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The American Journal of Surgical... Dec 2023Compared with vulva, precursor lesions of human papillomavirus (HPV)-independent invasive squamous cell carcinoma (SCC) of the penis are insufficiently characterized. We...
Compared with vulva, precursor lesions of human papillomavirus (HPV)-independent invasive squamous cell carcinoma (SCC) of the penis are insufficiently characterized. We analyzed the histologic and immunohistochemical characteristics of 70 peritumoral precursor lesions and correlated them with the histology and mutational profile of the adjacent HPV-negative invasive penile SCC. Atypical basal keratinocyte proliferation with variously elongated epithelial rete with premature squamatiziation, but regular superficial cornification, termed differentiated penile intraepithelial neoplasia (d-PeIN), were identified adjacent to 42/70 (60%) SCC (36/42 keratinizing ( P <0.001); 3 papillary, and 1 each verrucous, clear cell, sarcomatoid SCC). d-PeIN were associated with chronic inflammatory dermatoses (32/42; P <0.001), p53 overexpression (26/42; P <0.001), and hotspot mutations in TP53 (32/42; P <0.001), CDKN2A (26/42; P <0.001) or both (21/42; P =0.003) in the adjacent SCC. Cytoplasmic p16 ink4a overexpression in 5/42 d-PeIN correlated with CDKN2A missense mutations in the adjacent SCC. In all, 21/70 (30%) cornified verrucous or glycogenated verruciform precursors with minimal atypia and wild-type p53 (18/21; P <0.001) occurred adjacent to verrucous or papillary SCC (17/21; P <0.001) and keratinizing (4/21) SCC, which harbored mutations in HRAS and/or PIK3CA (12/21; P <0.004). Undifferentiated p16 ink4a -negative full-thickness precursors were identified in 7/70 (10%) SCC. Four histologically different HPV-independent penile precursor lesions can be assigned to 2 major genetic/biological pathways with characteristic highly differentiated precursors requiring different clinical management decisions. These include d-PeIN in chronic inflammatory dermatoses, with p53 overexpression and TP53/CDKN2A mutations, and the p53 wild-type verrucous and verruciform precursors unassociated with dermatoses, but with mutations in oncogenes PIK3CA and HRAS .
Topics: Male; Female; Humans; Papillomavirus Infections; Tumor Suppressor Protein p53; Human Papillomavirus Viruses; Skin Neoplasms; Carcinoma in Situ; Carcinoma, Squamous Cell; Penile Neoplasms; Penis; Papillomaviridae; Class I Phosphatidylinositol 3-Kinases; Vulvar Neoplasms
PubMed: 37768009
DOI: 10.1097/PAS.0000000000002130 -
Human Genomics Dec 2023The effect of SPP1 in squamous cell carcinoma of the penis (PSCC) remained unknown. We attempted to clarify the function of the SPP1 gene in PSCC.
BACKGROUND
The effect of SPP1 in squamous cell carcinoma of the penis (PSCC) remained unknown. We attempted to clarify the function of the SPP1 gene in PSCC.
METHOD
Eight paired penile cancer specimens (including penile cancer tissue, paracancerous tissue, and positive lymph node tissue) subjected to whole transcriptome sequencing were analysed to identify differentially expressed genes. We used immunohistochemistry to detect the expression of SPP1 protein and immune cell related proteins in penile cancer tissue. Then, we performed weighted gene coexpression network analysis (WGCNA) to identify the genes related to SPP1 in penile cancer tissue and positive lymph node tissue. Based on the GSE57955 dataset, the CIBERSORT and ssGSEA algorithms were carried out to investigate the immune environment of PSCC. GSVA analysis was conducted to identify the signaling pathways related to SPP1 subgroups. Enzyme-linked immunosorbent assay (ELISA) method was adopted to detect SPP1 level in the serum of 60 patients with penile cancer.
RESULTS
Differential analysis indicated that SPP1 was the most differentially upregulated gene in both penile cancer tissues and positive lymph node tissues. Survival analysis suggested that the prognosis of the low-SPP1 group was significantly poorer than that of the high-SPP1 group. Subsequently, immune-related bioinformatics showed that SPP1 was significantly associated with B cells, CD8 + T cells, CD4 + T cells, macrophages, helper T cells, neutrophils and dendritic cells. The immunohistochemical results showed that the high-SPP1 group was characterized by relatively high expression of CD16 and relatively low expression of CD4. GSVA analysis indicated that high-SPP1 group was significantly associated with immune-related pathways such as PD-L1 expression and the PD-1 checkpoint pathway in cancer and the TNF signaling pathway. ELISA demonstrated that the serum level of SPP1 in patients with positive lymph node metastasis of penile cancer was significantly higher than that in patients with negative lymph node metastasis of penile cancer.
