José E. Barreto

Histologic grade and perineural invasion are more important than tumor thickness as predictor of nodal metastasis in penile squamous cell carcinoma invading 5 to 10 mm.

Penile squamous cell carcinomas (SCCs) invading to a depth inferior to 5 mm usually have very low risk for regional metastasis, whereas tumors thicker than 10 mm have a high metastatic potential. A significant number of squamous cell carcinomas, however, belong to an intermediate category (5 to 10 mm in thickness) in which the incidence of regional lymph node metastasis is very difficult to predict. Consequently, a frequent clinical dilemma is whether to perform or not inguinal dissection in this group of lesions. The objective of this study was to evaluate multiple risk factors for regional metastasis in tumors 5 to 10-mm thick. One hundred thirty-four partial penectomies with invasive carcinomas 5 to 10-mm thick, all of which with corresponding inguinal lymph node dissection, were evaluated. Factors evaluated were—patients age, anatomic site, histologic grade, tumor thickness, anatomic levels of invasion, and vascular and perineural invasion. Grades were classified as 1, well; 2, moderately; and 3, poorly differentiated. To evaluate independent significance of various prognostic factors, a logistic regression analysis was performed, and a nomogram was prepared to evaluate metastatic risk according to histologic grade and perineural invasion. Groin metastasis was found in 66 of 134 patients (49%). High histologic grade and perineural invasion were statistically significant pathologic factors associated with groin metastasis. Nodal metastases were found in 2 of 25 grade 1 (8%), 24 of 46 grade 2 (52%), and 40 of 63 grade 3 carcinomas (63%) (P value 0.0001). Of 48 patients with perineural invasion, metastasis was found in 33 cases (69%) (P value 0.001). The average tumor thickness, anatomic level of invasion, and presence of vascular invasion were not statistically significantly different in metastasizing and nonmetastasizing neoplasms. Fifty percent of tumors invading 5 to 10 mm were not associated with metastasis and may be spared a nodal dissection. In this subset of patients, high histologic grade and perineural invasion were significant and useful risk factors associated with regional metastasis. The probability of inguinal node metastasis in patients with grade 1 tumors without perineural invasion is almost nonexistent whereas for high-grade tumors associated with perineural invasion is near 80%.

Sarcomatoid carcinoma of the penis: a clinicopathologic study of 15 cases.

Sarcomatoid carcinomas are uncommon, high-grade tumors, predominantly composed of spindle cells. Only a few cases arising in the penis have been reported. The aim of this study is to better define the clinicopathologic features of this neoplasm. A total of 400 cases of squamous cell carcinoma of the penis were reviewed from which 15 sarcomatoid carcinomas (4%) were identified. Clinical and pathologic features were evaluated in all cases. Immunohistochemical studies for expression of AE1/AE3, Cam 5.2, 34βE12, EMA, vimentin, muscle specific actin, smooth muscle actin, desmin, S-100, p63, and p53 and in situ hybridization studies for HPV were performed in 5 cases. Information about lymph node status was available in 9 cases, and follow-up in 5 cases. The mean age was 59 years, and mean tumor size was 5 cm. Grossly, most tumors were large, polypoid, and ulcerated masses frequently affecting the glans (93%) and deeply invading corpora cavernosa (80%) and skin. Microscopically, the lesions were predominantly composed of atypical spindle cells disposed in interlacing fascicles, resembling fibrosarcoma or leiomyosarcoma, sometimes admixed with pleomorphic giant cells mimicking malignant fibrous histiocytoma. One case was predominantly composed of myxoid areas. Less frequent and focal patterns were pseudoangiomatous and epithelioid. Mitotic figures were numerous, and necrosis was prominent. Foci of heterologous differentiation toward bone (osteosarcomatous component) were present in 1 case. Four cases showed a minor mixed component of usual, papillary, verrucous, and basaloid carcinoma. Intrapenile metastasis (“satellitosis”) was present in 4 tumors. One of the cases was multicentric with a separate independent focus of well-differentiated carcinoma with pseudohyperplastic features. Associated low- and high-grade squamous intraepithelial lesions were noted in 73% of the cases. Immunohistochemical studies and HPV in situ hybridization were done in 5 cases. The spindle cells were diffusely positive for vimentin and p53 and showed at least intermediate expression of 34βE12 and p63 in all cases. EMA and AE1/AE3 were focally positive in 60% of the cases, and Cam 5.2 was focally positive in 1 case. Tumor cells failed to express muscle specific actin, smooth muscle actin, desmin, and S-100. HPV in situ hybridization was negative in all cases. Inguinal metastases were present in 89% of the cases. Two of five patients with adequate follow-up died of disease within 8 months of the diagnoses. In conclusion, penile sarcomatoid carcinomas are unusual, large, and aggressive tumors usually associated with lymph node metastasis and poor outcome. Differential diagnoses include sarcoma and melanoma. Cytokeratin 34βE12 and p63 appear to be the more specific and sensitive markers to categorize these tumors as epithelial. Diffuse immunoreactivity for p53, compared with a more basal and focal reactivity in differentiated squamous cell carcinoma, may be indicative of a late mutation in the natural progression of the disease.

