including intrahepatic bile ducts
Protocol
applies to hepatocellular carcinoma and cholangiocarcinoma.
Procedures
Cytology
Hepatectomy, Partial
or Complete
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 specimen obtained
4. Other clinical information
a. Relevant history
(1) family history of liver tumors
(2) prior surgery for cancer
(3) ulcerative colitis
(4) viral hepatitis
(5) hemochromatosis
(6) cirrhosis
(7) bile duct disease (e.g., liver-fluke
infection)
b. Relevant findings (e.g. serum
alpha-fetoprotein levels, imaging studies)
c. Clinical diagnosis
d. Procedure (e.g. FNA, other)
e. Type of specimen (aspiration)
f. Anatomic site(s) of specimen (e.g. right or
left lobe of liver)
B. MACROSCOPIC
EXAMINATION
1. Specimen
a. Description
b. Unfixed/fixed(specify fixative)
c. Number of slides received
d. Quantity and appearance of fluid specimen
e. Other (e.g. tissue received for cytologic
preparation)
f. Results of intraprocedural consultation
2. Material submitted for microscopic evaluation
(e.g. smear, cytocentrifuge, touch or filter preparation, cell block)
3. Special studies (specify) (e.g.
immunohistochemical stains, histochemical stains, electron microscopy, flow
cytometry, cytogenetic studies )
C. MICROSCOPIC
EVALUATION
1. Adequacy of specimen (if unsatisfactory for
evaluation, specify reason)
2. Tumor, if present (Note A)
a. Histologic type, if possible (Note
B)
b. Other descriptive features (e.g. nuclear
grade, necrosis, bile production)
3. Additional pathologic findings, if present
4. Comments
a. Correlation with intraprocedural
consultation, as appropriate
b. Correlation with other specimens, as
appropriate
c. Correlation with clinical information, as
appropriate
any surgical
approach
A. CLINICAL
INFORMATION
1. Patient identification
a. Name
b. Identification number
c. Age (birth date)
d. Gender
2. Responsible physician(s)
3. Date specimen obtained
4. Other clinical information
a. Relevant history
(1) family history of liver tumors
(2) prior surgery for cancer
(3) ulcerative colitis
(4) viral hepatitis
(5) hemochromatosis
(6) cirrhosis
(7) bile duct disease (e.g., liver-fluke
infection)
b. Relevant findings (e.g. serum
alpha-fetoprotein levels, imaging studies)
c. Clinical diagnosis
d. Procedure (e.g. needle biopsy, wedge biopsy)
e. Type of specimen(s) (e.g. tumor biopsy,
random liver)
f. Anatomic site(s) of specimen(s) (e.g.
right/left lobe, adjacent sites)
B. MACROSCOPIC
EXAMINATION
1. Specimen
a. Tissue(s) received
b. Unfixed/fixed (specify fixative)
c. Size (three dimensions, if appropriate)
d. Number of cores/fragments
e. Descriptive features (e.g. color/bile
stained)
f. Orientation (if indicated by surgeon)
g. Result of intraoperative consultation
2. Tumor, if identifiable
a. Size (three dimensions if possible)
b. Descriptive features (e.g. hemorrhage/necrosis/bile)
3. Additional pathologic findings, if
identifiable (e.g. cirrhosis)
4. Tissue submitted for microscopic evaluation
a. Tumor (Note C)
b. Other lesions (e.g. regenerative
nodules/cirrhosis)
c. Frozen section tissue fragment(s)
