Anus
Protocol applies to
all carcinomas of the anus and anal canal.
Procedures
• Cytology
I. Cytologic material back Top Main Page
1. Patient identification
a. Name
b. Patient identification
c. Age (birth date)
d. Gender
2. Responsible physician(s)
3. Date of procedure
4. Other clinical information
a. Relevant history
(1) sexually transmitted diseases (HIV, HSV, HPV)
(2) genital neoplasms
(3) immunosuppression
(4) inflammatory bowel disease
(5) cigarette smoking
b. Relevant findings (e.g., direct inspection, endoscopic and/or imaging studies)
c. Clinical diagnosis
d. Procedure (brushing, washing, other)
e. Anatomic site(s) of specimen(s) (Note A)
B. MACROSCOPIC EXAMINATION
1. Specimen
a. Unfixed/fixed (specify fixative)
b. Number of slides received, if appropriate
c. Quantity and appearance of fluid specimen, if appropriate
d. Other (e.g., cytologic preparation from tissue)
e. Results of intraprocedural consultation
2. Material submitted for microscopic evaluation
3. Special studies, specify (e.g.,
cytochemistry, immunocytochemistry, DNA
analysis (specify type), morphometry, cytogenetic analysis)
C. MICROSCOPIC EVALUATION
1. Adequacy of specimen (if unsatisfactory for evaluation, specify reason)
2. Tumor, if present (Note B)
a. Histologic type, if possible (Note C)
b. Other characteristics of neoplasm (e.g., nuclear grade, necrosis)
3. Additional pathologic findings, if present (specify)
4. Results/status of special studies (specify)
5. Comments
a. Correlation with intraprocedural consultation, as appropriate
b. Correlation with other specimens, as appropriate
c. Correlation with clinical information, as appropriate
II. Biopsy back
Top Main
Page
(endoscopic, local excision, or other)
1. Patient identification
a. Name
b. Patient identification number
c. Age (birth date)
d. Gender
2. Responsible physician(s)
3. Date of procedure
4. Other clinical information
a. Relevant history
(1) sexually transmitted diseases (HIV, HSV, HPV)
(2) genital neoplasms
(3) immunosuppression
(4) inflammatory bowel disease
(5) cigarette smoking
b. Relevant findings (e.g., direct inspection, endoscopic and/or imaging studies)
c. Clinical diagnosis
d. Procedure (e.g., endoscopic biopsy, local excision)
e. Anatomic site(s) of specimen(s) (Note C)
1. Specimen
a. Unfixed/fixed (specify fixative)
b. Number of pieces
c. Largest dimension of each piece
d. Color
e. Results of intraoperative consultation
2. Tumor (if discernible)
a. Dimensions
b. Configuration
3. Margins, relation to tumor in an excisional biopsy
4. Additional pathologic findings, if present
5. Tissue submitted for microscopic evaluation
a. Incisional biopsy: submit entirely
b. Excisional biopsy
(1) lesion(s)
(2) margin(s) of excision (if identifiable)
(3) other lesions, if applicable
c. Frozen section tissue fragment(s) (unless saved for special studies)
6. Special studies (specify) (e.g., histochemistry, immunohistochemistry, DNA analysis (specify type), morphometry, cytogenetic analysis)
1. Tumor
a. Histologic type (Note B)
b. Histologic grade (Note C)
c. Extent of invasion (as appropriate)
d. Relationship of tumor to anal transitional zone, anal squamous or rectal mucosa, if possible
2. Margins (excisional biopsy)
3. Additional pathologic findings, if present
a. Condyloma
b. Anal canal intraepithelial neoplasia
c. Inflammatory processes
d. Other(s)
4. Results/status of special studies (specify)
5. Comments
a. Correlation with intraoperative consultation, as appropriate
b. Correlation with other specimens, as appropriate
c. Correlation with clinical information, as appropriate
III. Abdominal-perineal resection back Top Main Page
1. Patient identification
a. Name
b. Patient identification
c. Age (birth date)
d. Gender
2. Responsible physician(s)
3. Date of procedure
4. Other clinical information
a. Relevant history
(1) sexually transmitted diseases (HIV, HSV, HPV)
(2) genital neoplasms
(3) immunosuppression
(4) inflammatory bowel disease
(5) cigarette smoking
b. Relevant findings (e.g., endoscopic and/or imaging studies)
c. Clinical diagnosis
d. Procedure (e.g., abdominal-perineal resection)
e. Anatomic site(s) of specimen(s) (Note A)
1. Specimen
a. Organ(s)/tissue(s) received (specify)
b. Unfixed/fixed (specify fixative)
c. Number of pieces
d. Dimensions
e. Descriptive characteristics
f. Orientation of specimen (if indicated by surgeon)
g. Results of intraoperative consultation
2. Tumor
a. Location (Note A)
b. Configuration (Note D)
c. Dimensions (three dimensions)
d. Descriptive characteristics (e.g., color/consistency)
e. Ulceration/perforation
f. Distance from margins
(1) proximal
(2) distal
(3) radial (soft tissue margin closest to deepest tumor penetration)
g. Estimated depth of invasion
3. Additional pathologic findings, if present
4. Regional lymph nodes (Notes E and F)
