Carcinoma) (Figs. 43,44)

A malignant tumour with cells and growth patterns similar to those of
small cell carcinomas of the lung.
Most tumours are composed of round or fusiform cells arranged
in sheets, nests, cords and festoons. Rosette-like structures and tu-
bules are occasionally present. Extensive necrosis and subepithelial
growth are constant features. In necrotic areas, intense basophilic
staining of the blood vessels occurs. Membrane-bound, round, dense
core granules are seen by electron microscopy. Neuron-specific eno-
lase is often demonstrated by immunocytochemistry. Endocrine man-
ifestations rarely occur. About 20% of these tumours contain a minor
adenocarcinomatous component. Small cell carcinomas appear to be
more common in the gallbladder than in the extrahepatic bile ducts.
Some small cell carcinomas simulate carcinoid tumours (see
Sect. 2.1).
 Endocrine Tumours 13

1.3.11 Undifferentiated Carcinoma (Figs. 45-47)

A malignant epithelial tumour in which glandular structures are typi-
cally absent. Most tumours resemble a sarcoma and consist of variable
proportions of spindle, polygonal and giant cells.
These tumours have been referred to as pleomorphic spindle and
giant cell adenocarcinomas or sarcomatoid carcinomas. Foci of well-
differentiated neoplastic glands are found in some of these tumours
after extensive sampling. Areas of squamoid differentiation may also
be seen. Rarely, osteoclast-like multinucleated giant cells predomi-
nate. The presence of cytokeratin in the spindle cells may help to dis-
tinguish this tumour from carcinosarcoma. Undifferentiated carcino-
mas are more common in the gallbladder than in the extrahepatic bile
ducts.

2 Endocrine Tumours

2.1 Carcinoid Tumour (Figs. 48-50)

A tumour of the diffuse endocrine system that exhibits characteristic
growth patterns and is of a low grade of malignancy.
Carcinoid tumours are composed of small cells with eosinophilic
granular cytoplasm and uniform round nuclei. The cells are arranged
in nests, cords or trabeculae and show peripheral palisading. Tubular
or glandular structures may be present and can predominate in some
tumours (so-called tubular carcinoid). The stroma is usually desmo-
plastic. In carcinoid tumours of the bile ducts, perineural invasion is
often seen. Grossly, these tumours appear as small yellow to grey in-
tramural nodules. In the bile ducts, they often produce> obstruction
whereas in the gallbladder they are usually incidental findings. Carci-
noid tumours are rare in the gallbladder and extrahepatic bile ducts,
accounting for fewer than 1% of all digestive tract carcinoids.
Most carcinoid tumours of the extrahepatic biliary tract are argen-
taffin and synthesize serotonin. With liver metastases they can give
rise to the carcinoid syndrome. Carcinoid tumours may also produce
peptide hormones, even when they do not contain serotonin.
Immunocytochemistry permits functional classification into so-
matostatinoma, gastrinoma, etc. The Zollinger-Ellison syndrome
has been associated with a gastrinoma of the gallbladder. Some small
cell carcinomas, especially those with numerous festoons or trabecu-
lae, simulate carcinoid tumours. A diffuse chromatin pattern, mitoses
14 Definitions and Explanatory Notes

and foci of necrosis favour a diagnosis of small cell carcinoma. The

presence of many serotonin-containing cells points to a carcinoid tu-
mour.

2.2 Mixed Carcinoid-Adenocarcinoma

A malignant tumour that exhibits variable proportions of adenocarcino-
ma and carcinoid.
These tumours behave as adenocarcinomas and, therefore, are
clinically more aggressive than carcinoids.

2.3 Paraganglioma (Figs. 51,52)

A tumour composed of chief cells and sustentacular cells arranged in a
zellballen pattern.
The chief cells are argyrophilic and stain for neuron-specific eno-
lase and chromogranin. The sustentacular cells are S-100 protein pos-
itive. The tumour is located in either the subserosa or muscular wall
of the gallbladder and apparently arises from normal paraganglia.
This rare and small tumour is usually an incidental finding in chole-
cystectomy specimens. Paragangliomas also occur in the extrahepatic
bile ducts, where they may be symptomatic.

