Protocol
applies to all carcinomas of the gallbladder including those showing focal
endocrine differentiation.
Procedures
Cholecystectomy with Wedge Resection
Cholecystectomy with Lymph Node Dissection
This protocol is intended to assist
pathologists in providing clinically useful and relevant information as a
result of the examination of surgical specimens. Use of this protocol is
intended to be entirely voluntary. If equally valid protocols or similar
documents are applicable, the pathologist is, of course, free to follow those
authorities. Indeed, the ultimate judgment regarding the propriety of any
specific procedure must be made by the physician in light of the individual
circumstances presented by a specific patient or specimen.
It should be understood that adherence to
this protocol will not guarantee a successful result. Nevertheless,
pathologists are urged to familiarize themselves with the document. Where a
physician chooses to deviate from the protocol based on the circumstances of a
particular patient or specimen, the physician is advised to make a
contemporaneous written notation of the reason for the procedure followed.
The College recognizes that this document
may be used by hospitals, attorneys, managed care organizations, insurance
carriers, and other payers. However, the document was developed solely as a
tool to assist pathologists in the diagnostic process by providing information
that reflects the state of relevant medical knowledge at the time the protocol
was first published. It was not developed for credentialing, litigation, or
reimbursement purposes. The College cautions that any uses of the protocol for
these purposes involve considerations that are beyond the scope of this
document.
A. CLINICAL
INFORMATION
1. Patient identification
a. Name
b. Identification number
c. Age (birth date)
d. Gender
2. Responsible physician(s)
3. Date of procedure
4. Other clinical information
a. Relevant history (e.g. right upper abdominal
pain)
b. Relevant findings (e.g. ultrasound, other
imaging studies)
c. Clinical diagnosis (e.g. chronic
cholecystitis)
d. Procedure (e.g. abdominal cholecystectomy)
e. Operative findings
B. MACROSCOPIC
EXAMINATION
1. Specimen
a. Organ(s)/tissue(s) received (Note
A)
b. Unfixed/fixed (specify fixative)
c. Previously opened
d. Orientation (if indicated by surgeon)
e. Dimensions (measure attached tissues
individually)
f. Gallstones (number, type) (Note
B)
g. Results of intraoperative consultation
2. Tumor
a. Location (fundus/body/neck)
b. Configuration (Note C)
c. Dimensions (include entire tumor)
d. Descriptive features (e.g. color, consistency,
necrosis)
e. Extent of invasion (Note D)
3. Margins
a. Cystic duct
b. Liver bed
c. Other(s) (as appropriate)
4. Regional lymph nodes
a. Location (if possible)
b. Number
5. Additional pathologic findings, if present
6. Tissues submitted for microscopic evaluation
a. Tumor, including:
(1) point of deepest penetration
(2) overlying serosa
(3) interface with adjacent tissue
b. Gallbladder uninvolved by tumor
c. Margin of cystic duct
d. Liver (including margin of resection closest
to tumor)
e. All lymph nodes
f. Other lesion(s)
g. Frozen section tissue fragment(s) (unless
saved for special studies)
h. Other tissue(s)/organ(s)
7. Special studies (specify) (e.g.
histochemistry, immunohistochemistry, morphometry, DNA analysis, cytogenetic
analysis)
C. MICROSCOPIC
EVALUATION
1. Tumor (Note E)
a. Histologic type (Note F)
b. Histologic grade (Note G)
c. Depth of invasion (Note D)
d. Blood/lymphatic vessel invasion (Note
H)
e. Perineural invasion (Note I)
2. Margins
a. Cystic duct
b. Liver bed
c. Other(s) (as appropriate)
3. Additional pathologic findings, if present (Note J)
a. Dysplasia
b. Intestinal metaplasia
c. Other(s)
4. Regional lymph nodes (Note K)
a. Number
b. Number involved by tumor (specify location,
if possible)
5. Other organ(s) or structure(s) (specify
sites) (Note K)
a. Involvement by tumor by direct extension
b. Metastasis involvement
6. Other tissue(s)/organ(s)
7. Results/status of special studies (specify)
8. Comments
a. Correlation with intraoperative consultation,
as appropriate
b. Correlation with other specimens, as
appropriate
c. Correlation with clinical information, as
appropriate
EXPLANATORY NOTES
A. Application back Top Main Page
The protocol applies
only to carcinomas of the gallbladder including those showing endocrine
differentiation but excludes carcinoid tumors. More than 98% of malignant
tumors of the gallbladder are carcinomas.
B. Gallstones back Top Main Page
The presence or
absence of stones should be reported. Gallbladder cancer occurring in the
absence of stones may result from an anomalous choledocho-pancreatic junction
or from an association with chronic inflammatory bowel disease.