Limitations in the Interpretation of Biopsies in Patients with Penile Squamous Cell Carcinoma

Surgeons often perform small or superficial penile biopsies that are difficult to classify definitely with regard to a benign or malignant nature, and if malignant, cannot always be accurately subclassified. Staging and therapeutic decisions rely on the identification, in these materials, of pathologic parameters related to prognosis. In this study, we evaluated the accuracy and completeness of pathologic information obtained from biopsies of 57 consecutive patients with squamous cell carcinoma (SSC) of the penis, and compared it with the information obtained from penectomies. Diagnostic accuracy was determined by recording discordances of critical factors in biopsies and penectomies. The evaluated parameters were as follows: cancer diagnosis, histologic type, tumor grade, depth of invasion (anatomical levels), and vascular invasion. Histologic subtypes of SCC were the following: usual 37, verruciform 11, mixed 7, pseudohyperplastic 1, and sarcomatoid 1. Grades were 1, 2, and 3 (well, moderately and poorly differentiated). Levels of invasion were lamina propria, corpus spongiosum, and corpus cavernosum in the glans; and lamina propria, dartos, and skin in the foreskin. In 2 patients with well-differentiated tumors a diagnosis of cancer could not be established in biopsy material. In 17 cases (30%) there was a biopsy-penectomy discordance of histologic types, especially of verruciform and mixed carcinomas. Biopsies failed to identify the correct histologic grade in 30% of the cases. A higher grade was usually identified in penectomy specimens. Because biopsies were superficial, the deepest point of invasion could not be determined in 91% of the cases. Vascular invasion was identified in biopsies in only 1 of 8 patients. In summary, biopsies were useful for cancer diagnosis except in 2 differentiated variants of penile squamous cell carcinoma. However, important pathologic parameters related to prognosis were missed on biopsy materials, and they were more accurately evaluated in penectomy specimens. We conclude that clinical and pathologic staging of penile cancer, at least in our material, cannot depend on biopsy information alone. Data from biopsies may be insufficient to make a decision whether to perform a groin dissection, or for prognostic evaluation in those patients in whom other treatment modalities (such as radiotherapy or chemotherapy) are being considered.

Histologic Grade in Penile Squamous Cell Carcinoma: Visual Estimation Versus Digital Measurement of Proportions of Grades, Adverse Prognosis With any Proportion of Grade 3 and Correlation of a Gleason-like System With Nodal Metastasis