3 Non-epithelial Tumours

A number of non-epithelial tumours occur in the extrahepatic biliary

tract. Among the benign are granular cell tumour, leiomyoma, lipo-
ma, haemangioma, lymphangioma, neurofibroma and ganglioneuro-
fibromatosis. Among the malignant are_rhabdomyosarcoma, Kaposi
sarcoma, leiomyosarcoma, malignant fibrous histiocytoma and angio-
sarcoma. Because of their clinico-pathological significance several
are discussed. For detailed definitions and explanatory notes, refer-
ence should be made to the Histological Typing of Soft Tissue Tu-
mours.
 Non-epithelial Tumours 15

3.1 Benign

3.1.1 Granular Cell Tumour (Figs. 53-55)

This is the most common benign non-epithelial tumour of the ex-
trahepatic biliary tract. It is more common in the bile ducts than in
the gallbladder; in the former location it frequently causes obstruc-
tion. Although usually single, granular cell tumours may be multicen-
tric or may coexist with one or more granular cell tumours in other
sites, especially the skin. Granular cell tumours are poorly circum-
scribed, firm, yellow-tan nodules usually less than 2 cm in diameter.
They are composed of sheets or clusters of large, ovoid or round cells
separated by connective tissue bands. The cells have abundant granu-
lar eosinophilic cytoplasm and small hyperchromatic nuclei. The
cytoplasm is PAS positive, diastase resistant and contains lysosomes
when seen with the electron microscope. S-100 protein is present in
most tumour cells. Though benign, this tumour may extend into the
peri ductal connective tissue and even into adjacent lymph nodes.
Reactive hyperplasia of the overlying epithelium occurs.

3.1.2 Ganglioneurofibromatosis
Ganglioneurofibromatosis of the gallbladder is a component of the
type lIb multiple endocrine neoplasia syndrome. The histological
changes consist of Schwann cell and ganglion cell proliferation in the
lamina propria as well as enlarged and distorted nerves in the muscle
layer and subserosa. Sporadic ganglioneurofibromatosis is exceeding-
ly rare in the gallbladder.

3.2 Malignant

3.2.1 Rhabdomyosarcoma (Figs. 56, 57)

Embryonal rhabdomyosarcoma (sarcoma botryoides) is the most

common malignant neoplasm of the biliary tract in childhood. It oc-
curs more frequently in the bile ducts than in the gallbladder. Embry-
onal rhabdomyosarcoma forms soft polypoid structures with a char-
acteristic grape-like appearance that project into the lumen. Micro-
scopically, the polypoid structures are covered with normal biliary
epithelial cells. Immediately beneath the epithelium is a concentra-
tion of primitive mesenchymal cells, some of which contain abundant
eosinophilic cytoplasm (rhabdomyoblasts). About one-third of these
rhabdomyoblasts show cross-striations. Myxoid areas contain undif-
ferentiated stellate cells. Myoglobin, myosin, des min and muscle-spe-
16 Definitions and Explanatory Notes

cific actin can be demonstrated in tumour cells by immunocytochem-

istry.

3.2.2 Kaposi Sarcoma

Foci of Kaposi sarcoma involving the extrahepatic biliary tract are in-
cidental autopsy findings in the acquired immune deficiency syn-
drome. The haemorrhagic lesions are usually located in the subserosa
or muscular wall of the gallbladder or in the periductal connective
tissue of the bile ducts. The tumours show the characteristic spindle
cells and vascular slits.

4 Miscellaneous Tumours

4.1 Carcinosarcoma (Figs. 58-60)

A malignant tumour consisting of a mixture of two components,' carci-
nomatous and sarcomatous.
The epithelial elements usually form glands but may be arranged
in cords or sheets. Foci of malignant squamous cells are occasionally
seen. The mesenchymal component may include areas of chondrosar-
coma, osteosarcoma and rhabdomyosarcoma. Cytokeratin and car-
cinoembryonic antigen are absent from the mesenchymal component.
This helps to distinguish carcinosarcomas from spindle cell carcino-
mas.

4.2 Malignant Melanoma

Primary malignant melanoma may occur in the gallbladder. Junction-
al activity in the epithelium overlying the tumour is an important fea-
ture to distinguish primary from the more commonly occurring me-
tastatic melanoma. However, mucosal ulceration frequently prevents
an assessment of junctional activity.

4.3 Malignant Lymphomas (Figs. 61-63)

Malignant lymphomas of the biliary tract are usually part of a sys-
temic process. Primary lymphomas of the gallbladder and extrahepat-
ic bile ducts are of non-Hodgkin type. They are extremely rare.
 Tumour-like Lesions 17

5 Unclassified Tumours

6 Secondary Tumours
Metastatic tumours in the gallbladder and extrahepatic bile ducts are
not common. They are often discovered at autopsy. The majority re-
sult from transcoelomic spread and are associated with peritoneal
carcinomatosis. Blood-borne metastases may be symptomatic and
simulate primary tumours. The more common are malignant melano-
ma and carcinomas of the kidney, lung, breast and oesophagus. The
gallbladder and extrahepatic bile ducts may be involved by direct ex-
tension from carcinomas of the pancreas, stomach, colon and liver
(Fig. 80).