5. Other organ(s) or structure(s)
6. Tissues submitted for microscopic evaluation
a. Tumor, including
(1) point of deepest penetration
(2) interface with adjacent proximal rectal mucosa
(3) interface with distal anal mucosa
b. Margins
(1) proximal
(2) distal
(3) radial (soft tissue margin closest to deepest tumor penetration)
c. All lymph nodes (Note E)
d. Other lesions (e.g., ulcers, polyps)
e. Rectal and anal tissue uninvolved by tumor
f. Other tissue(s)/organ(s)
g. Frozen section tissue fragment(s) (unless saved for special studies)
7. Special studies (specify) (e.g., histochemistry, immunohistochemistry, DNA analysis [specify type], morphometry, cytogenetic analysis) (Note F)
1. Tumor
a. Histologic type (Note B)
b. Histologic grade (Note C)
c. Extent of invasion (Note G)
d. Relation of tumor to anal transition zone, anal squamous or rectal mucosa (if possible)
e. Blood/lymphatic vessel invasion
2. Margins
a. Proximal
b. Distal
c. Radial (soft tissue margin closest to deepest tumor penetration)
3. Regional lymph nodes (Notes E and G)
a. Number
b. Number with metastases
4. Other organs or structures (Note F)
a. Involvement by tumor, direct extension
b. Metastatic involvement by tumor
5. Additional pathologic findings, if present
a. Condyloma
b. Anal canal intraepithelial neoplasia
c. Polyps
d. Fistula
e. Inflammatory bowel disease
f. Other(s)
6. Other tissues submitted (specify)
7. Results of special studies (specify)
8. Comments
a. Correlation with intraoperative consultation, as appropriate
b. Correlations with other specimens, as appropriate
c. Correlation with clinical information, as appropriate
EXPLANATORY NOTES
A. Location back Top Main Page
The location of the tumor within the anal region should be noted if possible. Accurate assessment of location may be complicated by several factors. First, because many anal carcinomas are managed successfully without surgery using combination chemotherapy and radiation therapy, resection specimens of anal tumors are seen only infrequently (primarily for small anal margin lesions or following failure of other treatment modalities). Precise determination of the primary tumor location from biopsy specimens may be very difficult or impossible. The stage of the neoplasm is also difficult or impossible to determine from biopsy specimens alone.
Assessment of tumor location is further complicated by the controversy and confusion over the normal anatomy of the anal canal.(6,7) Traditionally, the surgical anal canal has been defined as that part of the distal intestinal tract enclosed by the internal sphincter muscle. By this definition, however, a significant portion of the rectum is included. The anatomic anal canal is defined as beginning at the dentate line and extending distally to the anal verge (i.e., beginning of perianal skin). This definition excludes the anal transition zone (ATZ) from which many of the most important and characteristic anal carcinomas develop.(6,7) Others define the anal canal as only that portion from the dentate line extending proximally to its junction with rectal mucosa, reserving the term anal margin for the entire nonhair/sweat gland-bearing squamous mucosa-lined portion extending distally to the junction with perianal skin. A histologic definition based on the lining mucosa is perhaps most logical and includes the anal transition zone (ATZ) proximally to its junction with rectal mucosa and the nonhair/sweat gland-bearing mucosa extending distally to the junction with perianal skin.
The American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) staging system defines anal canal as extending from the rectum to the perianal skin and lined by the mucous membrane overlying the internal sphincter.(5) This definition includes the dentate line, and the anal transition zone epithelium as well as the non-hair/sweat gland-bearing squamous mucosa extending distally to its junction with skin and, therefore, incorporates the histologic approach. In this scheme anal margin refers only to the junction of skin and squamous mucosa of the anal canal. For staging purposes, anal margin tumors are staged according to the system used for skin cancers.
B. Histologic Type back Top Main Page
For consistency in reporting, the histologic classification proposed by the World Health Organization (WHO) is recommended.(1) However, this protocol does not preclude the use of other systems of classification or histologic types.
Classification of neoplasms arising in the anus is a
confusing and controversial subject due in large measure to the complex gross
and microscopic anatomy of the region (see note A). The great majority of
carcinomas of the anus are variants of squamous cell carcinoma with the varied
histologic patterns reflecting the diverse microscopic anatomy of the area.
