Protocol for the examination of specimens from patients with carcinoma of the penis.The College of American Pathologists offers these protocols to assist pathologists in providing clinically useful and relevant information when reporting results of surgical specimen examinations. The College regards the reporting elements in the "Surgical Pathology Cancer Case Summary (Checklist)" portion of the protocols as essential elements of the pathology report. However, the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice.
The College developed these protocols as an educational tool to assist pathologists in the useful reporting of relevant information. It did not issue the protocols for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the protocols might be used by hospitals, attorneys, payers, and others. Indeed, effective January 1, 2004, the Commission on Cancer of the American College of Surgeons mandated the use of the checklist elements of the protocols as part of its Cancer Program Standards for Approved Cancer Programs. Therefore, it becomes even more important for pathologists to familiarize themselves with these documents. At the same time, the College cautions that use of the protocols other than for their intended educational purpose may involve additional considerations that are beyond the scope of these documents.
PROTOCOL FOR THE EXAMINATION OF SPECIMENS FROM PATIENTS WITH CARCINOMA OF THE PENIS
This protocol applies to primary carcinoma of the penis. The 7th edition TNM staging system for carcinoma of the penis of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) is recommended.
SURGICAL PATHOLOGY CANCER CASE SUMMARY (CHECKLIST)
Penis: Incisional Biopsy, Excisional Biopsy, Partial Penectomy, Total Penectomy, Circumcision
Select a Single Response Unless Otherwise Indicated
* Data elements with asterisks are not required. However, these elements may be clinically important but are not yet validated or regularly used in patient management.
Procedure --Incisional biopsy --Excisional biopsy --Partial penectomy --Total penectomy --Circumcision --Other (specify):-- --Not specified Foreskin (Presence and Type) (select all that apply) (note A) --Present (uncircumcised) * --Short * --Medium * --Long * --Phimotic --Not identified (circumcised) --Cannot be determined Lymphadenectomy --Not applicable --Sentinel node biopsy --Inguinal (superficial and deep) --External iliac --Internal iliac --Pelvic nodes --Other (specify):-- Lymph Node Sampling (note B) Number of involved lymph nodes: -- Total number of lymph nodes examined: -- Specimen Size Specify: -- x -- x -- cm Tumor Site (if multiple sites are involved, select all that apply) --Glans --Foreskin mucosal surface --Foreskin skin surface --Coronal sulcus (balanopreputial sulcus) --Skin of the shaft --Penile urethra Tumor Size Greatest dimension: -- cm * Additional dimensions: -- x -- cm * Tumor Focality * --Unicentric * --Multicentric * Tumor Macroscopic Features (select all that apply) * --Flat * --Ulcerated * --Polypoid * --Verruciform * --Necrosis * --Hemorrhage * --Other (specify): -- * Tumor Deep Borders (select all that apply) (note C) * --Pushing (broadly based) * --Infiltrative (jagged) * --Other (specify): -- * Macroscopic Extent of Tumor (select all that apply) * In the Glans * --Tumor involves lamina propria * --Tumor involves corpus spongiosum * --Tumor involves tunica albuginea * --Tumor involves corpus cavernosum * --Tumor involves distal (penile) urethra * --Not applicable * In the Foreskin * --Tumor involves lamina propria * --Tumor involves dartos * --Tumor involves preputial skin * --Not applicable * In the Shaft * --Tumor involves skin * --Tumor involves dartos * --Tumor involves Buck fascia * --Tumor involves corpus spongiosum * --Tumor involves corpus cavernosum * --Tumor involves proximal urethra * --Not applicable Macroscopic Assessment of Resection Margins (select all that apply) --Cannot be assessed --Grossly uninvolved --Grossly involved (specify for penectomy or circumcision specimen below) For Penectomy Specimens --Urethral --Periurethral tissues (lamina propria, corpus spongiosum, Buck fascia) --Corpora cavernosa --Buck fascia at penile shaft --Skin --Other (specify):-- For Circumcision Specimens --Coronal sulcus margin --Cutaneous margin Histologic Type (select all that apply) (note D) --Squamous cell carcinoma (SCC) --Usual (keratinizing) --Basaloid * --Warty (condylomatous) --Verrucous * --Cuniculatum * --Papillary, not otherwise specified (NOS) --Sarcomatoid * --Pseudohyperplastic * --Acantholytic (pseudoglandular) * --Mixed SCCs --Adenosquamous --Primary neuroendocrine carcinoma --Paget disease --Adnexal carcinoma (specify type): -- --Clear cell carcinoma --Carcinoma, type cannot be determined --Other (specify): -- Histologic Grade (note E) --Not applicable --GX: Cannot be assessed --G1: Well differentiated --G2: Moderately differentiated --G3: Poorly differentiated Microscopic Tumor Extension (select all that apply) Anatomic Levels In the Glans --Tumor involves lamina propria --Tumor involves corpus spongiosum --Tumor involves tunica albuginea --Tumor involves corpus cavernosum --Not applicable In the Coronal Sulcus --Tumor involves lamina propria --Tumor involves dartos --Tumor involves Buck fascia --Not applicable In the Foreskin --Tumor involves lamina propria --Tumor involves dartos --Tumor involves preputial skin --Not applicable In the Shaft --Tumor involves skin --Tumor involves dartos --Tumor involves Buck fascia --Tumor involves corpus spongiosum --Tumor involves corpus cavernosum --Not applicable Other Extension --Penile (distal) urethra --Proximal urethra --Prostate --Scrotum --Regional skin (pubis, inguinal) * Tumor Thickness/Depth (note F) * Specify: -- mm Margins of Resection (select all that apply) (note G) --Cannot be assessed --Histologically uninvolved --Histologically involved (specify for penectomy or circumcision specimens below): For Penectomy Specimens --Urethral --Periurethral tissues (lamina propria, corpus spongiosum, Buck fascia) --Corpus cavernosum --Buck fascia at penile shaft --Skin --Other (specify): -- For Circumcision Specimens --Coronal sulcus margin --Cutaneous margin Lymph-Vascular Invasion (note H) --Not identified --Present --Indeterminate Perineural Invasion (note I) --Not identified --Present --Indeterminate Pathologic Staging (pTNM) (1) (note J) TNM Descriptors (required only if applicable) (select all that apply) --m (multiple primary tumors) --r (recurrent) --y (posttreatment) Primary Tumor (pT) --pTX: Primary tumor cannot be assessed --pT0: No evidence of primary tumor --pTis: Carcinoma in situ --pTa: Noninvasive verrucous carcinoma (a) --pT1a: Tumor invades subepithelial connective tissue without lymph vascular invasion and is not poorly differentiated (ie, grade 3-4) --pT1b: Tumor invades subepithelial connective tissue with lymph vascular invasion or is poorly differentiated --pT2: Tumor invades corpus spongiosum or cavernosum --pT3: Tumor invades urethra --pT4: Tumor invades other adjacent structures Regional Lymph Nodes (pN) --pNX: Regional lymph nodes cannot be assessed --pN0: No regional lymph node metastasis --pN1: Metastasis in a single inguinal lymph node --pN2: Metastasis in multiple or bilateral inguinal lymph nodes --pN3: Extranodal extension of lymph node metastasis or pelvic lymph node(s) unilateral or bilateral Distant Metastasis (pM) --Not applicable --pM1: Distant metastasis (b) * Additional Pathologic Findings (select all that apply) (note K) * --None identified * --Penile intraepithelial neoplasia (PeIN) * --Differentiated (simplex) * --Warty * --Basaloid * --Mixed (warty/basaloid) * --Other (specify): -- * --Focal * --Multifocal * --Margins uninvolved * --Margins involved (specify margin): -- * --Lichen sclerosus * --Squamous hyperplasia * --Condyloma acuminatum * --Other (specify): -- * Ancillary Studies * Specify: -- * -- Not performed * Comment(s): -- (a) Broad pushing penetration (invasion) is permitted, but destructive invasion argues against this diagnosis. (b) Lymph node metastasis outside of the true pelvis in addition to visceral or bone sites.
