The dual pathogenesis of penile neoplasia: The heterogeneous morphology of human papillomavirus-related tumors.

Objective: Penile neoplasia, usually of squamous histogenesis, is currently classified into human papillomavirus (HPV)-related or -dependent and non-HPV-related or -independent. There are distinct morphological differences among the two groups. New research studies on penile cancer from Northern countries showed that the presence of HPV is correlated with a better prognosis than virus negative people, while studies in Southern countries had not confirmed, perhaps due to differences in staging or treatment. Methods: We focused on the description of the HPV-related carcinomas of the penis. The approach was to describe common clinical features followed by the pathological features of each entity or subtype stressing the characteristics for differential diagnosis, HPV genotypes, and prognostic features of the invasive carcinomas. Similar structure was followed for penile intraepithelial neoplasia, except for prognosis because of the scant evidence available. Results: Most of HPV-related lesions can be straightforwardly recognized by routine hematoxylin and eosin stains, but in some cases surrogate p16 immunohistochemical staining or molecular methods such as in situ hybridization or polymerase chain reaction can be utilized. Currently, there are eight tumor invasive variants associated with HPV, as follows: basaloid, warty, warty-basaloid, papillary basaloid, clear cell, medullary, lymphoepithelioma-like, and giant condylomas with malignant transformation. Conclusion: This review presents and describes the heterogeneous clinical, morphological, and genotypic features of the HPV-related subtypes of invasive and non-invasive penile neoplasia.

Cancer mortality in Itapúa--A rural province of Paraguay 2003-2012.

BACKGROUND: Itapúa is a rural department in Paraguay with a population of about 500,000 and a high degree of agro-mechanization for the production of soybean and other crops. So far, only basic health care is provided. Here we analyzed the cancer mortality in this region as a first step towards epidemiological data for cancer prevention. METHODS: We calculated the age-adjusted mortality rates according to world standard (AMRWs) for the major cancer sites in both males and females between 2003 and 2012, and estimated the differences between the capital and more central districts of Itapúa vs. remote districts. RESULTS: There were about 2000 cancer deaths in the decade studied, with AMRWs for all malignancies of 90.9/100,000 in males from central vs. 49.1/100,000 in remote districts and 69.0/100,000 vs. 45.0/100,000 in women. Cancer was mentioned in 12.4% of all death certificates and outweighed mortality from certain infectious and parasitic diseases (3.6%). Cause of death was ill-defined in 19.6% of all death certificates, especially in remote regions and among the elderly. The part of cancer located in the uterus (47.8%) or cell type of neoplasm of the lymphatic or hematopoietic system (73.1%) were often not specified. The uterus (mainly the cervix) (C53-C55) was the leading cancer site in women with AMRWs of 17.2/100,000 in central and 14.0/100,000 in remote districts, followed by the breast. Lung and prostate were the leading cancer sites among men. The lung cancer mortality rate was 19.3/100,000 in the central region but 9.5/100,000 in remote districts. Although children comprised 36% of the population, only 24 death certificates listed cancer as cause of death in this decade. CONCLUSIONS: Analysis of cancer mortality in this rural region of Paraguay, which lacks resources for diagnostics and care, revealed an already large number of cases, with higher rates in the central region than in remote districts. Lung and uterus (primarily the cervix) are common cancer sites and indicate the potential for prevention. However, the quality of the vital statistics needs to be improved. The true cancer burden is most likely underestimated, especially in remote regions and children.

Clinicopathologic and outcome features of superficial high-grade and deep low-grade squamous cell carcinomas of the penis.

