EphrinB2: Expression of a novel potential target in renal cell carcinoma.

Introduction: Renal cell carcinoma (RCC) is primarily managed by surgery with the use of systemic targeted therapy in a metastatic setting. Newer targeted therapeutic options are evolving; Eph-ephrin is a potential new pathway. The therapeutic potential of targeting the EphB4-EphrinB2 pathway has been demonstrated in many solid tumors; however, its expression in RCC has only been evaluated in a few studies with limited cases. We herein determine the immunohistochemical expression of EphrinB2 in RCC. Methods: A tissue microarray comprising 110 cases of different histological subtypes of RCC and 10 normal kidney tissues were stained with monoclonal anti-EphrinB2 antibody (Abcam, AB201512). The tumor and endothelial cells expressing the EphrinB2 were examined and its expression was correlated with sex, histological subtypes, and tumor nodes metastasis (TNM) stage. Results: Twenty cases of urothelial carcinoma and two unsatisfactory conventional clear cell RCC cases were excluded, and EphrinB2 expression was interpreted in the remaining 88 tumors. EphrinB2 was expressed in 42 out of 88 tumors (47.7%) and was negative in the normal renal parenchyma. There was a statistically significant difference in the expression of EphrinB2 in males (55%) and females (32%). However, no such difference of expression was noted for the histological subtypes and the stages. Half (51%) of Stage 1 (n = 30) and Stage 2 (n = 11) tumors showed EphrinB2 positivity. Conclusions: EphrinB2 is expressed in approximately half of RCC cases. EphrinB2 expression in the early stage cancer might indicate its induction as an early event.

A comparative study of AJCC and the modified staging system in pT2/pT3 penile squamous cell carcinoma - a validation on an external data set.

AIMS: The recent changes in the American Joint Commission on Cancer, 8th edition (AJCC-8E) pT2 and pT3 tumour definitions for penile cancer need robust validation studies. A recent study redefined and modified the pT2 and pT3 stages incorporating the histopathological variables (tumour grade, lymphovascular invasion, perineural invasion) similar to that used in the current AJCC-8E pT1 stage tumour subclassification. In this study, we validate and compare this proposed staging with the AJCC staging systems on an external data set. METHODS AND RESULTS: The data set from a previously published study was obtained. pT2 and pT3 stages were reconstructed as per AJCC 7th edition (AJCC-7E), AJCC-8E and the proposed staging. The staging systems were correlated with nodal metastasis, disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). All systems were compared using receiver operating characteristic (ROC) curves. A total of 281 cases formed the study cohort. AJCC-8E (P = 0.031) and the proposed staging (P = 0.003) correlated with nodal metastasis on adjusted analysis, the latter with a better strength of association (AJCC-8E, γ = -0.471; proposed, γ = -0.625). On adjusted analysis, all the staging systems had a significant correlation with DFS, while only AJCC-8E and the proposed staging correlated with CSS and OS. On ROC curve analysis, the proposed staging had the highest area under the curve and was the only staging system to statistically correlate with all the outcome variables. CONCLUSIONS: The proposed staging for pT2/pT3 tumour stages in penile cancer may improve the prognostic and predictive ability.

Primary angiosarcoma of the seminal vesicle.

Angiosarcomas are rare but highly aggressive malignancies originating from lymphatic or vascular endothelial cells and may arise from any site in the body. Angiosarcomas of the genitourinary tract, especially of seminal vesicle origin, are extremely rare with only five reported cases. Surgery forms the mainstay of therapy in localised disease while adjuvant therapies are still being refined. We present the case of a 40-year old gentleman who presented with lower urinary tract symptoms and, on evaluation, was found to have a localised angiosarcoma originating in right seminal vesicle and offered laparoscopic resection, adjuvant paclitaxel (12 weekly cycles) and adjuvant radiation therapy (66 gray in 30 fractions). He developed a peritoneal nodular recurrence after 6 months of radiotherapy that was successfully salvaged with excision and metronomic chemotherapy, which he is currently receiving. Localised angiosarcomas need multimodality management despite small size. Attempts should be made for surgical salvage of limited recurrences whenever feasible.

Systematic Biopsy of the Prostate can Be Omitted in Men with PI-RADS™ 5 and Prostate Specific Antigen Density Greater than 15.