C. Configuration back Top Main Page
Configuration types
include exophytic, endophytic, or diffusely infiltrating. Since papillary
carcinomas have a favorable prognosis, these lesions should be specifically
reported.(1)
D. TNM and Stage Grouping back Top Main Page
The TNM Staging
System for carcinomas of the gallbladder of the American Joint Committee on Cancer/International
Union Against Cancer is recommended by the protocol and shown below.(2,3) The
TNM does not apply to carcinoid tumors or to sarcomas. Carcinomas of the
gallbladder are staged according to their depth of penetration into the wall
and extension to adjacent organs, and the extent of invasion correlates
inversely with survival.(1)
By AJCC/UICC
convention, the designation "T" refers to a primary tumor that has
not been previously treated. The symbol "p" refers to the pathologic
classification of the TNM, as opposed to the clinical classification and is
based on gross and microscopic examination. pT entails a resection of the
primary tumor or biopsy adequate to evaluate the highest pT category; pN
entails removal of nodes adequate to validate lymph node metastasis; and pM
implies microscopic examination of distant lesions. Clinical classification
(cTNM) is usually carried out by the referring physician before treatment
during initial evaluation of the patient or when pathologic classification is
not possible.
Tumor remaining
in a patient after definitive therapy (e.g., surgical resection for cure)
is categorized by a system known as R classification, shown below.
RX Presence of residual tumor cannot be
assessed
R0 No residual tumor
R1 Microscopic residual tumor
R2 Macroscopic residual tumor.
For the surgeon,
the R classification may be useful to indicate the known or assumed status of
the completeness of a surgical excision. For the pathologist, the R
classification is relevant to the status of the margins of a surgical resection
specimen. That is, tumor involving the resection margin on pathologic
examination may be assumed to correspond to residual tumor in the patient and
may be classified as macroscopic or microscopic according to the findings at
the specimen margin(s).
In contrast,
tumor remaining in a resection specimen from a patient who has undergone
previous (neoadjuvant) treatment of any type (radiation therapy alone,
chemotherapy therapy alone, or any combined modality treatment) is codified by
the TNM using a prescript "y" (e.g., ypT1). Thus, yTNM indicates the
post-treatment status of the tumor. For many neoadjuvant therapies, the
classification of residual disease may be a strong predictor of postoperative
outcome. In addition, the ypTNM classification provides a standardized
framework for the collection of data needed to accurately evaluate new
neoadjuvant therapies.
In contrast to
"residual" tumor, classification of a tumor as "recurrent"
requires a documented disease-free interval after definitive therapy. Recurrent
tumor may also be classified according to the TNM categories, but the prefix
"r" (e.g., rpT1) is used to indicate the recurrent status of the
tumor.
Primary Tumor
(T)
TX Primary tumor cannot be
assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor invades lamina propria
or muscle layer
T1a Tumor invades lamina propria
T1b Tumor invades muscle layer
T2 Tumor invades perimuscular
connective tissue; no extension beyond
serosa or into liver
T3 Tumor perforates serosa
(visceral perito-neum) or directly invades into one adjacent organ, or both
(extension 2 cm or less into liver)
T4 Tumor 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)
Regional Lymph
Nodes (N)
NX Regional lymph nodes cannot be
assessed
N0 No regional lymph node
metastasis
N1 Metastasis in cystic duct,
pericholedochal, and/or hilar lymph nodes (i.e. in the hepatoduodenal ligament)
N2 Metastasis in peripancreatic
(head only), periduodenal, periportal, celiac, and/or superior mesenteric lymph
nodes
Note: The
frequency of nodal involvement depends on the depth of invasion into the
gallbladder wall by the primary tumor. To separate pN1 from pN2, the lymph
nodes must be specifically identified. Peripancreatic nodes located along the
body and tail of the pancreas are sites of distant metastasis. The hilar nodes
include those along the inferior vena cava, hepatic artery, portal vein and
hepatic pedicle.
Distant
Metastasis (M)
MX Presence of distant metastasis
cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Stage Groupings
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T1 N1 M0
T2 N1 M0
T3 N0 M0
T3 N1 M0
Stage IVA T4 N0 M0
T4 N1 M0
Stage IVB Any T N2 M0
Any T Any N M1
E. Occult Carcinomas back Top Main Page
Occasionally carcinoma
is found in gallbladders removed by laparoscopic surgery. Not recognized
clinically or by imaging techniques, tumor is discovered during pathologic
evaluation of the resected specimen. In this setting, tumor spillage with
seeding along the endoscopic tract or intra-abdominal dissemination may be a
major complication of the procedure. If carcinoma in situ is found in such
specimens, multiple sections should be examined to exclude invasive cancer.
To exclude occult carcinoma
in gallbladders excised intact, at least three sections, one from the fundus,
one from the body, and one from the neck should be submitted if no gross
lesions are found.