Many tumors, especially of the proximal anal canal, have a mixed histologic
appearance including squamous, basaloid and occasional glandular elements, the
latter being designated as mucoepidermoid or squamous carcinoma with mucinous
microcysts in some classifications. Some systems of classification, such as the
WHO classification, designate all squamous carcinoma variants of the anal canal
as cloacogenic, whereas others classify only those tumors with a predominant
basaloid pattern as cloacogenic. Another pattern of growth that is designated
as a separate histologic type in some classifications is vaguely reminiscent of
adenoid cystic carcinoma of salivary gland and is referred to as the
pseudo-adenoid cystic pattern. Tumors of the more distal anal canal and
especially anal margin are generally purely squamous and show fewer basaloid or
glandular features.(2-4)
WHO Classification of
Carcinoma of the Anus(1)
Malignant epithelial tumors:
Squamous cell (cloacogenic) carcinoma
- large cell non-keratinizing (transitional)
- basaloid
Adenocarcinoma
- rectal type
- of anal glands
- within anorectal fistula
Small cell carcinoma*
Undifferentiated**
*By convention, this histologic type is assigned grade 3.
**Undifferentiated carcinomas are assigned grade 4.
Malignant epithelial tumors:
Squamous cell carcinoma
Giant condyloma (verrucous carcinoma)+
Basal cell carcinoma+
Others
Bowen’s disease+
Paget’s disease+
+These histologic types are not usually graded.
The term carcinoma, NOS (not otherwise specified) is not part of the WHO classification.
C. Histologic Grade back Top Main Page
Histologic grades for
anal squamous carcinoma are as follows:(1,5)
Grade X Grade cannot be assessed
Grade 1 Well differentiated
Grade 2 Moderately differentiated
Grade 3 Poorly differentiated
Grade 4 Undifferentiated
If there are variations in the differentiation within the tumor, the highest (least favorable) grade is recorded.
Histologic grades for adenocarcinoma of the anus based on the proportion of gland formation by the tumor are suggested as follows:
Grade X Grade cannot be assessed
Grade 1 Well differentiated (>95% of tumor forms glands)
Grade 2 Moderately differentiated (50-95% of tumor forms glands)
Grade 3 Poorly differentiated (5-49% of tumor forms glands)
Grade 4 Undifferentiated* (<5% of tumor forms glands)
*These tumors would correspond to the undifferentiated histologic type of carcinoma defined in the WHO classification.
D. Configuration back Top Main Page
Configurations include exophytic (fungating), endophytic (ulcerative), and diffusely infiltrative, but overlap among these types is common. Complex configurations may be reported using more than one descriptor.
E. Regional Lymph Nodes back Top Main Page
Regional lymph nodes (N) comprise the perirectal (anorectal, perirectal and lateral sacral), the internal iliac (hypogastric) and the inguinal (superficial and deep).(5) All other nodal groups represent sites of distant metastasis (M). The sites of regional node involvement correspond to the local lymphatic drainage, above to the rectal ampulla and below to the perineum. Tumors that arise in the anal canal usually spread initially to the anorectal and perirectal nodes, and those that arise at the anal margin spread to the superficial inguinal nodes.
F. Special Studies back Top Main Page
Immunohistochemistry may be an especially helpful adjunct to
the pathologic analysis of perianal Paget’s disease. Immunohistochemical
staining for cytokeratin (CK)7 is a sensitive method for detection of Paget’s
cells within involved anal and perianal epithelium. In addition, however, the
specific immunophenotype of Paget’s cells has been shown to correlate with
pathogenesis and may be important in patient management. Staining for CK20 has
been shown to identify Paget’s disease that is likely to be associated with
underlying rectal adenocarcinoma (presenting either synchronously or
metachronously). In contrast, Paget’s cells that do not express CK20 but
instead are positive for gross cystic disease fluid protein (GCDFP) are likely
to represent primary cutaneous intraepithelial malignancy (with sweat gland
differentiation).(8)
G. TNM and Stage Groupings back Top Main Page
The TNM Staging System for anal carcinoma of the AJCC/UICC is recommended by the protocol and shown below.(5) The primary tumor is staged according to its size and local extention, as determined by clinical or pathologic examination. For most histologic types of anal canal cancer the diameter of the tumor correlates with the depth of penetration. The staging system applies to all carcinomas arising in the anal canal including carcinomas that arise within anorectal fistulas. The classification includes all squamous carcinoma variants, including cloacogenic, but excludes melanomas. Cancers that arise at the anal margin are staged according to the classification for cancers of the skin.