5. Special studies (specify) (e.g.
immunohistochemical stains, histochemical stains, electron microscopy, flow
cytometry, cytogenetic studies)
C. MICROSCOPIC
EVALUATION
1. Tumor
a. Histologic type (Note B)
b. Histologic grade (Note D)
c. Pattern of growth (if appropriate)
(1) trabecular
(2) tubular
(3) solid
2. Blood vessel invasion
3. Additional pathologic findings, if present
a. Benign neoplasms
b. Cirrhosis
c. Iron overload
d. Hepatitis
e. Liver cell dysplasia
f. Other(s)
4. Other tissue(s)/organ(s)
5. Results/status of special studies (specify)
6. Comments
a. Correlation with intraoperative consultation,
as appropriate
b. Correlation with other specimens, as
appropriate
c. Correlation with clinical information, as
appropriate
A. CLINICAL
INFORMATION
1. Patient identification
a. Name
b. Identification number
c. Age (birth date)
d. Gender
2. Responsible physician(s)
3. Date specimen obtained
4. Other clinical information
a. Relevant history
(1) family history of liver tumors
(2) prior surgery for cancer
(3) ulcerative colitis
(4) viral hepatitis
(5) hemochromatosis
(6) cirrhosis
(7) bile duct disease (e.g., liver-fluke
infection)
b. Relevant findings (e.g. serum
alpha-fetoprotein levels, imaging studies)
c. Clinical diagnosis
d. Procedure (e.g. left lobectomy, partial
hepatectomy, total hepatectomy)
e. Operative findings
f. Anatomic site (e.g. right/left lobe of
liver, related sites)
B. MACROSCOPIC
EXAMINATION
1. Specimen
a. Tissue(s)/organ(s) received
b. Unfixed/fixed (specify fixative)
c. Size (three dimensions)
d. Weight
e. Descriptive features (external/cut surfaces)
f. Orientation (if indicated by surgeon)
g. Results of intraoperative consultation
2. Tumor(s)
a. Number (Note E)
b. Location
c. Size (three dimensions), for all major tumor
nodules
d. Circumscribed/infiltrative
e. Descriptive features (e.g.
hemorrhage/necrosis/bile; central scar)
f. Extension to adjacent organs/tissues (e.g.
adrenal/diaphragm) (Note E)
g. Blood vessel invasion (Note E)
3. Margins (Note F)
4. Pathologic findings in noncancerous liver
a. Cirrhosis (type)
b. Iron deposition
c. Bile stasis
d. Other(s)
5. Regional lymph nodes
a. Location (if designated)
b. Number
6. Tissues submitted for microscopic evaluation
a. Tumor
b. Nodules (Note G)
c. Margins of resection (Note F)
d. Non-neoplastic liver
e. Portal/hepatic veins
f. Porta hepatis
g. All lymph nodes
h. Other lesions
i. Gallbladder (if present)
j. Other tissues or organs (specify)
k. Frozen section tissue fragment(s)
7. Special studies (specify, e.g.
immunohistochemical stains, histochemical stains, electron microscopy, flow
cytometry, cytogenetic studies)
C. MICROSCOPIC
EVALUATION
1. Tumor(s)
a. Histologic type (Note B)
b. Histologic grade (Note D)
c. Pattern of growth (if appropriate)
(1) trabecular
(2) tubular
(3) solid
d. Number and location
e. Blood/lymphatic vessel invasion
2. Additional pathologic findings, if present (Note H)
a. Benign tumor
b. Cirrhosis (type)
c. Iron overload
d. Portal vein thrombosis
e. Liver cell dysplasia
f. Hepatitis
g. Other(s)
3. Margins (Note F)
4. Regional lymph nodes (pN)
a. Number
b. Number with metastasis (specify location of
nodes with metastasis, if possible)
5. Other tissues/organs (specify)
6. Status/results of special studies (specify)
7. Metastasis to other organ(s) or structure(s)
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
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Page
This protocol applies
only to primary carcinomas of the liver [hepatocellular carcinoma (hepatoma)
and cholangiocarcinoma]. It excludes hepatoblastoma.
B.
Histologic Type back
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The protocol
recommends the following modified classification of the World Health Organization
(WHO). In the United States, almost 70 percent of the primary malignant tumors
of the liver are hepatocellular carcinomas.(1)
WHO
Classification of Carcinomas of the Liver (Modified)
Hepatocellular carcinoma
Combined hepatocellular cholangiocarcinoma
Cholangiocarcinoma, intrahepatic
Bile duct cystadenocarcinoma
Undifferentiated carcinoma
C. Submission of
Tissue back Top Main Page
For most biopsies, the
entire specimen should be submitted for histologic examination. Portions may be
retained for specific reasons only if the specimen is of sufficient size that
histologic evaluation will not be compromised. In a wedge biopsy, sections
should be submitted perpendicular to the capsule.