PURPOSE: To report the clinicopathologic and outcome features of superficial high-grade and deep low-grade penile squamous cell carcinomas. METHODS: From a retrospectively-collected series of patients with penile cancer we identified 41 cases corresponding to 12 superficial high-grade tumors and 29 deep low-grade tumors. As outcomes we evaluated inguinal lymph node status, presence of tumor relapse, final nodal status, and cancer-specific death. Follow-up ranged from 0.8 to 386.7 months (mean 152.5 months, median 157.3 months). RESULTS: Clinicopathologic features were similar between superficial high-grade and deep low-grade tumors, except for a tendency (Fisher's exact [Formula: see text]) of the former to include tumors with a verruciform pattern of growth. A significantly higher proportion of inguinal lymph node metastasis was found in superficial high-grade tumors compared to deep low-grade tumors [4/5 (80%) vs. 1/5 (20%) respectively, Fisher's exact [Formula: see text]]. No significant differences were found regarding tumor relapse (Fisher's exact [Formula: see text]), final nodal status (Mantel-Cox's [Formula: see text]), or cancer-related death (Mantel-Cox's [Formula: see text]). CONCLUSIONS: Patients with superficial high-grade tumors had a significantly higher proportion of inguinal lymph node metastasis compared to patients with deep low-grade tumors. On this regard, prophylactic inguinal lymphadenectomy might be indicated in cases of superficial tumors with high-grade histology while in deeply invasive low-grade penile carcinomas a more conservative approach may be considered.

Immunohistochemical expression of the mammalian target of rapamycin pathway in penile squamous cell carcinomas: a tissue microarray study of 112 cases.

AIMS: The aim of this study was to evaluate the immunohistochemical expression of mammalian target of rapamycin (mTOR) pathway-related biomarkers in penile carcinomas, and to assess associations with histological type, histological grade, and human papillomavirus (HPV) infection. METHODS AND RESULTS: We built four tissue microarrays from 112 invasive penile squamous cell carcinomas, and evaluated the immunohistochemical expression of PTEN, phospho-AKT, phospho-mTOR, and phospho-S6. We found decreased or loss of PTEN expression in 87% of cases. Warty and/or basaloid carcinomas had a higher proportion of PTEN loss (P = 0.02), whereas keratinizing tumours showed higher levels of phospho-S6 (P = 0.009); phospho-AKT and phospho-mTOR levels were not significantly different between warty/basaloid and keratinizing carcinomas (P = 0.75 and P = 0.77, respectively). PTEN was not associated with histological grade (P = 0.18). Expression levels of phospho-S6 were significantly higher in low-grade tumours (P = 0.001), whereas expression levels of phospho-AKT and phospho-mTOR were slightly higher in high-grade tumours (P = 0.01 and P = 0.35, respectively). We did not find any association between HPV infection and mTOR markers (P ≥ 0.2 in all cases). CONCLUSIONS: Our results provide evidence of dysregulation of the mTOR pathway in penile carcinomas independently of HPV infection. Future clinical studies should further evaluate the prognostic and predictive usefulness of these markers in patients with penile cancer.

Dysregulation of the mammalian target of rapamycin pathway in chromophobe renal cell carcinomas.

Targeted therapy in advanced clear cell renal cell carcinomas (RCC) is now an established modality. The latter is in stark contrast to non-clear cell subtypes. We explored the translational support for the use of antagonists of the mammalian target of rapamycin (mTOR) and the vascular endothelial growth factor pathways in chromophobe RCC. The immunoexpression of PTEN, phos-AKT, phosphorylated S6 (phos-S6), 4EBP1, p27, c-MYC, and HIF-1α was evaluated in 33 patients with chromophobe RCC who were treated by partial/radical nephrectomy without adjuvant therapy. PTEN was lower in tumor than in normal kidney (P<.001), and loss of PTEN expression was found in 67% of the tumors. In tumor tissues, phos-S6 and 4EBP1 were higher than in normal kidney (P≤.005). Conversely, scores of p27 were lower in tumor than in normal kidney (P<.001). Finally, scores of phos-AKT, c-MYC, and HIF-1α were not significantly different in tumor and in normal kidney. Overall mortality and cancer-specific mortality were 9% and 0%, respectively. Multifocal tumors had higher levels of PTEN, phos-AKT, and HIF-1α (P≤.01). None of the clinicopathologic variables (age, ethnicity, gender, pT stage, tumor size, multifocality, and positive surgical margins) was associated with outcome. Similarly, none of the tested biomarkers predicted overall mortality, either in unadjusted or adjusted Cox regression models. In summary, our study provides new evidence of dysregulation of the mTOR pathway in chromophobe RCC. Immunohistochemistry for mTOR pathway and hypoxia-induced pathway members lacked prognostic significance in our cohort.