A: Types of Foreskin.--There are 3 foreskin types: in the short foreskin, the preputial orifice is located behind the glans corona; in the medium foreskin, the orifice is between the corona and the meatal orifice; in the long foreskin, the entire glans is covered and the meatus is not identified without retracting the foreskin. Phimotic foreskins are unretractable and long. (2) Phimosis is present in up to one-half of patients with penile carcinoma, (2) and its presence is considered a risk factor for the development of this tumor. (3-5)
B: Number of Involved Lymph Nodes and Extension of the Lymphadenectomy.--The presence of more than 2 positive lymph nodes in 1 inguinal basin increases the likelihood of contralateral inguinal and ipsilateral pelvic nodal involvement. (6) In such cases, prophylactic contralateral inguinal and ipsilateral pelvic lymphadenectomy is advised. The number and percentage of positive nodes involved also has an impact on survival. (7,8)
C: Tumor Base of Infiltration.--Two patterns are recognized: infiltrating (invasion in blocks of small solid strands of cell tumors broadly infiltrating the stroma) and pushing infiltration (tumor cells invading in large cell blocks with well-defined tumor-stroma interface). The infiltrating pattern of invasion is associated with a higher risk for nodal involvement. (9)
D: Histologic Subtype of Squamous Cell Carcinoma.--Most penile cancers are squamous cell carcinomas (SCCs), and most arise from the epithelium of the distal portion of the penis (including glans, coronal sulcus, and mucosal surface of the prepuce). Squamous cell carcinoma of the usual type (keratinizing SCC) comprises about 50% to 60% of all cases. (10-12) There are other SCC variants showing distinctive morphologic and outcome features. (10-12) The different histologic subtypes correlate with different rates of regional/nodal and systemic dissemination. Penile cancer subtypes can be prognostically stratified in 3 groups. The low-risk group includes verruciform tumors such as verrucous, papillary, and warty/condylomatous carcinomas. (13,14) More recently described subtypes, such as pseudohyperplastic and carcinoma cuniculatum of the penis, also belong to this category of excellent prognosis. (15,16) The high-risk category is comprised by basaloid, sarcomatoid, adenosquamous, and poorly differentiated SCC of the usual type. (17-19) There is an intermediate category of metastatic risk that includes most SCCs of the usual type, some mixed neoplasms (such as hybrid verrucous carcinomas), and high-grade variants of warty/ condylomatous carcinomas. (14)
E: Histologic Grade.--Histologic grade has been consistently reported as an influential predictive factor of groin metastasis and dissemination of penile cancer. (20-22) We recommend a method to grade penile SCCs as follows:
Grade 1 is an extremely well-differentiated carcinoma, with a minimal deviation from the morphology of normal/hyperplastic squamous epithelium.
Grade 2 tumors show a more disorganized growth as compared to grade 1 lesions, higher nuclear to cytoplasmic ratio, evident mitoses, and, although present, less prominent keratinization.
Grade 3 are tumors showing any proportion of anaplastic cells, identified as solid sheets or irregular small aggregates, cords or nests of cells with little or no keratinization, high nuclear to cytoplasmic ratio, thick nuclear membranes, nuclear pleomorphism, clumped chromatin, prominent nucleoli, and numerous mitoses. (22,23)
A tumor should be graded according to the least differentiated component. Any proportion of grade 3 should be noted in the report. (23)
F: Depth of Invasion.--The tumor depth in small lesions is best obtained by perpendicularly sectioning along the tumor central axis. For large glans tumors, we prefer to section the specimen longitudinally in half, with additional parallel sections of each half, using as an axis the central and ventral penile urethra. The depth of invasion of SCC is defined as a measurement in millimeters from the epithelial-stromal junction of the adjacent non-neoplastic epithelium to the deepest point of invasion. In larger tumors, especially verruciform ones, the previously mentioned system is not applicable, and we measure the thickness from the surface (excluding the keratin layer) to the deepest point of invasion. Depth of invasion and tumor thickness are of equivalent significance. There is a correlation between depth of invasion and outcome in penile cancers.Minimal risk formetastasiswas reported for tumors measuring less than 5mmin thickness. (22,24) Tumors invading deeper into penile anatomic levels are usually associated with a higher risk for nodal involvement. There is also a correlation between deeper infiltration and higher histologic grade, although some exceptions do occur. (25) Tumors invading corpus cavernosum are at higher risk for presenting nodal metastases than those invading only corpus spongiosum, (26,27) and the deepest erectile tissue invaded should be clearly stated in the final pathology report.
G: Resection Margins.--Positive margins adversely affect prognosis in patients with penile squamous cell carcinomas. (10,12,28) Important margins to be examined in partial penectomy specimens include (1) proximal urethra and surrounding periurethral cylinder consisting of epithelium, lamina propria, corpus spongiosum, and penile fascia; (2) proximal shaft with corresponding corpora cavernosa separated and surrounded by the tunica albuginea and Buck fascia; and (3) skin of shaft with underlying corporal dartos (28) (Figure 1). The coronal sulcus margin and cutaneous margin should be entirely examined when evaluating circumcision specimens.
H: Lymph-Vascular Invasion.--Vascular invasion, lymphatic or venous, adversely affects prognosis of penile cancer. (29-33) The new TNM staging classification in the 7th edition of the AJCC Cancer Staging Manual1 subdivides T1 tumors into T1a and T1b by the absence or presence of lymphovascular invasion or poorly differentiated tumors.