CONCLUSION
Our study shows that the SPP1 gene might be an effective biomarker for predicting the prognosis and the efficacy of immunotherapy in PSCC patients.
Topics: Carcinoma, Squamous Cell; Penile Neoplasms; Immunotherapy; Osteopontin; Biomarkers, Tumor; Gene Expression Profiling; Survival Analysis; Sequence Analysis, RNA
PubMed: 38111044
DOI: 10.1186/s40246-023-00558-5 -
Human Pathology Dec 2023There is an unmet need for therapeutically relevant biomarkers for advanced penile squamous cell carcinoma (pSCC). Proposed immunohistochemistry (IHC)-based biomarkers...
OBJECTIVES
There is an unmet need for therapeutically relevant biomarkers for advanced penile squamous cell carcinoma (pSCC). Proposed immunohistochemistry (IHC)-based biomarkers include programmed death-ligand 1 (PD-L1), trophoblast cell-surface antigen 2 (TROP2), and nectin-4; however, there is a paucity of data pertaining to these biomarkers. Herein, we investigated the expression of PD-L1, TROP2, and nectin-4 in a well-annotated cohort of pSCCs.
METHODS
A single-institution pathology archive was queried for patients who had a partial or total penectomy for pSCC between January 2000 and December 2022. Whole-slide sections were stained with antibodies against PD-L1 (22C3), TROP2, and nectin-4. Expression in tumor cells was quantified using H-scores (0-300). Associations between IHC expression, human papilloma virus (HPV) status, clinicopathologic findings, and outcome parameters were evaluated.
RESULTS
This study included 121 patients. For PD-L1, the median combined positive and H-scores were 1 and 0, respectively; 32.7 % of the cases had an H-score>0. Compared to PD-L1-negative tumors, PD-L1-positive tumors had higher pT stage and grade. The median TROP2 and nectin-4 H-scores were 230 and 140, respectively, with high TROP2 and nectin-4, defined by an H-score>200, noted in 80.7 % and 10.9 % of cases, respectively. High-risk HPV-positive cases had higher TROP2 and nectin-4 scores compared to HPV-negative cases. Patients with high TROP2 expression had significantly more disease progression, and patients with high nectin-4 expression had significantly fewer deaths due to disease.
CONCLUSIONS
High expression of TROP2 and nectin-4 in pSCC support evaluation of these markers as therapeutic targets pending validation of our findings.
Topics: Male; Humans; B7-H1 Antigen; Nectins; Papillomavirus Infections; Carcinoma, Squamous Cell; Biomarkers; Penile Neoplasms; Biomarkers, Tumor
PubMed: 37977513
DOI: 10.1016/j.humpath.2023.10.003 -
Clinical Genitourinary Cancer Jun 2024Penile cancer is a rare malignancy with scant data on the impact of systemic therapy on outcomes. (Observational Study)
Observational Study
BACKGROUND
Penile cancer is a rare malignancy with scant data on the impact of systemic therapy on outcomes.
METHODS
Retrospective observational study of patients with a histological diagnosis of carcinoma penis treated with systemic therapy at the Tata Memorial Centre (Mumbai, India) between August 2010 and February 2018. Primary objective was overall survival (OS); secondary objectives included assessment of clinical characteristics, treatment approaches, and toxicity profiles.
RESULTS
We included 91 patients with penile carcinoma who received systemic therapy at our center. Intent of therapy was curative in 71 patients (78%), and palliative in 20 (22%). Median age was 57 years (interquartile range [IQR], 50-65.5) for curatively treated patients and 58.5 years (IQR, 44-65.2) for those with advanced disease. Common presenting symptoms were lumps (70%), and pain (57%). Neoadjuvant chemotherapy (NACT) with paclitaxel + platinum was administered to 19 patients (20.9%), of which 7 (37%) attained complete or partial response. Six patients (31.5%) underwent R0 surgery post-NACT. All 71 patients underwent primary surgery; 47 (66.2%) undergoing partial penectomy. Of the 20 patients treated with palliative first-line chemotherapy, 4(20%) attained a partial response. Median OS of patients treated in curative and palliative settings was 33.8 months (95% CI, 17.2-not recorded) and 11.4 months (95% CI, 9.53-23.3), respectively.
CONCLUSIONS
Patients with penile cancer treated with systemic therapy have poor outcomes. Little over a third of the patients respond to neoadjuvant chemotherapy and those with advanced disease have poor survival despite systemic therapy, emphasizing the need for early detection and optimum management of primary and nodal disease.