7 Tumour-like Lesions

7.1 Regenerative Epithelial Atypia (Fig. 64)

A non-dysplastic atypia occurring in regenerating or injured biliary epi-
thelium.
Although the changes resemble dysplasia or carcinoma in situ, the
most reliable distinguishing features are heterogeneity of the epithe-
lial cell population and ulceration. In contrast to the relative unifor-
mity of dysplasia, atypical regenerative epithelium contains columnar
cells with or without mucus, atrophic low cuboidal cells and tall thin,
basophilic, pencil-like cells. Mitotic activity and nuclear pleomor-
phism are not reliable distinguishing features. A diagnosis of dyspla-
sia should be made with caution in the presence of extensive ulcera-
tion or acute inflammation. This is a common diagnostic pitfall.

7.2 Papillary Hyperplasia (Figs. 65,66)

A proliferative lesion composed of tall exaggerated epithelial folds lined
by normal-appearing biliary epithelium.
Papillary hyperplasia is usually secondary to chronic cholecystitis
or other inflammatory diseases such as ulcerative colitis and primary
sclerosing cholangitis. In these cases intestinal metaplasia is frequent-
ly present. Secondary papillary hyperplasia is focal or segmental in
distribution. Less frequently, papillary hyperplasia is not associated
with chronic inflammation. This is termed primary papillary hyper-
plasia. It may be focal, segmental or involve the entire mucosa of the
18 Definitions and Explanatory Notes

biliary tract. There is no intestinal metaplasia in primary papillary hy-

perplasia. Dysplasia develops in secondary but not in primary papil-
lary hyperplasia.

7.3 Adenomyomatous Hyperplasia (Fig. 67)

Branching duct-like structures in the wall of the gallbladder accompa-
nied by hyperplasia of smooth muscle cells.
These duct-like structures are dilated invaginations of the surface
epithelium, i. e. Rokitansky-Aschoff sinuses. Secondary gland forma-
tion typically of pyloric type occurs. Adenomyomatous hyperplasia
can be localized (so-called adenomyoma), segmental or diffuse.

7.4 Intestinal Metaplasia (Figs. 68, 69)

A lesion in which the normal biliary epithelium is focally replaced by any
or all of the following." goblet, Paneth and endocrine cells; cells with in-
testinal-type microvilli; and supetficial gastric-type epithelium.
In most cases, only goblet cells are seen. In the lamina propria
colonic and pyloric-type glands can occur. Intestinal (gastrointestinal)
metaplasia is often associated with lithiasis and inflammatory bowel
diseases such as ulcerative colitis. Dysplasia may develop in areas of
intestinal metaplasia and can progress to adenocarcinoma.

7.5 Pyloric Gland Metaplasia (Fig. 70)

A lesion in which pyloric-type glands occur in the wall of the biliary tract.
The glands form small lobules which are usually confined to the
lamina propria. Rarely, however, they may extend to the muscle layer
and even to the serosa. The glands are lined by columnar cells with
basal nuclei and vacuolated cytoplasm. In some cases endocrine and
Paneth cells are found among the mucin-containing cells. Pyloric
gland metaplasia occurs alone or with intestinal metaplasia. This le-
sion is usually associated with chronic cholecystitis.

7.6 Squamous Metaplasia (Fig. 71)

A metaplastic lesion characterized by focal replacement of the biliary ep-
ithelium by squamous cells.
This is an exceedingly rare lesion. In the gallbladder squamous
metaplasia is usually associated with cholelithiasis. Progression to
dysplasia and carcinoma in situ occurs in some cases. Squamous
 Tumour-like Lesions 19

metaplasia is often seen in the mucosa adjacent to invasive squamous

cell carcinoma.

7.7 Heterotopias (Figs. 72, 73)

Ectopic tissues such as pancreas, gastric mucosa, liver, adrenal cortex
and thyroid may occur in the wall of the biliary tree. Only ectopic
pancreas and gastric mucosa are symptomatic. The other tissues are
incidental surgical or autopsy findings.

7.8 Xanthogranulomatous Cholecystitis (Figs. 74, 75)

A tumour-like lipid-containing inflammatory lesion of the gallbladder
that appears as a poorly demarcated yellow nodule which often involves
the full thickness of the wall.
The lesion is nearly always associated with gallstones. Foamy his-
tiocytes, lymphocytes, polymorphonuclear leukocytes, plasma cells
and foreign-body giant cells are present. In some cases, fibroblastic
proliferation is a prominent feature and can simulate malignant fi-
brous histiocytoma. Some histiocytes contain bile or ceroid pigment;
others with coarsely granular cytoplasm are PAS positive.

