A study into the association between local recurrence rates and surgical resection margins in organ-sparing surgery for penile squamous cell cancer.

OBJECTIVE: To evaluate the significance of close surgical margins in organ-sparing surgery (OSS) in the treatment of penile squamous cell carcinoma (pSCC) and clinicopathological factors that may influence local recurrence. PATIENTS AND METHODS: At our tertiary referral centre, between March 2001 and September 2012, 332 patients treated with OSS for pSCC had clear surgical margins. As the focus was the impact of close clear margins on local recurrence, patients with positive margins were excluded for the purpose of this study. Our overall positive margin rate for OSS in penile cancer is 7.6% (42 patients). Analysis was carried out on an on-going prospective database, including prospective accurate pathological recording of surgical margins. Patients underwent OSS after multidisciplinary team (MDT) discussion. Local recurrence was the primary outcome measured and Fisher's exact test and time-to-recurrence curves were used in the analysis. All local recurrences were scrutinised by the MDT and were categorised into: true recurrences or metachronous new occurrences (i.e. tumours arising from a background of penile intraepithelial neoplasia and forming on an epithelial surface not related to the site of initial resection). A multivariate analysis was also conducted to elucidate other factors influencing local recurrence. RESULTS: In all, 64% of the patients had a <5 mm clear deep surgical margin, with 16% clear by <1 mm. Overall, 4% of patients had a true local recurrence, with a median time to recurrence of 6 months. In all, 53% were due to embolic spread, with residual occult local disease accounting for 47%. There was a statistically significant relationship between cavernosal involvement (P = 0.014) and lymphovascular invasion (LVI; P = 0.001) and local recurrence. Although multivariate analysis revealed that the extent of clear margin was not a predictor of disease (P = 0.405), we found an increased risk of local recurrence in the clear margin cohort of <1 mm compared to those of >1 mm (P < 0.001). Those patients considered to have metachronous tumours were scrutinised by our MDT, and eight patients (2.4%) were found to have new occurrences. Our overall proportion of patients therefore needing further treatment for either new occurrences or recurrent disease after OSS stands at 6.4%. CONCLUSIONS: Overall the presence of local recurrent disease in OSS in our experience is low (4%). We report an embolic mechanism of local recurrence, strongly suggested by the presence of cavernosal involvement and LVI. We conclude that a deep clear margin of >1 mm has a very low risk of local recurrence in penile OSS.

Glans resurfacing for precancerous and superficially invasive carcinomas of the glans penis: Pathological specimen handling and reporting.

Glans resurfacing is a recently described technique in the management of precancerous lesions and superficial invasive tumours of the glans penis as well as cases of indolent persistent lichen sclerosus. The technique is complex and is usually only practiced in specialist centres with combined urological and plastic surgical expertise. Cosmetic and functional results are better than in more extensive penile surgery, such as glansectomy, for such cases, cancer cure and control is comparable. Knowledge of the technique used and the spectrum of disease are vital for appropriate specimen handling and pathological reporting of these complex cases to aid further management and avoid over reporting of positive margins.

Primary cutaneous plasmacytoma occurring after pacemaker implantation and recurring in scar tissue.

Primary cutaneous plasmacytomas are rare and little is known about their treatment and progression. We describe for the first time the predilection of primary cutaneous plasmacytoma to occur in a scar or sites of trauma. We report an 89-year-old man who presented with a slowly expanding asymptomatic mass over his pacemaker implantation, 1 year after insertion. Further investigation ruled out multiple myeloma and histology confirmed it to be a cutaneous plasmacytoma. This was treated successfully by local radiotherapy after extraction of the pacemaker and implantation of a new pacemaker on the opposite side. The patient subsequently developed an additional cutaneous plasmacytoma over the new pacemaker site, followed by the development of progressive multiple myeloma. Primary cutaneous plasmacytoma can show predilection for sites of trauma or surgery. Surgical excision of the plasmocytoma and local radiotherapy may be a reasonable strategy in the first initially after pacemaker removal.

Analysis of the PI3K-AKT-mTOR pathway in penile cancer: evaluation of a therapeutically targetable pathway.