PURPOSE: We evaluated the prostate cancer and clinically significant prostate cancer detection on systematic biopsy (SB), target biopsy (TB) alone and combined SB and TB in men with Prostate Imaging Reporting and Data System™ (PI-RADS™) 5 lesion. MATERIALS AND METHODS: From a prospectively maintained prostate biopsy database, we identified consecutive patients with PI-RADS 5 lesion on multiparametric magnetic resonance imaging. The patients underwent multiparametric magnetic resonance imaging followed by transrectal TB of PI-RADS 5 lesion and 12-core SB. The prostate cancer and clinically significant prostate cancer (Grade Group, GG ≥2) detection on SB, TB and SB+TB were determined for all men and accordingly to prostate specific antigen density. Statistic significant was set a p <0.05. RESULTS: Overall, 112 patients met inclusion criteria. The detection rate of prostate cancer for SB, TB and SB+TB was 89%, 93% and 95%, respectively, and for clinically significant prostate cancer it was 72%, 81% and 85%, respectively. SB added 2% prostate cancer and 4% clinically significant prostate cancer detection to TB. A total of 78 patients had prostate specific antigen density >0.15 ng/ml2, and the detection rate of PCa for SB, TB and SB+TB was 92%, 97% and 97%, respectively, and for clinically significant prostate cancer it was 79%, 91% and 95%, respectively. In this population, if SB was omitted, 0 prostate cancer and only 4% (3) of clinically significant prostate cancer would be missed. The clinically significant prostate cancer detection rate improved with increased prostate specific antigen density for SB (p=0.01), TB (p <0.0001) and combined SB+TB (p=0.002). CONCLUSIONS: In patients with PI-RADS 5 on multiparametric magnetic resonance imaging and prostate specific antigen density >0.15 ng/ml2, SB marginally increases clinically significant prostate cancer detection, but not overall prostate cancer detection in comparison to TB alone. Systematic biopsy did not affect patients' management and can be omitted on this population.

MRI predicts prostatic urethral involvement in men undergoing radical prostatectomy: implications for cryo-ablation of localized prostate cancer.

PURPOSE: To determine whether multi-parametric magnetic resonance imaging (mpMRI) can reliably predict proximity of prostate cancer to the prostatic urethra in a contemporary series of men undergoing radical prostatectomy (RP) at two academic centers. METHODS: Clinical characteristics of consecutive men undergoing pre-operative mpMRI prior to RP and whole-mount axial serial step-sectioned pathology examination at two academic centers between Jun 2016 and Oct 2018 were analyzed retrospectively. Every tumor was characterized by its pathologic minimum distance to the prostatic urethral lumen (pMDUL). Only the cancer closest to the urethra represented the prostatic urethral index lesion. The radiologic minimum distance of the index lesion to the prostatic urethral lumen was measured and noted as ≤ 5 mm versus > 5 mm. The sensitivity, specificity, positive and negative predicting values (PPV and NPV) and area under the receivers operating characteristics curve (AUC) were calculated for performance of mpMRI for predicting pMDUL ≤ 5 mm. RESULTS: Of the 163 surgical specimens examined, 112 (69%) exhibited a pMDUL ≤ 5 mm. These men had significantly higher grade group (GG) and advanced pathological and clinical stage. The rates of high PI-RADS score and presence of gross extracapsular extension were also significantly greater for the group with pMDUL ≤ 5 mm. The AUC, sensitivity, specificity, PPV, and NPV were 0.641, 51.8, 76.5, 82.9, and 42.4%, respectively, for mpMRI to predict pMDUL < 5 mm. CONCLUSIONS: Nearly 70% of men undergoing RP present with tumor within 5 mm of the prostatic urethra. These tumors present higher risk characteristics, and mpMRI exhibited moderate performance and high PPV in their pre-operative detection. Physicians performing partial gland ablation should take these results into consideration during treatment selection and planning.

Application and comparison of Fuhrman nuclear grading system with the novel tumor grading system for chromophobe renal cell carcinoma and its correlation with disease-specific events.

INTRODUCTION: The grading system of chromophobe renal cell carcinoma (ChRCC) is not well established. In this study, we aimed to compare the application of Fuhrman nuclear grade (FNG) with the novel chromophobe tumor grade (CTG). We also evaluated the correlation of these two grading systems with the clinical outcome. MATERIALS AND METHODS: Consecutive cases of ChRCC diagnosed on nephrectomy during 2005-2014 were identified. The clinical details of the patients were retrieved. Histopathology slides were reviewed and the nuclear grading was assigned using standard FNG and the CTG system. The CTG and FNG gradings were correlated with clinical outcome. RESULTS: A total of 80 cases were retrieved. Distribution of FNG was as follows: FNG-1, 1 (1.3%); FNG-2, 23 (28.3%); FNG-3, 44 (55.0%); and FNG-4, 12 (15%). CTG distribution was as follows: CTG-1, 48 (60.0%); CTG-2, 20 (25.0%); and CTG-3 12 (15.0%). Follow-up data was available in 46 cases; the median follow-up was 23.9 months (range 1-96.4 months). The median time to recurrence/metastasis was 17.2 months (range 3.2-31.2 months). Mean disease-free survival (DFS) was 68.5 months. Both CTG (P < 0.001) and FNG (P = 0.001) correlated with DFS; however, only CTG retained this significance when only the nonsarcomatous cases were analyzed. On receiver operating characteristics curve analysis, CTG had higher predictive accuracy for DFS for the entire group, while FNG lost the statistical significance when the nonsarcomatous cases were analyzed. CTG (P = 0.001) but not FNG (P = 0.106) correlated with the disease-specific adverse events in non-sarcomatous cases. CONCLUSIONS: It is possible to apply CTG in ChRCC. It is a better predictor of DFS and disease-specific adverse events. CTG is more appropriate and applicable than the FNG in grading ChRCC.