Histologic grade has been reported as an important pathologic parameter predictive of nodal metastases and outcome in patients with penile squamous cell carcinoma. There is no consensus about the criteria for grading and the proportion of anaplastic cells required to classify a tumor as high grade. The incidence and management of heterogeneous tumors (tumors harboring more than 1 histologic grade) are not well established. The purposes of this study were to present a grading model for penile cancer, to test the practicality of the system by comparing a visual (“naked-eye”) estimation of the proportions of grades with a digitally guided measuring system and to determine the influence on nodal metastasis of the various proportions of grades. A total of 117 penectomy and circumcision specimens with bilateral inguinal lymph node dissections were studied and 62 heterogeneous tumors were identified (53%). The following steps were taken: (1) design of a grading system model; (2) determination of proportions of histologic grades by naked-eye evaluation and by digital measurement; (3) evaluation of metastasis according to proportions of grades; (4) determination of the influence of site of grade 3 in nodal metastasis; (5) design of a Gleason-like scoring system; and (6) statistical evaluation. We designed a 3-tier grading system. Grade 1: well-differentiated cells, almost undistinguishable from normal squamous cells except for the presence of minimal basal/parabasal cell atypia. Grade 3: tumors predominantly composed of anaplastic cells. Grade 2: all tumors not fitting into criteria described for grade 1 or 3. A visual and digital-based (slides scanned and the corresponding areas measured with an image-editing software) proportions of grades were estimated and the metastatic rate between them were confronted using different proportions of grade 3. To evaluate the influence of site of grade 3 on nodal metastasis, we selected 20 heterogeneous tumors. We established 3 sites: superficial, at or within the main tumor and deep at front of invasion. There was no significant difference between the visual estimation and the digital measurement systems. Heterogeneous tumors comprised about half of penile squamous cell carcinomas. The majority of the heterogeneous tumors were composed of a combination of grades 2 and 3 (68%). No statistical differences were noted in the incidence of nodal metastasis when comparing tumors with various proportions of anaplastic cells (P>0.10 in all cases). Metastatic rate was significantly more frequent in tumors harboring any proportion of grade 3 as compared with tumors without grade 3 (58% vs. 14%, P=0.04). Any proportion of grade 3 was equally associated with a significant risk of nodal metastasis. A Gleason-like system showed a correlation of higher scores and rate of nodal metastasis. No predictive advantage was found when comparing the Gleason-like model with the proposed 3-tier grading system. The proposed grading system emphasized both ends of the differentiation spectrum and was based on easily recognizable morphologic criteria. When histologically evaluating penile carcinomas, we recommend a careful search of areas of grade 3. Any focus of grade 3 should be sufficient to grade the neoplasm as a high-grade tumor.

Positive resection margins in partial penectomies: Sites of involvement and proposal of local routes of spread of penile squamous cell carcinoma

Recurrence in patients with penile carcinoma occurs in about one third of cases, usually due to insufficient surgery or positive resection margins. An evaluation of surgical resection margins in penectomy specimens was performed to determine precise anatomic sites of tumor involvement, hoping to advance knowledge concerning the local routes of spread of penile carcinomas. A pathologic study of 80 partial penectomies revealed 14 positive margins. Margins were examined after their separation from the main specimen as follows: 1) proximal urethra and surrounding tissues consisting of urethral epithelium with Litree glands, lamina propria, corpus spongiosum, and penile fascia (periurethral cylinder); 2) proximal shaft with corresponding corpora cavernosa separated and surrounded by the tunica albuginea and penile fascia; and 3) skin of shaft with underlying corporal dartos. In 9 patients, only one site was involved by carcinoma, and in 5 there were multiple contiguous sites (for a total of 20 anatomic sites). The distribution of the various sites involved by carcinoma was as follows: urethral epithelium, 4 cases (2 in situ and 2 invasive carcinomas including intraluminal spread); lamina propria, 5 cases; corpus spongiosum, 3 cases; penile fascia, 6 cases; and corpora cavernosa and skin, 1 case each. One of the in situ lesions was discontinuous with the main glans tumor, and the other one was continuous with it. The penile fascia was the most commonly involved site followed by the urethral lamina propria and epithelium. Dissemination to outer skin, corpora cavernosa, and corpus spongiosum was less frequent. The highly vascularized and innervated loose connective tissue of the penile fascia appears to facilitate tumor spread. The urethra is either a pathway for in situ tumor progression from glans to urethra or part of a field prone to malignant transformation. The infrequent involvement of corpora cavernosa is probably due to the tunica albuginea acting as a barrier preventing tumor spread. Based on these observations and the examination of hundreds of penectomy specimens, we are proposing five probable routes of local spread for penile cancer: 1) horizontal and superficially spreading from one epithelial mucosal compartment (glans, coronal sulcus, and foreskin) to the other; 2) following the penile fascia; 3) through spaces created by feeding vessels in the tunica albuginea; 4) vertical spreading involving step-by-step different penile anatomic compartments; and 5) along the urethral epithelium.