OBJECTIVES: To determine whether phosphatidylinositol-4,5-bisphosphate 3- kinase, catalytic subunit alpha (PIK3CA) copy number gain is common and could prove a useful marker for the activation status of the PI3K-AKT-mTOR pathway in penile squamous cell carcinoma (PSCC). METHODS: Fresh frozen tissue and archival blocks were collected from 24 PSCC patients with 15 matched normal penile epithelium (NPE) tissue from St George's Hospital. PIK3CA mutational and copy number status (CNS) was assessed via Sanger sequencing and fluorescence in-situ hybridisation, respectively. PIK3CA RNA expression was quantified using TaqMan gene expression assay. HPV DNA was detected with INNO-LiPA assay. p-AKT and p-mTOR protein expression were assessed using western blot and immunohistochemistry. RESULTS: PIK3CA copy number gain was found in 11/23 (48%) patients, with mutations present in only 2/24 (8%) patients. In comparison to NPE, PSCC showed significantly lower PIK3CA RNA expression (p=0.0007), p-AKT (Ser473) nuclear immunoexpression (p=0.026) and protein expression of p-AKT (Thr308) (p=0.0247) and p-mTOR (Ser2448) (p=0.0041). No association was found between PIK3CA CNS and p-AKT and p-mTOR protein expression. CONCLUSION: Based on our results the PI3K-AKT-mTOR pathway is not a key driver in PSCC carcinogenesis and the therapeutic targeting of this pathway is unlikely to produce significant clinical benefit.

The Prognostic Value of PIK3CA Copy Number Gain in Penile Cancer.

OBJECTIVE: To determine whether phosphatidylinositol-4,5-bisphosphate 3- kinase, catalytic subunit alpha (PIK3CA) copy number gain in penile cancer has prognostic value and association with histopathological parameters, human papillomavirus (HPV), and clinical outcome. METHODS: PIK3CA copy number status was assessed with fluorescence in situ hybridization in tissue microarrays generated from archival paraffin embedded blocks of 199 patients with primary penile squamous cell carcinoma (PSCC). HPV DNA was detected with INNO-LiPA assay. Follow-up data were available for 174 patients. PIK3CA copy number status was correlated with histopathological parameters, high-risk HPV, cancer-specific survival and time to recurrence. RESULTS: PIK3CA copy number gain was found in 84/199 (42%) of penile cancer cases. PIK3CA copy number gain was associated with tumor subtype, grade, and stage (P = .0028, P < .0001, and P = .0397, respectively), but not with lymph node status (P = .2902). PIK3CA copy number gain showed a tendency to associate with cancer-specific survival (HR = 1.76, 95% CI; 0.94-3.3; P = .0753). In multivariate analysis, PIK3CA copy number gain was found to have no prognostic value for cancer-specific survival (P = .677). Only lymph node metastasis, high tumor grade and stage were found to be independent prognostic factors for cancer-specific survival. CONCLUSION: PIK3CA copy number gain could be used as a marker of high-risk disease as it correlates with more aggressive PSCC histological subtypes and higher tumor grade and stage. However, it shows no significant association with lymph node metastasis or prognostic value for cancer-specific survival in PSCC.

PIK3CA copy number aberration and activation of the PI3K-AKT-mTOR pathway in varied disease states of penile cancer.