7.9 Cholecystitis with Lymphoid Hyperplasia (Fig. 76)

Marked lymphoid hyperplasia may be associated with chronic chole-
cystitis. The lymphoid tissue is organized into follicles with germinal
centres. Occasionally, the lymphoid tissue forms polypoid structures
which project into the lumen of the gallbladder, similar to the benign
lymphoid polyp of the intestine. This lesion may mimic a lymphoma,
especially when the lymphoid follicles are poorly developed, or when
diffuse lymphoid hyperplasia predominates.

7.10 Inflammatory Polyp

A small polypoid lesion containing chronic inflammatory cells and nu-
merous dilated blood vessels.
When the vascular component is prominent, this lesion has been
referred to as a granulation tissue polyp.
20 Definitions and Explanatory Notes

7.11 Cholesterol Polyp (Fig. 77)

A small pedunculated polypoid structure of the gallbladder, containing
foamy histiocytes and covered by normal epithelium.

7.12 Malacoplakia
A tumour-like lesion composed of sheets of macrophages, lymphocytes
and plasma cells. The macrophages usually have a granular eosinophilic
cytoplasm and typically contain laminated calcified microspherules (Mi-
chaelis-Guttmann bodies).

7.13 Congenital Cyst

Congenital cystic dilatation is a common anomaly of the extrahepatic
biliary tract. It is most frequent in the common bile duct. Congenital
cysts may be large, measuring up to 15 cm in diameter, and contain
bile. The cyst wall is composed of dense fibrous tissue that may be
devoid of its columnar or cuboidal epithelial lining. Adenocarcinoma
is the most common malignant tumour complicating congenital cysts.
Other tumours, including sarcomas, have been reported.

7.14 Amputation Neuroma

A proliferation of distorted nerve fibres associated with cholecystectomy.
The lesion occurs shortly or many years after cholecystectomy
and can produce pain. Rarely a neuroma may grow into the lumen of
the extrahepatic bile duct, mimicking a true neoplasm and causing
obstructive jaundice. Amputation neuromas are commonly located in
the stump of the cystic duct, although other ducts may be involved. A
similar lesion may occur in the absence of prior surgery, presumably
as a sequel to chronic inflammation and mucosal erosion. The term
traumatic neuroma has been used for such lesions.

7.15 Primary Sclerosing Cholangitis (Figs. 78, 79)

Chronic iriflammation and fibrosis of the wall of the extrahepatic bile
ducts.
The affected segments are thickened. The lumen may be nar-
rowed or even obliterated. The architectural distortion of the subep-
ithelial glands by fibrosis and the regenerative epithelial atypia may
be confused with carcinoma, which may actually be a late complica-
 Tumour-like Lesions 21

tion. Many cases are associated with chronic ulcerative colitis. Pri-
mary sclerosing cholangitis usually extends into the gallbladder and
into the liver. Changes similar to those of primary sclerosing cholan-
gitis may occur as a result of chronic extrahepatic biliary obstruction,
bacterial cholangitis, choledocholithiasis, congenital cysts or follow-
ing the intravascular injection of some anticancer drugs (secondary
sclerosing cholangitis).
TNM Classification of Tumours
of the Gallbladder and Extrahepatic Bile Ducts

Gallbladder

Rules for Classification

The classification applies only to carcinoma. There should be histo-
logical confirmation of the disease.
The following are the procedures for assessment of the T, Nand
M categories:
T categories: Physical examination, imaging and/or surgical explora-
tion
N categories: Physical examination, imaging and/or surgical explora-
tion
M categories: Physical examination, imaging and/or surgical explora-
tion

Regional Lymph Nodes

The regional lymph nodes are the cystic duct node and the pericho-
ledochal, hilar, peripancreatic (head only), periduodenal, periportal,
coeliac and superior mesenteric nodes.

TNM Clinical Classification

T - Primary Tumour

TX Primary tumour cannot be assessed

TO No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumour invades mucosa or muscle layer
T1a Tumour invades mucosa
T1b Tumour invades muscle layer
24 TNM Classification of Tumours of the Gallbladder

T2 Tumour invades perimuscular connective tissue, no extension

beyond serosa or into liver
T3 Tumour invades beyond serosa or into one adjacent organ or
both (extension 2 cm or less into liver)
T4 Tumour extends more than 2 cm into liver and/or into two or
more adjacent organs (stomach, duodenum, colon, pancreas,
omentum, extrahepatic bile ducts, any involvement of liver)

N - Regional Nodes
NX Regional lymph nodes cannot be assessed
NO No regional lymph node metastasis
N1 Regional lymph node metastasis
N1a Metastasis in cystic duct, pericholedochal, and/or hilar
lymph nodes (i. e. those in the hepatoduodenalligament)
N1b Metastasis in peripancreatic (head only), periduodenal,
periportal, coeliac and/or superior mesenteric lymph nodes

M - Distant Metastasis
MX Presence of distant metastasis cannot be assessed.
MO No distant metastasis.
M1 Distant metastasis.

pTNM Pathological Classification

The pT, pN and pM categories correspond to the T, Nand M catego-
ries.