Epidemiologic profile, sexual history, pathologic features, and human papillomavirus status of 103 patients with penile carcinoma.

PURPOSE: The incidence of penile cancer is four times higher in Paraguay than in the United States or Europe. There are no adequate scientific explanations for this geographical variation. The goal of this study was to evaluate the interplay among risk factors, morphology of the primary tumor, and HPV status. METHODS: Information on socioeconomic status, education level, habits, and sexual history was obtained in 103 Paraguayan patients with penile cancer. All patients were then treated by surgery, and specimens were evaluated histopathologically. RESULTS: Patients usually dwelled in rural/suburban areas (82%), lived in poverty (75%), had a low education level (91%), and were heavy smokers (76%). Phimosis (57%), moderate/poor hygienic habits (90%), and history of sexually transmitted diseases (74%) were frequently found. Patients with >10 lifetime female partners had an odds ratio of 3.8 (95% CI 1.1, 12.6; P-trend = .03) for presenting HPV-positive tumors when compared to patients with <6 partners. However, this trend was not significant when the number of sexual partners was adjusted for age of first coitus and antecedents of sexually transmitted diseases. HPV-related tumors (found in 36% of the samples) were characterized by a warty and/or basaloid morphology and high histological grade in most cases. CONCLUSIONS: In our series, patients with penile cancer presented a distinctive epidemiologic and pathologic profile. These data might help explaining the geographical differences in incidence and aid in the design of strategies for cancer control in Paraguay.

Type-specific human papillomavirus distribution in invasive cervical carcinomas in Paraguay. A study of 432 cases.

Cervical carcinoma is the most common malignant tumor among woman in Paraguay. Cytological screening programs have not been successful and a plan for human papillomavirus (HPV) based-screening program and/or vaccination is under evaluation. This study aimed to identify the contribution of HPV genotypes in invasive cervical cancer in Paraguay to provide essential background data to guide and assess the introduction and impact of new preventive strategies based on HPV. Four hundred thirty two histologically confirmed cases (1960-2004) were analyzed. HPV detection in paraffin blocks was performed at the Catalan Institute of Oncology using PCR with SPF-10 broad spectrum primers followed by DNA enzyme immunoassay and genotyping with a reverse hybridization line probe analysis. The majority of cases were squamous cell carcinoma (92.8%). Mean patients age was 48 years old. HPV DNA was detected in 73.1% of the cases and single infections were predominant (97.8%). The most common HPV single types were 16, 18, 45, 33, 31, 52, 35, and 39. 73.1% of HPV positive cases had an HPV 16, 18 as single infection. HPV16 was frequent in SCC whereas HPV 18 and 45 were prevalent in glandular tumors. Significant decrease of HPV 16 with age groups (P-trend = 0.022) and increase in other HPV types (P-trend > 0.001) were observed. The potential impact of HPV 16 and 18 for a vaccination program was 73.1%. The study provide a profile of the HPV situation in the country, with robust clinical, pathological and virological data which would permit a better cervical cancer screening and vaccination programs.

Basaloid squamous cell carcinoma of the penis with papillary features: a clinicopathologic study of 12 cases.

There are 3 distinct variants of penile squamous cell carcinoma frequently associated with human papillomavirus (HPV): basaloid, warty-basaloid, and warty carcinomas. Considering the high incidence rates of penile cancer in some countries, a large international study was designed to evaluate the presence of HPV, its genotype distribution, and its association with histologic types of penile cancer. In this international review of >900 cases, we found a group of highly distinct papillary neoplasms composed of basophilic cells resembling urothelial tumors but frequently associated with HPV. Macroscopically, tumors were exophytic or exoendophytic. Microscopically, there was a papillomatous pattern of growth with a central fibrovascular core and small basophilic cells lining the papillae. Positivity for HPV was present in 11 of 12 tumors (92%). Single genotypes found were HPV-16 in 9 tumors and HPV-51 in 1 tumor. Multiple genotypes (HPV-16 and HPV-45) were present in another case. Overexpression of p16 was observed in all cases. Uroplakin-III was negative in all cases. The differential diagnosis was with basaloid, warty-basaloid, warty, and papillary squamous cell carcinoma and with urothelial carcinomas. Local excision (4 cases), circumcision (3 cases), or partial penectomy (5 cases) were preferred treatment choices. Tumor thickness ranged from 1 to 15 mm (average, 7 mm). Two patients with tumors invading 11 and 15 mm into the corpus spongiosum developed inguinal nodal metastasis. Of 11 patients followed up (median 48 mo), 7 were alive with no evidence of metastatic disease, 3 died from causes other than penile cancer, and another died postoperatively. This morphologically distinct tumor probably represents a papillary variant of basaloid carcinomas (papillary-basaloid carcinomas). Unlike typical basaloid carcinomas, the overall prognosis was excellent. However, deeply invasive tumors were associated with regional nodal metastasis indicating a potential for tumor-related death.