BACKGROUND: Therapeutic targeting of the PI3K-AKT-mTOR pathway may benefit patients with advanced penile squamous cell carcinoma (PSCC). OBJECTIVES: To determine the prevalence of PIK3CA copy number gain and correlate this with the activity status of PI3K-AKT-mTOR pathway in pre-malignant penile intraepithelial neoplasia (PeIN) and invasive PSCC. MATERIALS AND METHODS: Archival tissue blocks were obtained from 58 PeIN and 244 primary PSCC patients treated at St George's Hospital. PIK3CA copy number status (CNS) was assessed by fluorescence in-situ hybridisation. High-risk HPV DNA was detected with INNO-LiPA assay. p16INK4A, p-AKT and p-mTOR protein expression were assessed using immunohistochemistry (IHC). RESULTS: Increased prevalence of PIK3CA copy number gain was seen in PSCC in comparison to PeIN (84/199 (42%) vs. 10/58 (17%); p = 0.0009). Analysis of the p-AKT and p-mTOR revealed a tendency to a more common expression of cytoplasmic p-AKT (p = 0.1318), nuclear p-AKT (p<0.0001) and cytoplasmic mTOR (p = 0.0006) in PeIN than PSCC. A significant association between p-AKT cytoplasmic immunoexpression and PIK3CA CNS (p = 0.0404) was found in PeIN. CONCLUSION: Overall, PIK3CA copy number gain correlated with activation of the PI3K-AKT-mTOR pathway in PeIN and activation of this pathway is primarily involved in early penile carcinogenesis. Based on these results therapeutic targeting of this pathway in advanced PSCC is unlikely to produce significant clinical benefit. Future studies will need to focus on alternative therapeutic targets.

DNA Copy Number Aberrations, and Human Papillomavirus Status in Penile Carcinoma. Clinico-Pathological Correlations and Potential Driver Genes.

Penile squamous cell carcinoma is a rare disease, in which somatic genetic aberrations have yet to be characterized. We hypothesized that gene copy aberrations might correlate with human papillomavirus status and clinico-pathological features. We sought to determine the spectrum of gene copy number aberrations in a large series of PSCCs and to define their correlations with human papillomavirus, histopathological subtype, and tumor grade, stage and lymph node status. Seventy formalin-fixed, paraffin embedded penile squamous cell carcinomas were centrally reviewed by expert uropathologists. DNA was extracted from micro-dissected samples, subjected to PCR-based human papillomavirus assessment and genotyping (INNO-LiPA human papillomavirus Genotyping Extra Assay) and microarray-based comparative genomic hybridization using a 32K Bacterial Artificial Chromosome array platform. Sixty-four samples yielded interpretable results. Recurrent gains were observed in chromosomes 1p13.3-q44 (88%), 3p12.3-q29 (86%), 5p15.33-p11 (67%) and 8p12-q24.3 (84%). Amplifications of 5p15.33-p11 and 11p14.1-p12 were found in seven (11%) and four (6%) cases, respectively. Losses were observed in chromosomes 2q33-q37.3 (86%), 3p26.3-q11.1 (83%) and 11q12.2-q25 (81%). Although many losses and gains were similar throughout the cohort, there were small significant differences observed at specific loci, between human papillomavirus positive and negative tumors, between tumor types, and tumor grade and nodal status. These results demonstrate that despite the diversity of genetic aberrations in penile squamous cell carcinomas, there are significant correlations between the clinico-pathological data and the genetic changes that may play a role in disease natural history and progression and highlight potential driver genes, which may feature in molecular pathways for existing therapeutic agents.

Airway and parenchymal manifestations of pulmonary aspergillosis.

Pulmonary aspergillosis encompasses a heterogeneous group of mycoses that result from either colonisation or pathogenic damage of lung tissue by Aspergillus fungi. These clinical entities range from relatively benign saprophytic hypersensitivity associated with fungal inhabitation to life threatening invasive disease. The diagnosis of pulmonary disorders related to Aspergillus is on the increase and it is more important than ever those both general and respiratory physicians have a good understanding of these disorders. This paper reviews the contemporary understanding of the clinical, radiographic and histopathological aspects of pulmonary aspergillosis.

Chronic Pneumocystis jiroveci presenting as asymptomatic granulomatous pulmonary nodules in lymphoma.

We present a rare case of chronic Pneumocystis jiroveci infection presenting as multiple persistent granulomatous pulmonary nodules over a 12 month period in a patient with follicular lymphoma undergoing treatment with Rituximab, Cyclophosphamide, Vincristine, and Prednisolone chemotherapy. Remarkably during this period the patient remained asymptomatic. This is the first case to combine these atypical histological, radiological, and clinical manifestations of P. jiroveci infection highlighting unusual manifestations of the disease.