Stage Grouping
Stage 0 Tis NO MO
Stage I T1 NO MO
Stage II T2 NO MO
Stage III T1 N1 MO
T2 N1 MO
T3 AnyN MO
Stage IV T4 AnyN MO
AnyT AnyN M1
 TNM: Extrahepatic Bile Ducts 25

Summary
T1 Gallbladder wall
T1a Mucosa
T1b Muscle
T2 Perimuscular connective tissue
T3 Serosa and/or one organ, liver .;;; 2 cm
T4 Two or more organs, or liver> 2 cm
N1a Hepatoduodenalligament
N1b Other regional

Extrahepatic Bile Ducts

Rules for Classification

The classification applies only to carcinoma. There should be histo-
logical confirmation of the disease.
The following are the procedures for assessment of the T, Nand
M categories:
T categories: Physical examination, imaging and/or surgical explora-
tion
N categories: Physical examination, imaging and/or surgical explora-
tion
M categories: Physical examination, imaging and/or surgical explora-
tion

Regional Lymph Nodes

The regional lymph nodes are the cystic duct, pericholedochal, hilar,
peri pancreatic (head only), periduodenal, periportal, coeliac and su-
perior mesenteric nodes.

TNM Clinical Classification

T - Primary Tumour

TX Primary tumour cannot be assessed

TO No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumour invades mucosa or muscle layer
26 TNM: Extrahepatic Bile Ducts

T1a Tumour invades mucosa

T1 b Tumour invades muscle layer
T2 Tumour invades perimuscular connective tissue
T3 Tumour invades adjacent structures: liver, pancreas, duodenum,
gallbladder, colon, stomach
N - Regional Lymph Nodes
NX Regional lymph nodes cannot be assessed
NO No regional lymph node metastasis
N1 Regional lymph node metastasis
N1a Metastasis in cystic duct, pericholedochal and/or hilar
lymph nodes (i. e. those in the hepatoduodenalligament)
N1b Metastasis in peripancreatic (head only), peri duodenal,
periportal, coeliac and/or superior mesenteric lymph nodes
M - Distant Metastasis
MX Presence of distant metastasis cannot be assessed
MO No distant metastasis
M1 Distant metastasis

pTNM Pathological Classification

The pT, pN and pM categories correspond to the T, Nand M catego-
ries.

Stage Grouping
Stage 0 Tis NO MO
Stage I T1 NO MO
Stage II T2 NO MO
Stage III T1 N1 MO
T2 N1 MO
Stage IVA T3 AnyN MO
Stage IVB AnyT AnyN M1

Summary
T1 Ductal wall T3 Adjacent structures
T1a Mucosa N1a Hepatoduodenalligament
T1b Muscle N1b Other regional
T2 Perimuscular connective
tissue
 TNM: Ampulla of Vater 27

Ampulla of Vater

Rules for Classification

The classification applies only to carcinoma. There should be histo-
logical confirmation of the disease.
The following are the procedures for assessment of the T, Nand
M categories:
T categories: Physical examination, imaging and/or surgical explora-
tion
N categories: Physical examination, imaging and/or surgical explora-
tion
M categories: Physical examination, imaging and/or surgical explora-
tion

Regional Lymph Nodes

The regional lymph nodes are:
Superior: Superior to head and body of the pancreas
Inferior: Inferior to head and body of the pancreas
Anterior: Anterior pancreaticoduodenal, pyloric and proximal
mesenteric lymph nodes
Posterior: Posterior pancreaticoduodenal, common bile duct and
proximal mesenteric
Note: The splenic lymph nodes and those at the tail of the pancreas
are not regional; metastases to these lymph nodes are coded M1.

TNM Clinical Classification

T - Primary Tumour

TX Primary tumour cannot be assessed

TO No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumour limited to ampulla of Vater
T2 Tumour invades duodenal wall
T3 Tumour invades 2 cm or less into pancreas
T4 Tumour invades more than 2 cm into pancreas and/or into oth-
er adjacent organs
28 TNM: Ampulla of Vater

N - Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed
NO No regional lymph node metastasis
N1 Regional lymph node metastasis

M - Distant Metastasis
MX Presence of distant metastasis cannot be assessed
MO No distant metastasis
M1 Distant metastasis

pTNM Pathological Classification

The pT, pN and pM categories correspond to the T, Nand M catego-
ries.