Topics: Humans; Male; Penile Neoplasms; Middle Aged; Retrospective Studies; Aged; India; Tertiary Care Centers; Adult; Neoadjuvant Therapy; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome; Paclitaxel; Palliative Care
PubMed: 38442451
DOI: 10.1016/j.clgc.2024.02.004 -
Virchows Archiv : An International... Dec 2023The classification of the epithelial tumors of the male and female urethra includes benign and malignant neoplasms. Primary urethral carcinomas and adenocarcinomas of... (Review)
Review
The classification of the epithelial tumors of the male and female urethra includes benign and malignant neoplasms. Primary urethral carcinomas and adenocarcinomas of the accessory glands are the most relevant tumors, both from the morphologic and clinical point of view. An accurate diagnosis, grading and staging are essential for determining adequate treatment strategies and outcome. Information on anatomy and histology of the urethra is of fundamental importance in understanding the morphology of the tumors, including the clinical importance of their location and origin.
Topics: Humans; Male; Female; Urethra; Adenocarcinoma; Biomarkers, Tumor; Urethral Neoplasms
PubMed: 37233807
DOI: 10.1007/s00428-023-03565-y -
Journal of Clinical Oncology : Official... Nov 2023Patients with advanced penile squamous cell carcinoma have a poor prognosis (21% 2-year overall survival [OS] from diagnosis). We assessed the activity of atezolizumab...
PURPOSE
Patients with advanced penile squamous cell carcinoma have a poor prognosis (21% 2-year overall survival [OS] from diagnosis). We assessed the activity of atezolizumab (anti-PD-L1) in patients with advanced penile cancer, with or without radiotherapy (RT).
PATIENTS AND METHODS
A single-center, nonrandomized phase II study with two treatment arms was conducted in 32 patients with histologically confirmed advanced penile cancer. All patients received atezolizumab (1,200 mg) once every 3 weeks. Twenty patients, who were expected to benefit from RT for locoregional disease control, received additional irradiation. The primary end point was 1-year progression-free survival (PFS) for the complete cohort and was reached if the actual 1-year PFS was at least 35%. Secondary end points included OS, objective response rate (ORR), and tolerability. Exploratory biomarker analyses were conducted in pretreatment specimens.
RESULTS
Median follow-up was 29.1 months (IQR, 18.1-33.5). Grade 3-4 adverse events related to atezolizumab or RT were observed in 3/32 (9.4%) and 13/20 (65%) patients, respectively. One-year PFS was 12.5% (95% CI, 5.0 to 31.3), which did not meet the study's primary end point. Median OS was 11.3 months (95% CI, 5.5 to 18.7). In the objective response-evaluable population (n = 30; 93.8%), the ORR was 16.7% (95% CI, 6 to 35), including 2 (6.7%) complete responders and 3 (10%) partial responders. Improved PFS was observed in patients with high-risk human papillomavirus (hrHPV)-positive tumors ( = .003) and those with high infiltration of intratumoral CD3CD8 T cells ( = .037).
CONCLUSION
Although the primary end point of 1-year PFS was not met, durable antitumor activity to atezolizumab was observed in a subset of patients. Biomarkers, such as hrHPV and intratumoral CD3CD8 T-cell infiltration, may help to better select responders.
Topics: Male; Humans; CD8-Positive T-Lymphocytes; Penile Neoplasms; Carcinoma, Squamous Cell; Penis; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37487169
DOI: 10.1200/JCO.22.02894 -
Current Opinion in Organ Transplantation Dec 2023Penile transplantation has become an emerging option for patients with severe genital defects. Only transplantation restores anatomy, sexual, and reproductive function... (Review)
Review
PURPOSE OF REVIEW
Penile transplantation has become an emerging option for patients with severe genital defects. Only transplantation restores anatomy, sexual, and reproductive function of the penis. However, penile transplantation comes with important technical, psychosocial, ethical, and surgical challenges that must be considered for successful implementation. Indications for penile transplantation have yet to be clearly elucidated.
RECENT FINDINGS
Since 2006, only five penile transplants have been performed globally. Four of the five transplants have been performed following traumatic defects, and one was performed following a total penectomy from squamous cell carcinoma. Only two of the five penile transplants remain intact. However, long-term outcomes are encouraging with optimal surgical planning, patient selection, and immunologic compliance. Clinical implications and ethical considerations are discussed.
SUMMARY
Penile transplantation is a novel solution for penile defects not amenable to traditional reconstructive approaches. With an evidence-based surgical technique, potential advantages include improved urinary function, sensation, and cosmesis. While patient selection is challenging, there is an ongoing effort to identify potential candidates. Indications are discussed in this article.