Warty/basaloid penile intraepithelial neoplasia is more prevalent than differentiated penile intraepithelial neoplasia in nonendemic regions for penile cancer when compared with endemic areas: a comparative study between pathologic series from Paris and Paraguay.

Penile squamous cell carcinoma shows an ample geographic variation in its prevalence with regions of low (North America, Europe, Japan, and Israel) and high (Africa, Asia, and South America) incidence. However, the geographic variation in the distribution of penile intraepithelial neoplasia is not well established. The aim of the present study was to compare the distribution of in situ and invasive lesions between geographic areas with low (France) and high (Paraguay) penile cancer incidence using a series of consecutive cases. The French series included 86 cases (57 in situ and 29 in situ + invasive squamous cell carcinoma), and the Paraguayan series, 117 cases (31 in situ and 86 in situ + invasive squamous cell carcinoma). Incidence of invasive squamous cell carcinoma in the overall samples was higher in the Paraguayan series (P < .00001). Comparing the Paraguayan and the French series, differentiated penile intraepithelial neoplasia was more prevalent in the former (65.0% versus 19.8%), whereas lesions showing warty and/or basaloid features predominated in the latter (35.0% versus 80.2%) to a significant level (P < .00001). This distinctive pattern of differential distribution was maintained when cases with associated invasive squamous cell carcinoma were excluded. The pattern of distribution of lichen sclerosus was also distinctive, with a significantly higher prevalence in the Paraguayan population when compared with the French series (32.5% versus 12.8%, P = .0015). In summary, there appears to be a distinctive distribution of penile precursor lesions depending on the geographic region in consideration. Penile intraepithelial neoplasia with warty and/or basaloid features predominated in low-incidence areas, whereas differentiated penile intraepithelial neoplasia was more prevalent in endemic regions for penile cancer. Further prospective studies in matched populations and from different geographic regions are needed to further clarify the reasons for this discrepancy.

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.

AIMS: About 10-20% of all penile squamous cell carcinomas (SCCs) originate in the foreskin, but knowledge about preputial precursor and associated lesions is scant. The aims of the present study were to determine the prevalence of various precancerous and cancerous lesions exclusively affecting the foreskin, and to describe their pathological features. METHODS AND RESULTS: One hundred consecutive circumcision specimens from symptomatic patients living in a region of high penile cancer incidence were analysed. Clinical diagnoses included mostly phimosis and chronic balanoposthitis (40 and 35 cases, respectively), but also a tumour mass (11 cases). Histopathological lesions found included: squamous hyperplasia in 61 cases; lichen sclerosus in 53 cases; penile intraepithelial neoplasia (PeIN) in 30 cases (all differentiated PeIN, with two cases showing multicentric foci of basaloid and warty-basaloid PeIN); and invasive SCC in 11 cases (three usual, three pseudohyperplastic, two verrucous-pseudohyperplastic, and one case each of basaloid, papillary and mixed usual-basaloid carcinomas). Lichen sclerosus was present in all low-grade SCC cases. Patients with no lesions were younger (mean age 44 years) than those with precursor lesions (mean age 54 years) or with invasive SCC (mean age 68 years). Immunohistochemistry for p16(INK4a) was performed in 19 precancerous lesions. All differentiated PeINs (18 lesions) were negative, and one basaloid PeIN was positive. CONCLUSIONS: The frequent coexistence of lichen sclerosus, squamous hyperplasia, differentiated PeIN and low-grade SCC suggests a common non-human papillomavirus related pathogenic pathway for preputial lesions, and highlights the importance of circumcision in symptomatic patients for the prevention of penile cancer.