Embolic involvement of lymphatic vascular spaces occurs usually near the invasive tumor front, but it may also be found at a certain distance from the primary tumor in anatomic areas such as the lamina propria, penile fascia, and especially in the subepithelial connective tissues surrounding penile urethra. Venous invasion indicates a more advanced stage of the disease and is related to the compromise of the specialized erectile venous structures of corpora spongiosa and cavernosa.
I: Nomograms, Risk Groups, and Perineural Invasion.--An evaluation of clinical and pathologic variables with a nomogram was recently developed. (31) The selected factors were clinical stage of lymph nodes, microscopic growth pattern, grade, vascular invasion, and invasion of corpora spongiosa and cavernosa and urethra. The probability of nodal metastasis, as predicted by the nomogram, was close to the real incidence of metastasis observed at follow-up. A second nomogram to estimate predictions of survival at 5 years with the same clinical and pathologic factors gave similar results. (32) More recently, perineural invasion and histologic grade were found to be the strongest independent predictors of mortality in penile tumors 5 to 10 mm thick. A nomogram considering the predictive value of perineural invasion and histologic grade was accordingly constructed. (22) Risk-group stratification systems are available to predict the likelihood of inguinal nodal involvement and therapeutic planning and are based on a combination of histologic grade and pT stage. (34-37) Strongest predictive power is given by the combination of histologic grade, deepest anatomic level of infiltration, and presence of perineural invasion. These factors are used for constructing the Prognostic Index. (27)
J: TNM Staging Classification.--The protocol recommends the use of the TNM staging system of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) for carcinoma of the penis.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 a 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 lesion. Pathologic staging is usually performed after surgical resection of the primary tumor. The summary of changes in the TNM staging classification in the 7th edition of the AJCC Cancer Staging Manual1 is as follows:
* T1 has been subdivided into T1a and T1b by the presence or absence of lymphovascular invasion or poorly differentiated cancers.
* T3 category is limited to urethral invasion, and prostatic invasion is now considered T4.
* Nodal staging is divided into both clinical and pathologic categories.
* The distinction between superficial and deep inguinal lymph nodes has been eliminated.
* Stage II grouping includes T1bN0M0a as well as T2-3N0M0.
[FIGURE 1 OMITTED]
The "m" suffix indicates the presence of multiple primary tumors and is recorded in parentheses, for example, pTa(m)N0M0.
Anatomic Stage/Prognostic Groups
Prognostic Factors (Site-Specific Factors)
Factors required for staging: None.
Clinically significant factors:
* Involvement of corpus spongiosum
* Involvement of corpus cavernosum
* Percentage of tumor that is poorly differentiated
* Verrucous carcinoma depth of invasion
* Size of largest lymph node metastasis
* Extranodal/extracapsular extension
* Human papillomavirus (HPV) status
K: Penile Intraepithelial Neoplasia.--Penile intraepithelial neoplasia (PeIN) may be subclassified as differentiated (simplex), warty, basaloid, and warty/basaloid (mixed). (38,39) Differentiated PeIN shows parakeratosis, epithelial thickening, elongation of rete ridges, prominent bridges, basal cell atypia, enlarged nuclei, and prominent nucleoli. Differentiated PeIN is frequently associated with lichen sclerosus. It is considered HPV unrelated, there is no koilocytosis, and p16 immunohistochemical staining results (surrogate of high-risk types of HPV) are usually negative. Basaloid PeIN is characterized by a replacement of the normal epithelium by small, uniform cells with round nuclei and scant cytoplasm. Numerous mitoses and apoptotic cells are usually present. Warty PeIN shows a spiky surface with parakeratosis. The normal epithelium is replaced by markedly pleomorphic cells showing prominent koilocytosis. Mixed warty-basaloid lesions are not infrequent. Warty and basaloid PeIN are HPV-related lesions and usually overexpress p16.
L: Handling of the Specimen.--Circumcision Specimen.--Take measurements, describe specimen, and identify and describe tumor. Identify and ink the mucosal and cutaneous margins with different colors. Most SCCs arise from the mucosal surface of the foreskin; therefore, the coronal sulcus (mucosal) margin is especially important. Lightly stretch and pin the specimen to cardboard. Fix for several hours in formalin. Cut the whole specimen vertically, labeling from 1 to 12 clockwise.