F.
Histologic Type back Top Main Page
For consistency in
reporting, the histologic classification proposed by the World Health
Organization (WHO) is recommended.(4) However, this protocol does
not preclude use of other systems of classification or histologic types. A
modified WHO classification of gallbladder tumors follows:
WHO
Classification of Gallbladder Carcinomas
Carcinoma in situ*
Adenocarcinoma**
Papillary carcinoma
Adenocarcinoma, intestinal type
Clear cell adenocarcinoma
Mucinous carcinoma***
Signet ring cell carcinoma+
Squamous cell carcinoma
Adenosquamous carcinoma
Small cell carcinoma (oat cell carcinoma)++
Undifferentiated carcinoma
*Because carcinoma in
situ may be multifocal, cases of carcinoma in situ should be studied by
multiple sections or by the Swiss role method in order to exclude invasive
cancer in other areas of the gallbladder. Carcinoma in situ is often confused
with the epithelial atypia of repair.(5)
**Many adenocarcinomas
contain neuroendocrine cells. These tumors should not be considered
neuroendocrine carcinomas.
***A mucocele may be
mistaken for a mucinous carcinoma. Mucoceles often contain macrophages that
have engulfed mucin (muciphages). Consequently these macrophages may resemble
signet ring cells. Neoplastic signet ring cells are cytokeratin- and
CEA-positive, whereas muciphages do not stain for these markers.
+All
signet ring cell carcinomas are assigned Grade 3.
++Small
cell carcinomas should be specifically reported since they may cause endocrine
syndromes. In addition, small cell carcinomas are, by definition, high grade
(grade 4), an adverse prognostic factor.(6)
G. Histologic Grade back Top Main Page
The following grading
system, based on the extent of glandular formation in the tumor, is suggested.
Grade X - Grade
cannot be assessed
Grade 1 - Well
differentiated (>95% of tumor composed of glands)
Grade 2 - Moderately
differentiated (50-95% of tumor composed of glands)
Grade 3 - Poorly
differentiated (5-49% of tumor composed of glands)
Grade 4 - Undifferentiated
(<5% of tumor composed of glands)
The definitions of the
histologic grade are as follows:
Grade 1 - Well
differentiated adenocarcinomas are composed of more than 95% glands.
Grade 2 - Carcinomas
that are moderately differentiated are composed of 50%95% glands.
Grade 3 - Poorly
differentiated carcinomas are composed of 5%49% glands.
Grade 4 - Undifferentiated
carcinomas contain less than 5% glands and consist primarily of pleomorphic
spindle and giant cells or small cells with
considerable
nuclear atypia, small amounts of mucin, and no signficiant endocrine
differentiation.
*Grade 4 carcinomas
are classified as undifferentiated carcinomas (histologic type) by the WHO
classification (see above).
Published data
indicate that histologic grade is prognostically significant.(1)
H. Blood/Lymphatic Vessel Invasion back Top Main Page
Published data
indicate that blood vessel and/or lymphatic invasion has an adverse effect on
outcome and should be specifically recorded.(1)
I. Perineural Invasion back Top Main Page
Perineural invasion by
neoplastic cells is an adverse prognostic factor and should be reported. A
diagnostic pitfall may occur in cases of adenomyomatous hyperplasia, since the
ductal structures of adenomyomatous hyperplasia may invade perineural spaces.(7)
J. Additional Pathologic Findings back Top Main Page
Other common lesions
include chronic cholecystitis, dysplasia, carcinoma in situ, and various types of
metaplasia such as squamous, pyloric gland, and intestinal. Occasionally
changes consistent with inflammatory bowel disease are found in the
gallbladder.
K. Lymph Node Metastasis back Top Main Page
In general, carcinomas
of the gallbladder spread from some focus in the hepatoduodenal ligament toward
the nodes around the head of the pancreas. The cystic and pericholedochal nodes
are the key stations for spread toward the peripancreatic nodes. Lymph flows
through the pericholedochal nodes to these other regional nodes. Most often
tumor initially metastasizes to the pericholedochal lymph nodes.
1. Henson DE, Albores-Saavedra J, Corle D.
Carcinoma of the gallbladder. histologic types, stage of disease, grade, and
survival rates. Cancer. 1992;70:1493-1497.
2. Sobin LH, Wittekind C, eds. TNM
Classification of Malignant Tumours: International Union Against Cancer. 5th
ed. New York, NY: Wiley , 1997.
3. Fleming ID, Cooper JS, Henson DE, et al.,
eds. AJCC Manual for Staging of Cancer, 5th ed. Lippincott Raven, Philadelphia,
1997.
4. Albores-Saavedra J, Henson DE, Sobin LH.
Histological Typing of Tumours of the Gallbladder and Extrahepatic Bile Ducts.