Value of p16(INK)4(a) in the pathology of invasive penile squamous cell carcinomas: A report of 202 cases.

BACKGROUND: One third to one half of penile squamous cell carcinomas (SCCs) are related to human papillomavirus (HPV) infection. Viral detection is usually carried out by polymerase chain reaction (PCR) or other molecular methods. In this study, we evaluated p16(INK)4(a) immunohistochemical expression, which is simpler and less costly, as a potential marker of high-risk HPV (HR-HPV) infection in penile SCC. DESIGN AND METHODS: We pathologically classified 202 invasive penile carcinomas and performed HPV genotyping by short PCR fragment (SPF)10 PCR and p16(INK)4(a) immunohistochemistry. We also evaluated HPV and p16(INK)4(a) according to the histologic subtypes of penile SCC. Tumors depicting continuous p16(INK)4(a) immunostain in all neoplastic cells were considered positive. HPV and p16(INK)4(a) status were compared using classifier performances and concordance indexes. RESULTS: Evidence of HPV (low-risk and high-risk genotypes) was found in 63 cases (31%) by PCR. Fifty-three p16(INK)4(a)-positive cases were identified (26%). Overexpression of p16(INK)4(a) had a sensitivity of 67% and a specificity of 91% for defining the HPV status. Concordance indexes between p16(INK)4(a) and HPV status were high (≥78%) in general cases and in all histologic subtypes of penile SCC. The stain was useful in the differential diagnosis of basaloid and low-grade warty carcinomas. Low-risk HPV genotypes were found in 5 tumors, 4 of which were p16(INK)4(a) negative. Basaloid and nonbasaloid high-grade (grade 3) SCCs were more likely to be HR-HPV positive when compared with grades 1 to 2 tumors (P<0.000001 and 0.0417, respectively). CONCLUSIONS: p16(INK)4(a) overexpression was found to be a reliable marker for HR-HPV and a helpful tool in the differential diagnosis of low-grade verruciform and high-grade solid penile tumors. SCC variants depicting basaloid features were more likely to be HPV and p16(INK)4(a) positive than low-grade, keratinizing lesions. We also observed a tendency toward HPV positivity in high-grade nonbasaloid tumors. Our results indicated a concordance between HPV and p16(INK)4(a) status and this observation may have diagnostic and prognostic implications.

Metastatic tumors to the penis: a report of 17 cases and review of the literature.

This study presents clinicopathologic and outcome features of 17 patients with metastatic tumor to the penis. Primary sites and histological types were as follows: 6 urothelial carcinomas of urinary bladder, 4 prostatic carcinomas (2 adenocarcinomas and 2 adenosquamous carcinomas), 2 colorectal adenocarcinomas, 2 pulmonary carcinomas (1 squamous cell carcinoma and 1 small cell carcinoma), 1 squamous cell carcinoma of base of the tongue, 1 cutaneous malignant melanoma, and 1 acute myeloid leukemia. Literature review revealed similar distribution of organ sites in 437 cases. Most of our tumors were metachronous. Interval between primary and penile metastasis ranged from 3 to 60 months (mean 16 months). Most of the patients presented with a penile mass. Priapism was observed in 4 patients. The shaft was the commonest anatomical site involved (12 cases). Tumor emboli were usually found in the erectile tissues (14 cases), mainly corpora cavernosa. A total of 14 patients died of disseminated disease. Time interval between primary tumor and penile metastasis ranged from 3 to 60 months (mean 19 months) and between diagnosis of penile metastasis and death ranged from 0.25 to 18 months (mean 6 months), significantly shorter (P = .0058). Patients presented a median survival of 18 months from primary treatment and 5 months after diagnosis of penile metastasis. None of the patients who died of disseminated cancer lived more than 18 months after pathological diagnosis. Clinical evidence of penile involvement in a patient with a known malignancy is an ominous sign and should alert the clinicians to the dismal prognosis.

Autopsy findings in 14 patients with penile squamous cell carcinoma.