D. Histologic Grade back
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Page
Grading of Hepatocellular Carcinoma
The grading system of
Edmondson and Steiner is recommended for hepatocellular carcinomas.(2)
Grade
I: Reserved for those areas in
Grade-II hepatocellular carcinomas where the difference between the tumor cells
and hyperplastic liver cells is so minor that a diagnosis of carcinoma rests
upon the demonstration of more aggressive growths in other parts of the
neoplasm.
Grade
II: Cells show marked resemblance to
normal hepatic cells. Nuclei are larger and more hyperchromatic than normal
cells. Cytoplasm is abundant and acido-philic. Cell borders are sharp and clear
cut. Acini are frequent and variable in size. Lumina are often filled with bile
or protein precipitate.
Grade
III: Nuclei are larger and more
hyperchro-matic than Grade II cells. The nuclei occupy a relatively greater
proportion of the cell (high N/C ratio). Cytoplasm is granular and acidophilic,
but less so than Grade II tumors. Acini are less frequent and not as often
filled with bile or protein precipitate. More single cell growth in vascular
channels is seen than in Grade II.
Grade
IV: Nuclei are intensely hyperchromatic.
Nuclei occupy a high percentage of the cell. Cytoplasm is variable in amount,
often scanty. Cytoplasm contains fewer granules. The growth pattern is
medul-lary in character, trabeculae difficult to find, and cell masses seem to
lie loosely without cohesion in vascular channels. Only rare acini are
seen. Spindle cell areas have been seen
in some tumors. Short plump cell forms, resembling oat cell carcinoma of the
lung seen in some.
The pathologist should
specify the grading system used. The
higher the grade, the less the resemblance of the tumor to normal liver and
the more obvious its morphologic features are to malignant growth.
Histologic grade has
been shown to have a relationship to tumor size, tumor presentation, and
metastatic rate.(3,4) Low histologic grade has been shown to be
predictive of disease-free survival but not of overall actuarial survival.(5)
Grading
of Cholangiocarcinoma
For
cholangiocarcinomas, definitive criteria for histologic grading have not been
established, however a quantitative grading system based on the proportion of
gland formation within the tumor is suggested and shown below.
Grade
X Grade cannot be assessed
Grade
1 Well differentiated (>95% or
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)
E. TNM and Stage Groupings(6) back Top Main Page
The TNM staging system
of the American Joint Committee on Cancer (AJCC)/International Union Against Cancer
(UICC) applies to all primary carcinomas of the liver, including hepatocellular
carcinomas, intrahepatic bile duct carcinomas and mixed tumors. It does not
apply to hepatic sarcomas or to metastatic tumors of the liver. The T
classification depends on the number of tumor nodules, the size of the largest
nodule (2 cm is the discriminating limit), and the presence or absence of blood
vessel invasion. The TNM classification does not discriminate between multiple
independent primary tumors or intra-hepatic metastasis from a single primary
hepatic carcinoma. Vascular invasion includes either the gross or the
histologic involvement of vessels. Portal vein invasion is an important adverse
prognostic factor and should be reported.
The designation T
refers to the first resection of a primary tumor. The symbol pT refers to the
pathologic classification of the TNM, as opposed to the clinical
classification. Pathologic classification is based on gross and microscopic
examination. pT entails a resection of the primary tumor or biopsy adequate to
evaluate the 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.
Primary
Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Solitary tumor 2 cm or less in greatest
dimension without vascular invasion
T2 Solitary tumor 2 cm or less in greatest
dimension with vascular invasion; or multiple tumors limited to one lobe, none
more than 2 cm in greatest dimension
without vascular invasion; or solitary tumor more than 2 cm in greatest
dimension without vascular invasion
T3 Solitary tumor more than 2 cm in
greatest dimension with vascular invasion; or multiple tumors limited to one
lobe, none more than 2 cm in greatest dimension with vascular invasion; or multiple
tumors limited to one lobe, any more than 2 cm in greatest dimension, with or
without vascular
invasion
T4 Multiple tumors in more than one lobe;
or tumor(s) involve(s) a major branch of the portal or hepatic vein(s) or
invasion of adjacent organs other than the gallbladder or perforation of the
visceral peritoneum
Note: For
classification, the plane projecting between the bed of the gallbladder and the
inferior vena cava divides the liver into two lobes.