WHO International Histological Classification of Tumours. Springer-Verlag,
Berlin, 1991.
5. Albores-Saavedra J, Henson DE. Gallbladder,
In: Pathology of Incipient Neoplasia. Henson DE, Albores-Saavedra J, eds. WB
Saunders, Philadelphia. 1993.
6. Albores-Saavedra J, Henson, DE. Tumors of
the Gallbladder and Extrahepatic Bile Ducts. Atlas of Tumor Pathology, 2nd
Series, Fascicle 22. Washington, D.C. Armed Forces Institute of Pathology,
1986.
7. Albores-Saavedra J, Henson DE.
Adenomyomatous hyperplasia of the gallbladder with perineural invasion. Arch
Pathol Lab Med. 1995;119:1173-1176.
BIBLIOGRAPHY
Albores-Saavedra J, Manrique JJ,
Angeles-Angeles A, Henson DE. Carcinoma in situ of the gallbladder. A
clinicopathologic study of 18 cases. Am J Surg Pathol. 1984;8:323-333.
Albores-Saavedra J, Alcantra-Vazquez A,
Cruz-Ortiz H, Herrera-Goepfert R. The precursor lesions of invasive gallbladder
carcinoma. Cancer. 1980;45:919-927.
Albores-Saavedra J, Soriano J,
Larraza-Hernandez O, Aguirre J, Henson DE. Oat cell carcinoma of the
gallbladder. Hum Pathol. 1984;15:639-646.
Bergdahl L. Gallbladder carcinoma first
diagnosed at microscopic examination of gallbladders removed for presumed
benign disease. Ann Surg. 1980;191:19-22.
Bivins BA, Meeker WR Jr, Griffen WO Jr.
Importance of histologic classification of carcinoma of the gallbladder. Am
Surg. 1975;41:121-124.
Bivins BA, Meeker WR Jr, Weiss DL, Griffen
WO Jr. Carcinoma in situ of the gallbladder. South Med J. 1975;68:297-300.
Black WC. The morphogenesis of gall
bladder carcinoma, In, Progress in Surgical Pathology, Vol II. Fenoglio CM,
Wolff M. eds, Masson, NY, 1980.
Cavazzana AO, Fassina AS, Tollot M, Ninfo
V. Small-cell carcinoma of gallbladder: An immunocytochemical and
ultrastructural study. Pathol Res Pract. 1991;187:472-476.
Fahim RB, McDonald JR, Richards JC, Ferris
DO. Carcinoma of the gallbladder: A study of its modes of spread. Ann
Surg. 1962;156:114-124.
Friedman RB, Anderson RE. Gilchrest KW,
Carbone PP. Prognostic factors in invasive gallbladder carcinoma. J Surg Oncol.
1983;23:189-194.
Guo K-J, Yamaguchi K, Enjoji M.
Undifferentiated carcinoma of the gallbladder: A clinicopathologic,
histochemical, and immunohistochemical study of 21 patients with a poor
prognosis. Cancer. 1988;61:1872-1879.
Higgs WR, Mocega EE, Jordan PH. Malignant
mixed tumor of the gallbladder. Cancer. 1973;32:471-475.
Johnstone AK, Zuch RH, Anders KH. Oat cell
carcinoma of the gallbladder. A rare and highly lethal neoplasm. Arch Pathol
Lab Med. 1993;117:1009-1012.
Nevin JE, Moran TJ, Kay S, King R. Carcinoma
of the gallbladder. Staging, treatment, and prognosis. Cancer. 1976;37:141-148.
Ouchi K, Owada Y, Matsuno S, Sato T.
Prognostic factors in the surgical treatment of gallbladder carcinoma. Surgery.
1987;101:731-737.
Shirai Y, Tsukada K, Ohtani T, Watanabe H,
Hatakeyama K. Hepatic metastases from carcinoma of the gallbladder. Cancer.
1995;75:2063-2068.
Shirai Y, Yoshida K, Tsukada K, Ohtani T,
Muto T. Identification of the regional lymphatic system of the gallbladder by
vital staining. Br J Surg. 1992;79:659-662.
Wanebo HJ, Castle WN, Fechner RE. Is
carcinoma of the gallbladder a curable lesion? Ann Surg. 1982;195:624-630.
Yamaguchi K, Tsuneyoshi M. Subclinical
gallbladder carcinoma. Am J Surg. 1992;163:382-386.
Authors
Donald
E. Henson, MD; Jorge Albores-Saavedra, MD;
Carolyn
C. Compton, MD, PhD
©2000. College of
American Pathologists (CAP). All rights reserved. None of the contents of this
publication may be reproduced, stored in a retrieval system or transmitted in any
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otherwise) without prior written permission of the publisher.
Contributors: back Top Main Page
CAP Cancer Committee