The aim of this study was to describe pathologic features found at autopsy of 14 patients with penile cancer. Nine patients died from disseminated disease; 5 of them presented local/regional recurrences. Five patients died from other causes, 2 of them postoperatively. Local recurrence sites were corpus cavernosum, Buck's fascia and urethra, regional skin, and prostate. Metastatic sites were lymph nodes (9 cases), liver (7 cases), lungs (6 cases), heart (5 cases), adrenals, bone and skin (3 cases each), thyroid and brain (2 cases each), and pancreas, spleen, and pleura (1 case each). Patients with heart metastasis had arrhythmias. Patients who died and who did not die from penile cancer had different profiles: low-grade superficial tumors with usual and warty subtypes versus high-grade deeply invasive basaloid or hybrid verrucous/sarcomatoid carcinomas. A natural history model for penile cancer routes of spread is proposed: local intrapeneal, regional and systemic nodes, regional skin, liver, lungs, heart, and other multiple sites.

Developments in the pathology of penile squamous cell carcinomas.

Most penile cancers are squamous cell carcinoma (SCC) originating in the epithelium covering glans, coronal sulcus, and foreskin. Several histologic subtypes have been described, each with distinctive clinicopathologic and outcome features. The most common subtype is the usual SCC, representing one half to two thirds of penile carcinomas. Penile verruciform tumors encompass verrucous, warty (condylomatous), and papillary, not otherwise specified, carcinomas. As a group, verruciform tumors are low grade, with low metastatic and mortality rates. In contrast, basaloid and sarcomatoid carcinomas are among the most aggressive penile tumors. Other SCC variants, such as carcinoma cuniculatum and pseudohyperplastic, adenosquamous and acantholytic carcinomas, are rare. The most relevant clinicopathologic and outcome features are outlined for each of these SCC subtypes, and an algorithm that might aid the pathologist in the histologic classification is presented. In addition, recommendations for handling penile cancer specimens, frozen section specimens, and pathology reports are provided.

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.

Distinctive association of p16INK4a overexpression with penile intraepithelial neoplasia depicting warty and/or basaloid features: a study of 141 cases evaluating a new nomenclature.

From the pathogenic point of view, penile cancers may be grouped in human papillomavirus-related and unrelated tumors, each one of them with distinctive morphologic features. The former are predominantly composed of small, undifferentiated basaloid cells, with more or less prominent koilocytic changes, and the latter of keratinizing differentiated squamous cells. The same cellular types are observed in precancerous lesions. On the basis of these observations, we constructed a novel nomenclature for penile precancerous lesions and classified them as penile intraepithelial neoplasia (PeIN) of differentiated, warty, basaloid, and warty-basaloid types. The aim of this study was to test the usefulness of immunohistochemical p16 overexpression, considered as a surrogate for high-risk human papillomavirus infection, using this classification system. We pathologically evaluated 141 patients with PeIN, associated (123 cases) and unassociated (18 cases) with invasive cancer. Distribution of PeIN types was: differentiated, 72%; basaloid, 9%; warty-basaloid, 7%; warty, 4%; and mixed, 7%. There was a striking similarity in the morphology of in situ and invasive squamous cell carcinomas. Differentiated PeIN was commonly associated with usual, verrucous, papillary, and other low-grade keratinizing variants of squamous cell carcinoma whereas in basaloid and warty carcinomas the presence of in situ lesions with similar morphology was habitual. We evaluated p16 overexpression using a 4-tiered (0, 1, 2, and 3) pattern-based system. To properly distinguish differentiated PeIN from in situ lesions with warty and/or basaloid features only pattern 3, which requires full-thickness staining in all epithelial cells, was considered positive. Using this approach, there was a significant association of the negative patterns and differentiated PeIN and of the positive pattern and warty, basaloid, and warty-basaloid PeIN (P<0.0001). Basaloid variant had the strongest association. The sensitivity rate of p16 positivity for discriminating types of PeIN was of 82%, with a specificity of 100% and an accuracy of 95%. Lichen sclerosus was identified in 42 cases and their epithelial component was p16 negative in all cases. Although more studies are necessary to confirm these observations, p16 overexpression seems to be a useful tool for discriminating differentiated from warty, basaloid, and warty-basaloid PeIN.