Distinctive immunohistochemical profile of penile intraepithelial lesions: A study of 74 cases

Several classification schemes for penile precancerous lesions have been proposed, but none of them seems to correlate with the current understanding of penile cancer pathogenesis. Recently, a system, which takes into account morphologic features and purported etiopathogenesis, was proposed, separating penile intraepithelial neoplasia (PeIN) in differentiated and warty/basaloid subtypes. This study was designed to seek an immunohistochemical profile that can be helpful in the classification and differential diagnosis of penile epithelial abnormalities and precancerous lesions using the aforementioned system. The immunohistochemical panel included stains for p16INK4a, p53, and Ki-67. For p16INK4a immunostaining, only full-thickness positivity in all epithelial cells was considered as positive; for p53 and Ki-67 immunostaining, patchy or diffuse nuclear positivity above the basal layer was considered as positive. Seventy-four lesions in 59 patients were selected and classified as follows: differentiated PeIN, 34 cases; squamous hyperplasia (SH), 21 cases; basaloid PeIN, 15 cases; and warty PeIN, 4 cases. The mean age of patients was 64 years. Forty-two lesions (56.8%) were located in the glans and 32 (43.2%) in the foreskin. Overexpression of p16INK4a was useful for distinguishing SH from warty/basaloid PeINs (0% vs. 94.7%, P<0.0001) but not SH from differentiated PeINs (0% vs. 5.9%, P=0.519). In addition, p16INK4a allowed the distinction of differentiated and warty/basaloid PeINs (5.9% vs. 94.7%, P<0.0001). Immunohistochemistry results for p53 allowed the separation of SH and differentiated PeIN (9.5% vs. 44.1%, P=0.0078) and SH and warty/basaloid PeIN (9.5% vs. 55.6%, P=0.0042). Ki-67 immunostain was useful for distinguishing SH from differentiated PeIN (52.6% vs. 89.7%, P=0.0062) and SH from PeIN with warty and/or basaloid features (52.6% vs. 100%, P=0.0011). There seems to be a distinctive immunohistochemical profile for associated and precursor epithelial lesions of the penis. SH was p16INK4a and p53 negative, with variable Ki-67 positivity. Differentiated PeIN was p16INK4a negative and Ki-67 positive, with variable p53 positivity. Basaloid and warty PeINs were consistently p16INK4a and Ki-67 positive, with variable p53 positivity. The use of a triple p16INK4a/p53/Ki-67 immunohistochemical panel was found to be helpful in the classification, differential diagnosis, and morphologic standardization of penile intraepithelial lesions.

Distribution and characterization of subtypes of penile intraepithelial neoplasia and their association with invasive carcinomas: a pathological study of 139 lesions in 121 patients

We are presenting the morphological features of 121 cases of atypical penile intraepithelial lesions. The term penile intraepithelial neoplasia (PeIN) was used to encompass all of them, and lesions were classified into 2 major groups, differentiated and undifferentiated. The latter was further divided in warty, basaloid, and warty-basaloid subtypes. Ninety-five cases were associated with invasive squamous cell carcinomas. Differentiated lesions predominated (68%), followed by warty-basaloid (14%), basaloid (11%), and warty (7%) subtypes. Multifocality was found in 15% of the cases. Differentiated lesions were preferentially located in foreskin, whereas warty and/or basaloid subtypes were more prevalent in the glans. The former lesions were preferentially seen in association with keratinizing variants of squamous carcinoma, whereas the latter subtypes were found mostly in conjunction with invasive warty, basaloid, and warty-basaloid carcinomas. Lichen sclerosus was present in 51% of cases of differentiated lesions and absent in warty and/or basaloid subtypes. In summary, PeIN can be classified into 4 distinctive morphological subtypes. The proper pathological characterization of these lesions may provide important clues to the understanding of the pathogenesis and natural history of penile cancer.

Warty-basaloid carcinoma: clinicopathological features of a distinctive penile neoplasm. Report of 45 cases.