Stage Grouping
Stage 0 Tis NO MO
Stage I T1 NO MO
Stage II T2 NO MO
T3 NO MO
Stage III T1 N1 MO
T2 N1 MO
T3 N1 MO
Stage IV T4 AnyN MO
AnyT AnyN M1

Summary
T1 Ampulla only
T2 Duodenal wall
T3 Pancreas ~ 2 cm
T4 Pancreas > 2 cm, other organs
N1 Regional
Subject Index

Page Figures
Adenocarcinoma 10 20
clear cell type 11 36,37
intestinal type 11 30-34
mucinous . . . 11 35
papillary . . . 11 27-29
poorly differentiated 10 25-26
well differentiated . 10 19-24
Adenoma .. 7 8
papillary . . . . 8 5-8
tubular . . . . . 7 1-4
tubulopapillary 8
Adenomyomatous hyperplasia . 18 67
Adenosquamous carcinoma 12 39,40
Amputation neuroma 20
Angiosarcoma 14

Carcinoma .. 12
signet-ring cell 12 38
small cell type 12 43,44
squamous cell type 12 41,42
undifferentiated 13 45-47
Carcinoma in situ 9 13-18
Carcinoid tumour . 13 48-50
tubular . . . . . 13 50
Carcinoid-adenocarcinoma, mixed 14
Carcinosarcoma . . . . . . . . . . . 16 58-60
Cholecystitis with lymphoid hyperplasia 19 76
xanthogranulomatous . 19 74,75
Cholesterol polyp 20 77
Congenital cyst 20
Cystadenoma 8 9

Dysplasia . . . 9 12

Endocrine tumours 13 48-52

Ganglioneurofibromatosis 15
Granular cell tumour . . . 15 53-55
30 Subject Index

Haemangioma . . . . 14
Hepatocellular carcinoma 17 80
Heterotopias . . . 19 000
adrenal cortex 19
gastric .. 19 73
hepatic .. 19
pancreatic 19 72
thyroid .. 19

Inflammatory polyp . 19
Intestinal metaplasia 18 68,69

Kaposi sarcoma 16

Leiomyoma .. 14
Leiomyosarcoma 14
Lipoma . . . . . 14
Lymphangioma 14

Malacoplakia ........ . 20
Malignant fibrous histiocytoma 14
Malignant lymphoma 16 61-63
Malignant melanoma 16

Neurofibroma . . . . 14

Papillary hyperplasia 17 65,66

Papillomatosis . . . . 8 10,11
Paraganglioma. . . . 14 51,52
Primary sclerosing cholangitis 20 78, 79
Pyloric gland metaplasia . . . 18 70

Regenerative epithelial atypia 17 64

Rhabdomyosarcoma 15 56,57

Secondary tumours 17 80
Squamous metaplasia . 18 71

TNM classification . . 23

Unless otherwise stated, all the preparations shown in the photomicrographs re-
produced on the following pages were stained with haematoxylin-eosin.
 31

Fig. 1. Tubular adenoma, pedunculated, gallbladder

Fig. 2. Tubular adenoma, sessile, gallbladder

32

Fig. 3. Tubular adenoma, gallbladder

The columnar cells have vesicular nuclei

Fig. 4. Tubular adenoma with carcinoma in situ, gallbladder

Malignant cells line a few glands
 33

,.
Fig. 5. Papillary adenoma with intestinal phenotype, gallbladder

Fig. 6. Papillary adenoma with intestinal phenotype, gallbladder

Moderate dysplasia of the columnar cells
34

Fig. 7. Papillary adenoma, gallbladder

Cluster of Paneth cells (Colour illustration see p. 71)

Fig. 8. Papillary adenoma with intestinal phenotype, gallbladder

Serotonin-containing cells (Colour illustration see p. 71)
 35

Fig. 9. Mucinous cystadenoma, common hepatic duct

Columnar epithelium, cellular mesenchymal stroma and hyalinized fibrous tissue

Fig. 10. Papillomatosis, extrahepatic bile ducts

Complex papillary structures
36

Fig. 11. Papillomatosis, extrahepatic bile ducts

Fig. 12. Severe dysplasia, gallbladder

The dysplastic epithelium extends into an epithelial invagination
 37

Fig. 13. Carcinoma in situ, gallbladder

Papillary structures are lined by cells with vesicular nuclei

"
.;.:' ~
_. -r
. - ,.
...