The absence or
presence of residual tumor following nonsurgical therapy (e.g., chemotherapy,
radiation therapy, combination chemoradiation therapy or prior surgical therapy
such as polypectomy) may be described by the symbol R and classified as
follows:
RX Presence of residual tumor cannot be assessed
R0 No residual tumor
R1 Microscopic residual tumor
R2 Macroscopic residual tumor
If residual tumor is
present, its extent may be documented by the TNM classification preceded by the
symbol y (e.g., ypT1).
Local recurrence
following a previous resection should be classified as above with the prefix
r (e.g., rpT1) and the recurrent tumor topographically assigned to the
proximal segment of the anastomosis.
Regional
Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
Distant
Metastasis (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Stage
Groupings
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage IIIA T3 N0 M0
Stage IIIB T1 N1 M0
T2 N1 M0
T3 N1 M0
Stage IVA T4 Any
N M0
Stage IVB Any T Any
N M1
The evaluation of margins
for total or partial hepatectomy specimens depends on the method and extent of
resection. It is recommended that the surgeon be consulted to determine the
critical foci within the margins that require microscopic evaluation. The
transection margin of a partial hepatectomy may be large, rendering it
impractical for complete examination. In this setting, grossly positive margins
should be microscopically confirmed and documented. If the margins are grossly
free on tumor, judicious sampling of the cut surface in the region closest to
the nearest identified tumor nodule is indicated. In selected cases, adequate
random sampling of the cut surface may be sufficient. In cases of
cholangiocarcinoma the histologic examination of the bile ducts at the cut margin
is recommended to evaluate the lining epithelium for in-situ carcinoma or
dysplasia. If the neoplasm is found near the surgical margin, the distance from
the margin should be reported. For multiple tumors, the distance from the
nearest tumor should be reported.
G. Histologic Sampling back
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Page
Sections should be
prepared from each major tumor nodule with representative sampling of smaller
nodules, if macroscopically different in appearance.
H.
Additional Pathologic Findings back Top Main Page
Cirrhosis should be
specifically reported since it has an adverse effect on outcome. Specific types
of underlying disease such as viral hepatitis or hemochromatosis should be
separately evaluated and graded, if appropriate.
1. Ishak KG, Anthony PP, Sobin LH.
Histological Typing of Tumours of the Liver. WHO International Histological
Classification of Tumours. Berlin: Springer Verlag, 1994.
2. Edmondson HA, Steiner PE. Primary carcinoma
of the liver. A study of 100 cases among 48,900 necropsies. Cancer.
1954;7:462-503.
3. Kenmochi K, Sugihara S, Kojiro M.
Relationship of histologic grade of hepatocellular carcinoma (HCC) to tumor size,
and demonstration of tumor cells of multiple different grades in single small
HCC. Liver. 1987;7:18-26.
4. Anthony PP. Primary carcinoma of the liver:
A study of 282 cases in Ugandan Africans. J Pathol. 1973;110:37-48.
5. Ng IO, Lai EC, Fan ST, Ng MM, So MK.
Prognostic significance of pathologic features of hepatocellular carcinoma.
Cancer. 1995;76:2443-2448.
6. Fleming ID, Cooper JS, Henson DE, et al.,
eds. AJCC Manual for Staging of Cancer. 5th ed. Lippincott Raven, Philadelphia,
1997.
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Goodman ZD. Histologic diagnosis of
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Hayashi S, Miyazaki M, Kondo Y, Nakajima
N. Invasive growth patterns of hepatic hilar ductal carcinoma. A histologic
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Izumi R, Shimizu K, Ii T, et al.
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Nzeako UC, Goodman ZA, Ishak KG.
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Author
Stephen
G. Ruby, MD
©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 form or by any means (electronic, mechanical, photocopying, recording, or
otherwise) without prior written permission of the publisher.
Contributors: back Top Main Page
CAP Cancer Committee; Gregorio Chejfec,
MD; John Craig, MD; John A. Payne,
MD; Jerome B. Taxy, MD; Kay Washington, MD; Christopher Willett, MD; James
Williams, MD