Most penile cancers are squamous cell carcinomas, but there are several subtypes with different clinicopathologic, viral, and outcome features. We are presenting 45 cases of a distinctive morphological variant of penile squamous cell carcinoma composed of mixed features of warty and basaloid carcinomas. This tumor was earlier recognized in a recent viral study and showed a high association with human papillomavirus infection. However, clinicopathologic features are not well known. In this multi-institutional study, patients’ mean age was 62 years. Most tumors (64%) invaded multiple anatomical compartments, including glans, coronal sulcus, and, especially, inner foreskin mucosa. Tumor size ranged from 2 to 12 cm (mean 5.5 cm). Three morphological patterns were recognized: (1) the most common, observed in two-thirds of the cases was that of a typical condylomatous tumor on surface and basaloid features in deep infiltrative nests; (2) in 15% of the cases, there were non-papillomatous invasive carcinoma nests with mixed basaloid and warty features; and (3) unusually, predominantly papillomatous. Invasion of penile erectile tissues was frequent, either corpus spongiosum or cavernosum (47% each). Tumors limited to lamina propria were rare. Most tumors were of high grade (89%). Vascular and perineural invasion were found in about one-half and one-quarter of cases, respectively. Associated penile intraepithelial neoplasia was identified in 19 cases and mostly showed basaloid, warty–basaloid, or warty features. Inguinal nodal metastases were found in 11/21 patients with groin dissections. Invasion of corpora cavernosa, high histological grade, and presence of vascular/perineural invasion were more prevalent in metastatic cases. In 21 patients followed, the cancer-specific mortality rate was 33% with a mean survival time of 2.8 years. Warty–basaloid carcinomas are morphologically distinctive human papillomavirus-related penile neoplasms that, such as basaloid carcinomas, are biologically more aggressive than typical warty carcinoma from which they should be distinguished.

Epithelial abnormalities and precancerous lesions of anterior urethra in patients with penile carcinoma : a report of 89 cases

Urethral and penile tissues and their neoplasms are considered anatomically and pathogenetically different. Since we observed urethral dysplastic lesions and some similarities between noninvasive and invasive lesions of the anterior urethra and glans, we designed this study to document epithelial urethral abnormalities in patients with penile squamous cell carcinoma. We examined urethral epithelia from 170 penectomies with invasive squamous cell carcinoma finding a variety of primary epithelial abnormalities in 89 cases (52%) and secondary invasion of penile carcinoma to urethra in 42 cases (25%). Patients’ average age was 68 years. Primary tumors measured 4 cm in average diameter and the majority were squamous cell carcinoma of the usual (67%) or verrucous type (15%). Primary epithelial abnormalities found were squamous intraepithelial lesions, metaplasias and microglandular hyperplasias. Urethral squamous intraepithelial lesions of high grade was found in six patients and of low grade in eight cases. Squamous metaplasia, seen in 69 cases, was the most frequent finding. Metaplasias were classified as nonkeratinizing and keratinizing. Nonkeratinizing metaplasias (57 cases) were variegated in morphology: simplex (26 cases), hyperplastic (12 cases), clear cell (11 cases) and spindle (8 cases). Keratinizing metaplasias (12 cases) showed hyperkeratosis and were more frequently associated with verrucous than nonverrucous penile squamous cell carcinoma. Microglandular hyperplasia was present in eight cases. Lichen sclerosus was associated with simplex squamous metaplasia in four cases. Despite the large size of the primary tumors, direct urethral invasion by penile carcinoma was present in only 25% of the cases. The presence of precancerous lesions in urethra of patients with penile carcinoma indicates urethral participation in the pathogenesis of penile cancer. Simplex squamous metaplasia is a common finding probably related to chronic inflammation. Keratinizing and hyperplastic squamous metaplasias may be important in the pathogenesis of special types of penile carcinomas such as verrucous carcinoma.

Differentiated precursor lesions and low-grade variants of squamous cell carcinomas are frequent findings in foreskins of patients from a region of high penile cancer incidence.

Oertell J, Caballero C, Iglesias M, Chaux A, Amat L, Ayala E, Rodríguez I, Velázquez E F, Barreto J E, Ayala G & Cubilla A L
(2011) Histopathology 58, 925–933
Differentiated precursor lesions and low‐grade variants of squamous cell carcinomas are frequent findings in foreskins of patients from a region of high penile cancer incidence