-~
~ .. '
.- .... -
," .
Fig. 14. Carcinoma in situ. gallbladder
38
..
' J

Fig. 15. Carcinoma in situ, gallbladder

Stratification of cells and mitotic figures

,. ' . ... , .
", .
•
.. .. .' .1
•
.,
• •• 1
...
,'

Fig. 16. Carcinoma in situ, intestinal type, gallbladder

Goblet cells and colonic type epithelium
 39

~ .. ,.-.
......
'."'~
11'1;

Fig. 17. Carcinoma in situ, cystic duct

Fig. 18. Squamous cell carcinoma in situ, gallbladder

40

Fig. 20. Adenocarcinoma, well differentiated, gallbladder

Closely packed short tubular glands
 41

Fig. 21. Adenocarcinoma, well differentiated, gallbladder

Long tubular glands infiltrate the muscle coat

Fig. 22. Adenocarcinoma, well differentiated, common bile duct

42

Fig. 23. Adenocarcinoma, well differentiated, common hepatic duct

The columnar cells have a prominent brush border

Fig. 24. Adenocarcinoma, well differentiated, gallbladder

The glands are lined by cuboidal or flat epithelium
 43

Fig.25. Adenocarcinoma, poorly differentiated, gallbladder

The neoplastic cells are arranged in cords

Fig. 26. Adenocarcinoma, poorly differentiated, gallbladder

The cells have vesicular nuclei and prominent nucleoli
44

Fig. 27. Papillary adenocarcinoma, gallbladder

There is no invasion of the wall

Fig. 28. Papillary adenocarcinoma, gallbladder

Higher magnification of Fig. 27
 45

Fig. 29. Papillary adenocarcinoma, common hepatic duct

Minimal infiltration into the wall

Fig. 30. Adenocarcinoma, intestinal type, gallbladder

Colonic-like glands infiltrate the lamina propria
46

Fig.31. Adenocarcinoma, intestinal type, cystic duct

Colonic-like glands

Fig.32. Adenocarcinoma, intestinal type, gallbladder

The papillae are lined predominantly by goblet cells
 47

Fig.33. Adenocarcinoma, intestinal type, gallbladder

Grimelius-positive cells among columnar cells (Colour illustration see p. 72)

Fig. 34. Adenocarcinoma, intestinal type, gallbladder

Serotonin-positive cells among columnar cells (Colour illustration see p. 72)
48

Fig. 35. Mucinous adenocarcinoma, gallbladder

Fig. 36. Clear cell adenocarcinoma, right hepatic duct

Nesting pattern
 49

Fig. 37. Clear cell adenocarcinoma, right hepatic duct

Lymph node metastasis closely resembling renal cell carcinoma

Fig. 38. Signet-ring cell carcinoma, gallbladder

50

Fig. 39. Adenosquamous carcinoma, gallbladder

Fig. 40. Adenosquamous carcinoma, gallbladder

 51

.
..". . .
"..".~...

,
'\

, .

Fig. 41. Squamous cell carcinoma. gallbladder

Fig. 42. Squamous cell carcinoma. gallbladder

52

Fig. 43. Small cell carcinoma, gallbladder

Subepithelial growth

Fig. 44. Small cell carcinoma, gallbladder

 53

Fig. 45. Undifferentiated carcinoma, gallbladder

A focus of well-differentiated adenocarcinoma is seen

Fig. 46. Undifferentiated carcinoma, gallbladder

Spindle and giant cells predominate in the tumour
54

Fig. 47. Undifferentiated carcinoma, gallbladder

Cytokeratin-positive cells (Colour illustration see p.73)

Fig. 48. Carcinoid tumour, common bile duct

Neoplastic cells have clear or granular cytoplasm
 55

Fig. 49. Carcinoid tumour, common bile duct

Most cells are immunoreactive for serotonin (Colour illustration see p.73)

Fig. 50. Carcinoid tumour, tubular type, gallbladder

56

Fig. 51. Paraganglioma, gallbladder

Fig. 52. Paraganglioma, gallbladder

Sustentacular cells (Colour illustration see p.74)
 57

Fig. 53. Granular cell tumour, cystic duct

Fig. 54. Granular cell tumour, common hepatic duct

Direct extension into lymph node
58

Fig. 55. Granular cell tumour, common hepatic duct

S-100 protein positive cells in a lymph node (Colour illustration see p.74)

Fig. 56. Embryonal rhabdomyosarcoma, gallbladder

The tumour resembles a benign polyp
 59

Fig. 57. Embryonal rhabdomyosarcoma, common hepatic duct

60

"
, .' ;,

Fig. 59. Carcinosarcoma, gallbladder

A focus of malignant cartilage is present

Fig. 60. Carcinosarcoma, gallbladder

CEA-positive cells in the epithelial component (Colour illustration see p.75)
 61

Fig. 61. Malignant lymphoma, small lymphocytic type, gallbladder

62

Fig. 63. Malignant lymphoma, gallbladder

Leukocyte-common antigen positive cells (Colour illustration see p.75)