Papillary squamous cell carcinoma, not otherwise specified (NOS) of the penis: clinicopathologic features, differential diagnosis, and outcome of 35 cases.

There is a group of low-grade papillomatous squamous cell carcinomas (SCC) of the penis, collectively designated as "verruciform," that are difficult to classify. A proposal of classification grouped these tumors in warty (condylomatous), verrucous, and papillary carcinomas. Papillary SCC, not otherwise specified is the third distinctive type of penile low-grade verruciform neoplasms. We are presenting clinicopathologic features of 35 cases from 2 institutions. All specimens were penectomies or circumcisions. Mean age was 57 years. Sites of involvement were glans alone in 18 cases (51%), glans, coronal sulcus and foreskin in 13 cases (37%), glans and sulcus in 3 cases (9%), and foreskin in 1 case (3%). Papillary carcinomas were large (mean 5.6 cm) exophytic low-grade squamous neoplasms with hyperkeratosis and papillomatosis. Papillae were variable in length and shape. The tip was straight, undulated, spiky, or blunt. There was no koilocytosis. The interface between tumor and stroma was characteristically jagged and a moderate stromal reaction was evident in most cases. The majority of the tumors (94%) showed a low-grade histology with focally present poorly differentiated areas in 6% of the cases. The mean thickness of the tumor was 9.4 mm. The most commonly invaded anatomic levels were the corpus spongiosum and/or dartos (77% cases). Corpus cavernosum was invaded in 8 cases (23%). Vascular and perineural invasion were unusual. Frequent associated lesions were squamous hyperplasia, differentiated penile intraepithelial neoplasia, and lichen sclerosus (74%, 46%, and 34%, respectively). Nodal metastases were identified in 3 of 12 patients with bilateral groin dissections. Of the 20 patients followed, 18 were either with no evidence of disease (15 cases) or died from unrelated causes (3 cases). One patient was alive with evidence of systemic metastases and 1 died from disseminated penile cancer 32 months after original penectomy. In conclusion, papillary carcinomas were exophytic albeit, often deeply invasive low-grade neoplasms, with a low rate of nodal metastasis characterized by complex papillae, irregular fibrovascular cores, and jagged tumor base. Papillary SCC should be distinguished from other penile verruciform tumors, including verrucous and variants, warty and papillary basaloid carcinomas, and carcinoma cuniculatum. Helpful morphologic features for differential diagnosis are provided.

Comparison of subtypes of penile squamous cell carcinoma from high and low incidence geographical regions.

There is a worldwide geographical variation in the incidence of penile squamous cell carcinoma (PSCC); some subtypes are HPV-related (warty, basaloid) while others (keratinizing variants) are not. The aims of this study were to compare the distribution of different histological subtypes of PSCC from regions of low (Paraguay, 144 cases) and high (USA, 157 cases) incidence and to identify and compare tumors with and without warty and/or basaloid morphology. The distribution of subtypes in the Paraguayan and the American series was: usual, 49.3 and 46.5%; verrucous, 8.3 and 7.6%; papillary NOS, 7.6 and 5.7%; warty, 6.9 and 8.3%; basaloid, 4.2 and 7.0%; sarcomatoid, 0.7 and 0.6%; adenosquamous, 3.5 and 0.6%; and mixed, 19.4 and 23.6%, respectively. The distribution of mixed PSCC was: warty-basaloid, 50.0 and 59.5%; usual-verrucous, 21.4 and 21.6%; usual-warty, 14.3 and 8.1%; usual-basaloid, 7.1 and 0.0%; usual-papillary, 3.6 and 5.4%; and others, 3.6 and 5.4%, respectively. In conclusion, we found no geographical difference in the incidence of histological subtypes (p = 0.6501), mixed PSCC (p = 0.5937) or HPV-related tumors (p = 0.2505). Geographical variation may be the result of staging variation at clinical presentation or of pathological diagnosis. The identification of similar histological subtypes in both series validates this classification approach for penile cancer. The tendency for typical SCC to mix with verrucous and papillary carcinomas and of the basaloid to preferentially mix with benign condyloma and condylomatous (warty) carcinomas would support the hypothesis of the existence of an etiologically different dual population of penile tumors.