Topics: Male; Humans; Urogenital System; Transplants; Patient Selection; Plastic Surgery Procedures
PubMed: 37909925
DOI: 10.1097/MOT.0000000000001111 -
Cureus Mar 2024Background Penile cancer is a rare malignancy usually requiring surgery to achieve oncological control of the primary tumour but often at the expense of functional...
Background Penile cancer is a rare malignancy usually requiring surgery to achieve oncological control of the primary tumour but often at the expense of functional length. The presenting stage of the primary is a crucial factor in determining the most appropriate surgical procedure. Accurate preoperative staging is essential, and current modalities include clinical and radiological assessment. Clinical staging can, however, be hampered by patient body habitus and unreliable for more advanced T4 tumours, whereas radiological staging allows for more detailed identification of tissue planes and tumour involvement. There is no clear consensus on the preferred imaging technique, although, in the current European Association of Urology penile cancer guidelines, MRI is recommended with the use of ultrasound when MRI is not available. It was recommended that having the penis in an erect state by the administration of intra-cavernosal prostaglandin gave a more detailed picture enabling a greater predictor of corporal involvement. Recent studies have, however, suggested that there may be no such advantage. Methodology A retrospective review was conducted of all patients who underwent surgery for penile cancer comparing the preoperative MRI stage with the final pathological stage between July 2009 and June 2023. In addition to the MRI, patients were given an intra-cavernosal injection of prostaglandin E1 to induce tumescence unless otherwise indicated. All imaging was reported by a single consultant uro-radiologist with surgery undertaken by a single surgeon and pathology reviewed through the supra-regional penile multidisciplinary team. Results A total of 136 penile cancer patients were included in the review. Within this cohort, 98 patients had an MRI without intra-cavernosal prostaglandin and the number who had Ta, T1, T2, T3 and T4 histopathological stages was 3, 31, 45, 18, and 1, respectively. The preoperative MRI stage had a low agreement with the final histological stage for early tumours, with sensitivities and specificity of 35% and 97% for T1 and 56% and 80% for T2, respectively. Sensitivity and specificity increased for cavernosal involvement at 83% and 95%, respectively. In addition, a further 38 patients had an MRI in conjunction with an injection of prostaglandin E1 which failed to show any diagnostic improvement in sensitivity or specificity in the preoperative MRI stage. Conclusions The use of MRI as a preoperative modality for staging penile cancer performs best for identifying tumour involvement of the cavernosal bodies. Performing the MRI with the penis erect with the use of an intra-cavernosal injection did not offer any additional benefit in accurately staging penile cancer.
PubMed: 38606225
DOI: 10.7759/cureus.56016 -
Histopathology Jul 2023To elucidate the spectrum of metastatic tumours to the penis and their clinicopathologic features.
AIMS
To elucidate the spectrum of metastatic tumours to the penis and their clinicopathologic features.
METHODS
The databases and files of 22 pathology departments from eight countries on three continents were queried to identify metastatic solid tumours of the penis and to characterize their clinical and pathologic features.
RESULTS
We compiled a series of 109 cases of metastatic solid tumours that secondarily involved the penis. The mean patient age at diagnosis was 71 years (range, 7-94 years). Clinical presentation commonly included a penile nodule/mass (48/95; 51%) and localised pain (14/95; 15%). A prior history of malignancy was known in 92/104 (89%) patients. Diagnosis was made mainly on biopsy (82/109; 75%), or penectomy (21/109; 19%) specimens. The most common penile locations were the glans (45/98; 46%) and corpus cavernosum (39/98; 39%). The most frequent histologic type was adenocarcinoma (56%). Most primary carcinomas originated in the genitourinary (76/108; 70%) and gastrointestinal (20/108; 18%) tracts, including prostate (38/108; 35%), urinary bladder (27/108; 25%), and colon/rectum (18/108; 17%). Concurrent or prior extrapenile metastases were identified in 50/78 (64%) patients. Clinical follow-up (mean 22 months, range 0-171 months) was available for 87/109 (80%) patients, of whom 46 (53%) died of disease.
CONCLUSION
This is the largest study to date of metastatic solid tumours secondarily involving the penis. The most frequent primaries originated from the genitourinary and gastrointestinal tracts. Metastatic penile tumours usually presented with penile nodules/masses and pain, and they often occurred in the setting of advanced metastatic disease, portending poor clinical outcomes.
Topics: Male; Humans; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Penis; Penile Neoplasms; Adenocarcinoma; Biopsy
PubMed: 37071396
DOI: 10.1111/his.14927