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 therapy with curative intent (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
Tis Carcinoma in situ
T1 Tumor 2 cm or less in greatest dimension
T3 Tumor more than 5 cm in greatest dimension
T4 Tumor of any size invades adjacent organ(s), e.g., vagina, urethra, bladder (involvement of sphincter muscle(s) alone is not classified at T4)
Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in perirectal lymph node(s)
N2 Metastasis in unilateral internal iliac and/or inguinal lymph node(s)
N3 Metastasis in perirectal and inguinal lymph nodes and/or bilateral internal iliac and/or inguinal lymph nodes
Distant Metastasis
(M)
MX Presence of distant metastasis cannot be assessed
M0 No distant metastasis
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2 N0 M0
T3 N0 M0
Stage IIIA T1 N1 M0
T2 N1 M0
T3 N1 M0
T4 N0 M0
Stage IIIB T4 N1 M0
Any T N2 M0
Any T N3 M0
Stage IV Any T Any N M1
1. Jass JR, Sobin LH. Histologic Typing of Intestinal Tumours: World Health Organization. 2nd ed. Berlin-NY: Springer-Verlag; 1989:41-47.
2. Fenger C. Anal canal tumors and their precursors. Pathol Annu. 1988 Part 1; 23:45-66.
3. Fenger C. Anal neoplasia and its precursors: facts and controversies. Sem Diag Pathol. 1991;8:190-201.
4. Williams GR, Talbot IC. Anal carcinoma — A histologic review. Histopathology. 1994;25:507-516.
5. Fleming ID, Cooper JS, Henson DE, et al. eds., AJCC Manual for Staging of Cancer, 5th ed., Lippincott Raven, Pa, 1997.
6. Fenger C. Histology of the anal canal. Am J Surg Pathol. 1988;12:41-55.
7. Lewin KJ, Riddell RH, Weinstein WM. The anal canal. In, Lewin KJ, Riddell RH, Weinstein WM (ed): Gastrointestinal Pathology and Its Clinical Implications. NY: Igaku-Shoin 1992, pp 1318-1359.
8. Goldblum JR, Hart WR. Perianal Paget’s Disease. A histological and immunohistochemical study of 11 cases with and without associated rectal adenocarcinoma. Am J Surg Pathol. 1998;22:170-179.
BIBLIOGRAPHY
Beckmann AM, Acker R, Christiansen AE, Sherman KJ. Human papillomavirus infection in women with multicentric squamous cell neoplasia. Am J Obstet Gynecol. 1991: 165;1431-1437.
Boman B, Moertel CG, O’Connell MJ, et al. Carcinoma of the anal canal. A clinical and pathological study of 188 cases. Cancer. 1984;54:114-125.
Daling JR, Weiss NS, Hislop G, et al. Sexual practices, sexually transmitted diseases and the incidence of anal cancer. N Engl J Med. 1987;317:973-977
Daling JR, Sherman KJ, Hislop G, et al: Cigarette smoking and the risk of anogenital cancer. Am J Epidemiol. 1992;135:180-189.
Dixon AR, Pringle JH, Holmes JT, Watkin DFL. Cervical intraepithelial neoplasia and squamous cell carcinoma of the anus in sexually active women. Postgrad Med J. 1991;67:557-559.
Duggan, MA, Boras VF, Inoue M, McGregor SE. Human papillomavirus DNA in anal carcinomas: Comparison of in situ and dot blot hybridization. Am J Clin Pathol. 1991;96:318-325.
Higgins GD, Uzelin DM, Phillips GE, et al. Differing characteristics of human papillomavirus, RNA-positive and RNA-negative anal carcinomas. Cancer. 1991;68:561-567.
Mitchell EP. Carcinoma of the anal canal. Semin Oncol. 1988;15:146-153.
Noffsinger AE, Suzuk L, Hui Y. Differential sensitivities of E6 type-specific and L1 consensus primers in the detection of human papillomavirus in anal carcinoma. Mod Pathol. 1995;8:509-514.
Papillon J, Montbaron JT. Epidermoid carcinoma of the anal canal: a series of 276 cases. Dis Colon Rectum. 1987;30:324-333.
Rickert RR: Disorders of the anal region. In: Ming SC, Goldman H, eds. Pathology of the Gastrointestinal Tract. Philadelphia, Pa: Saunders; 1992:882-903.
Salmon RJ, Zafrani B, Labib A, et al. Prognosis of cloacogenic and squamous cancers of the anal canal. Dis Colon Rectum. 1986;29:336-340.
Shepherd NA, Scholefield JH, Love SB, England J, Northover JM. Prognostic factors in anal squamous carcinoma: A multivariate analysis of clinical, pathological and flow cytometric parameters in 235 cases. Histopathology. 1990;16:545-555.
Wolber R, Dupuis B, Thiyagaratnam P, Owen D. Anal cloacogenic and squamous carcinomas. Am J Surg Pathol. 1990;14:176-182.
Zaki SR, Judd R, Coffield LM, et al. Human papillomavirus infection and anal carcinoma. Am J Pathol. 1992;140:1345-1355.
Authors
R. R. Rickert, MD, Carolyn C. Compton, MD, PhD
Contributors: back Top Main Page
CAP Cancer Committee