Artigo Revisado por pares

Protocol for the Examination of Specimens From Patients With Carcinoma of the Penis

2010; American Medical Association; Volume: 134; Issue: 6 Linguagem: Inglês

10.5858/134.6.923

ISSN

1543-2165

Autores

Elsa F. Velázquez, Mahul B. Amin, Jonathan I. Epstein, David J. Grignon, Peter A. Humphrey, Curtis A. Pettaway, Andrew A. Renshaw, Victor E. Reuter, John R. Srigley, Antonio L. Cubilla,

Tópico(s)

Urologic and reproductive health conditions

Resumo

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.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.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 specifiedForeskin (Presence and Type) (select all that apply) (note A)___ Present (uncircumcised) *___ Short *___ Medium *___ Long *___ Phimotic___ Not identified (circumcised)___ Cannot be determinedLymphadenectomy___ 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 SizeSpecify: ___ × ___ × ___ cmTumor 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 urethraTumor SizeGreatest dimension: ___cm*Additional dimensions: ___ × ___ 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 applicableMacroscopic 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 marginHistologic 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 differentiatedMicroscopic Tumor Extension (select all that apply)Anatomic LevelsIn the Glans___ Tumor involves lamina propria___ Tumor involves corpus spongiosum___ Tumor involves tunica albuginea___ Tumor involves corpus cavernosum___ Not applicableIn the Coronal Sulcus___ Tumor involves lamina propria___ Tumor involves dartos___ Tumor involves Buck fascia___ Not applicableIn the Foreskin___ Tumor involves lamina propria___ Tumor involves dartos___ Tumor involves preputial skin___ Not applicableIn the Shaft___ Tumor involves skin___ Tumor involves dartos___ Tumor involves Buck fascia___ Tumor involves corpus spongiosum___ Tumor involves corpus cavernosum___ Not applicableOther Extension___ Penile (distal) urethra___ Proximal urethra___ Prostate___ Scrotum___ Regional skin (pubis, inguinal)*Tumor Thickness/Depth (note F)*Specify: ___ mmMargins 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 marginLymph-Vascular Invasion (note H)___ Not identified___ Present___ IndeterminatePerineural Invasion (note I)___ Not identified___ Present___ IndeterminatePathologic 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 carcinomaa___ 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 structuresRegional 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 bilateralDistant Metastasis (pM)___ Not applicable___ pM1: Distant metastasisb*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): ________________________________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.3–5The 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.7,8Two 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.9Most 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.14Histologic 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.22,23A tumor should be graded according to the least differentiated component. Any proportion of grade 3 should be noted in the report.23The 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 nonneoplastic 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 for metastasis was reported for tumors measuring less than 5 mm in 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.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 dartos28 (Figure 1). The coronal sulcus margin and cutaneous margin should be entirely examined when evaluating circumcision specimens.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.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.27The 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:The “m” suffix indicates the presence of multiple primary tumors and is recorded in parentheses, for example, pTa(m)N0M0.Factors required for staging: None.Clinically significant factors: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.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.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.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.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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