Fig. 64. Regenerative epithelial atypia, gallbladder

Heterogeneity of the epithelial cell population
 63

Fig. 65. Primary papillary hyperplasia, gallbladder

Fig. 66. Primary papillary hyperplasia, common bile duct

Columnar cells have subnuclear vacuoles
64

Fig. 67. Adenomyomatous hyperplasia, gallbladder

Fig. 68. Intestinal metaplasia, gallbladder

 65

Fig. 69. Intestinal metaplasia, gallbladder

Grimelius-positive cells

Fig. 70. Pyloric gland metaplasia, gallbladder

66

Fig. 71. Squamous metaplasia, gallbladder

Fig. 72. Pancreatic heterotopia, gallbladder

 67

Fig. 73. Heterotopia of gastric mucosa, gallbladder

Fig. 74. Xanthogranulomatous cholecystitis

Foamy histiocytes and polymorphonuclear leukocytes predominate
68

Fig. 75. Xanthogranulomatous cholecystitis

Fibroblastic proliferation and foreign body giant cells

Fig. 76. Cholecystitis with lymphoid hyperplasia

 69

Fig. 77. Cholesterol polyp, gallbladder

Fig. 78. Primary sclerosing cholangitis

70

Fig. 79. Primary sclerosing cholangitis

Fig. 80. Hepatocellular carcinoma extending into wall of gallbladder

 71

Fig. 7. Papillary adenoma, gallbladder

Cluster of Paneth cells

Fig. 8. Papillary adenoma with intestinal phenotype, gallbladder

Serotonin-containing cells
72

Fig. 33. Adenocarcinoma, intestinal type, gallbladder

Grimelius-positive cells among columnar cells

Fig.34. Adenocarcinoma, intestinal type, gallbladder

Serotonin-positive cells among columnar cells
 73

Fig. 47. Undifferentiated carcinoma, gallbladder

Cytokeratin-positive cells

Fig. 49. Carcinoid tumor, common bile duct

Most cells are immunoreactive for serotonin
74

Fig. 52. Paraganglioma. gallbladder

Sustentacular cells

Fig. 55. Granular cell tumor. common hepatic duct

S-100 protein-positive cells in a lymph node
 75

Fig. 60. Carcinosarcoma, gallbladder

CEA-positive cells in the epithelial component

Fig. 63. Malignant lymphoma, gallbladder

Leukocyte-common antigen-positive cells
WHO International Histological Classification of Tumours
Albores-Saavedra et al.: Histological Typing of Tumours of the Gall-
bladder and Extrahepatic Bile Ducts, 2nd edn.

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 H. Watanabe, Niigata
University, Niigata, Japan;
J. R. Jass, University of
Auckland, New Zealand;
L. H. Sobin, WHO
Collaborating Centre,
Washington, D.C.

Histological Typing
of Oesophageal
and Gastric Tumours
In Collaboration with Pathologists in 8 Countries
2nd ed. 1990. XII, 109 pp. 120 figs. 4 tabs.
Softcover DM 78,- ISBN 3-540-51629-8

This second edition is a collaborative effort of pathologists from

eight countries. Significant changes in our understanding of
lymphomas, endocrine tumours and the dysplasias have led to
modifications in the classification. A bridge between the
purely morphological and the immunolog-
ical classification oflymphomas is given.
Considerable attention is given to endo-
crine tumours, namely carcinoids, and
their relevance in diagnostic pathology.
New entries discuss fundic gland polyp,
endocrine cell hyperplasia and micronest
and small cell carcinoma. The classifica-
tions of Lauren and Ming gastric
carcinomas are also presented.
J.R.Jass, University of Auckland, New Zealand;
L.H.Sobin, Armed Forces Institute of Pathology, Washington, D.C.

Histological Typing
of Intestinal TUl1Jours
In Collaboration with Pathologists in 9 Countries
2nd ed. 1989. XII, 127 pp. 136 figs. Softcover DM 90,-
ISBN 3-540-50711-6

Contents: Introduction. - Histological Classification of Intestinal

Tumours. - Definitions and Explanatory Notes. - Small Intestine. -
Appendix. - Large Intestine. - Anal Canal. - Anal Margin. - Subject
Index.

C. Hedinger, WHO, University of Zurich

Histological Typing
of Thyroid TUl1Jours
In Collaboration with E. D. Williams and L. H. Sobin
2nd ed. 1988. XII, 67 pp. 92 figs. Softcover DM 68,-
ISBN 3-540-19244-1

Contents: Introduction. - Histological Classi-

fication of Thyroid Tumours. - Definitions
and Explanatory Notes. Follicular Adenoma.
Other Adenomas. Follicular Carcinoma.
Papillary Carcinoma. Medullary Carcinoma
(C-Cell Carcinoma). Undifferentiated
(Anaplastic) Carcinoma. Other Carcinomas.
Non-epithelial Tumours. Malignant Lympho-
mas. Miscellaneous Tumours. Secondary
Tumours. Unclassified Tumours. Tumour-
like Lesions. - Subject Index.

Prices are subject to change without notice.