Penectomy Specimen.--Take measurements, describe specimen, and identify and describe tumor. Most SCCs of the penis arise from the epithelium of the distal portion of the organ (glans, coronal sulcus, and mucosal surface of the prepuce; the tumor may involve 1 or more of these anatomic compartments). (40) If present, classify the foreskin as short, medium, long, and/or phimotic. (2) Cut the proximal margin of resection en face, making sure to include the entire circumference of the urethra (Figure 1). If the urethra has been retracted, it is important to identify its resection margin and submit it entirely. The resection margin can be divided in 3 important areas that need to be analyzed: the skin of the shaft with underlying dartos and penile fascia; corpora cavernosa with albuginea; and urethra with periurethral cylinder that includes lamina propria, corpus spongiosum, albuginea, and penile fascia (Figure 1). The urethra and periurethral cylinder can be placed in 1 cassette. The skin of the shaft with dartos and fascia can be included together with the corpora cavernosa. Because this is a large specimen, it may need to be included in several cassettes to include the entire resection margin. Fix the rest of the specimen overnight. Then, in the fixed state and if the tumor is large and involves most of the glans, cut longitudinally and centrally by using the meatus and the proximal urethra as reference points. Do not probe the urethra. Separate the specimen into halves, left and right (Figures 2 and 3). Then cut 2 to 6 serial sections of each half. If tumor is small and asymmetrically located in the dorsal or ventral area, the central portion of the tumor may be used as the axis of sectioning. If the tumor is large, involving multiples sites (glans, sulcus, and foreskin), it is important not to remove the foreskin, leaving the entire specimen intact for sectioning.
[FIGURE 2 OMITTED]
[FIGURE 3 OMITTED]
In cases of small carcinomas exclusively located in the glans with no foreskin involvement, one may choose to remove the foreskin, leaving a 3-mm redundant edge around the sulcus. Proceed to cut the foreskin as indicated for circumcision specimens. Even if the primary tumor is located in the glans, submit the foreskin serially and in orderly fashion, labeled from 1 to 12 clockwise. The rest of the penectomy specimen should be handled as described above.
M: Pathology Report for Penile Squamous Cell Carcinoma.--The report should contain the following information: primary tumor (tumor site or sites), size in centimeters, histologic subtype, histologic grade, anatomic level of invasion, tumor thickness in millimeters, and vascular and perineural invasion. In penectomy specimens, the margins of resection to be reported are urethral/periurethral, corporal, and skin of the shaft. (28) In circumcision specimens, margins include coronal sulcus mucosal margin and cutaneous margin. Commonly associated lesions to be reported are penile intraepithelial neoplasia (differentiated or undifferentiated), lichen sclerosus, and other "inflammatory dermatologic" conditions.
If the specimen is accompanied by inguinal nodes, the number and size of nodes should be described. All nodes should be included for microscopic examination. The number of positive nodes and total number of nodes examined should be reported as well as the presence of extracapsular extension and the number and site (eg, inguinal versus pelvic) of metastatic nodes. The distinction between superficial and deep inguinal lymph nodes has been eliminated in the 7th edition TNM classification. (1)
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Elsa F. Velazquez, MD; Mahul B. Amin, MD; Jonathan I. Epstein, MD; David J. Grignon, MD; Peter A. Humphrey, MD, PhD; Curtis A. Pettaway, MD; Andrew A. Renshaw, MD; Victor E. Reuter, MD; John R. Srigley, MD; Antonio L. Cubilla, MD; for the Members of the Cancer Committee, College of American Pathologists
Accepted for publication January 20, 2010.
From the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (Dr Velazquez); the Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California (Dr Amin); the Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland (Dr Epstein); the Department of Pathology, Indiana University, Indianapolis (Dr Grignon); the Department of Pathology and Immunology, Washington University School of Medicine and Barnes-Jewish Hospital, St Louis, Missouri (Dr Humphrey); the Department of Urology, University of Texas M. D. Anderson Cancer Center, Houston (Dr Pettaway); the Department of Pathology, Baptist Hospital of Miami, Miami, Florida (Dr Renshaw); the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (Dr Reuter); the Department of Laboratory Medicine, Credit Valley Hospital, Mississauga, Ontario, Canada (Dr Srigley); and the Department of Pathology, National University of Asuncion and Instituto de Patologia e Investigacion, Asuncion, Paraguay (Dr Cubilla). Dr Velazquez is now with Caris/ Cohen Dermatopathology, Newton, Massachusetts.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Elsa F. Velazquez, MD, Caris/Cohen Dermatopathology, 320 Nedham St, Suite 200, Newton, MA 02464 (e-mail: elsafvelazquez@ yahoo.com).
Anatomic Stage/Prognostic Groups Group T N M Stage 0 Tis N0 M0 Ta N0 M0 Stage I T1a N0 M0 Stage II T1b N0 M0 T2 N0 M0 T3 N0 M0 Stage IIIa T1-3 N1 M0 Stage IIIb T1-3 N2 M0 Stage IV T4 Any N M0 Any T N3 M0 Any T Any N M1