One-Stop MRI and MRI/transrectal ultrasound fusion-guided biopsy: an expedited pathway for prostate cancer diagnosis.

PURPOSE: To assess the feasibility, safety, and outcomes of an expedited One-Stop prostate cancer (PCa) diagnostic pathway. PATIENTS AND METHODS: We identified 370 consecutive patients who underwent multiparametric magnetic resonance imaging (mpMRI) and transrectal ultrasound fusion prostate biopsy (MRI/TRUS-PBx) from our institutional review board-approved database. Patients were divided according to diagnostic pathway: One-Stop (n = 74), with mpMRI and same-day PBx, or Standard (n = 296), with mpMRI followed by a second visit for PBx. mpMRIs were performed and interpreted according to Prostate Imaging-Reporting and Data System (PI-RADS v2). Grade group ≥ 2 PCa defined clinically significant PCa (csPCa). Statistical significance was considered when p < 0.05. RESULTS: Age (66 vs 66 years, p = 0.59) and PSA density (0.1 vs 0.1 ng/mL2, p = 0.26) were not different between One-Stop vs Standard pathway, respectively. One-Stop patients lived further away from the hospital than Standard patients (163 vs 31 km; p < 0.01), and experienced shorter time from mpMRI to PBx (0 vs 7 days; p < 0.01). The number (p = 0.56) and distribution of PI-RADS lesions (p = 0.67) were not different between the groups. All procedures were completed successfully with similar perioperative complications rate (p = 0.24). For patients with PI-RADS 3-5 lesions, the csPCa detection rate (49% vs 41%, p = 0.55) was similar for One-Stop vs Standard, respectively. The negative predictive value of mpMRI (PI-RADS 1-2) for csPCa was 78% for One-Stop vs 83% for Standard (p = 0.99). On multivariate analysis, age, prostate volume and PI-RADS score (p < 0.01), but not diagnostic pathway, predicted csPCa detection. CONCLUSION: A One-Stop PCa diagnostic pathway is feasible, safe, and provides similar outcomes in a shorter time compared to the Standard two-visit diagnostic pathway.

Spindle cell oncocytoma of adenohypophysis: Review of literature and report of another recurrent case.

Spindle cell oncocytoma (SCO) of adenohypophysis was first described in 2002 by Roncaroli et al. as a new entity in the tumors originating from adenohypophysis. It was subsequently recognized as a distinct entity in the 2007 WHO classification of CNS tumors and retained in the current updated classification. In contrast to that suggested by the original authors, this tumor does have a potential for recurrence as first described by Kloub et al. and later with many such case reports. This tumor can be confused with other sellar tumors like pituicytomas and pituitary adenoma, both radiologically and histopathologically. However, it is imperative to differentiate these tumors from the above-mentioned differential diagnoses as it certainly has a recurrent potential. To date only 34 cases of SCO have been published in the English literature. Herein we present a rare SCO case with unusually aggressive course in a 64-year-old man, which recurred 4 years after the initial diagnosis.

Chromoblastomycosis of the leg.

CASE REPORT: We herein report a case of chromoblastomycosis presenting as a verrucous lesion over the leg. A 56-year-old male patient was a known case of carcinoma larynx and was treated for the same. At presentation to our hospital, the patient, in addition to the recurrent local disease, was suspected to have second primary in the form of verrucous carcinoma of the leg. Histopathological examination of the skin biopsy revealed the presence of characteristic pigmented sclerotic bodies with pseudoepitheliomatous hyperplasia of the overlying epithelium. The case was reported as chromoblastomycosis and the patient responded well to anti-fungal chemotherapy in the form of itraconazole.

Comparison of a modified staging system with 8th edition AJCC criteria in a North American cohort of pT2/pT3 HPV-negative penile squamous cell carcinoma.

The staging for pT2/pT3 penile squamous cell carcinoma (pSCC) has undergone major changes. Some authors proposed criteria wherein the distinction between pT2/pT3 was made using the same histopathological variables that are currently utilized to differentiate pT1a/pT1b. In this single-institution, North American study, we focused on (HPV-negative) pT2/3 pSCCs (i.e., tumors invading corpus spongiosum/corpus cavernosum), and compared the prognostic ability of the following systems: (i) AJCC (8th edition) criteria; (ii) modified staging criteria proposed by Sali et al. (Am J Surg Pathol. 2020; 44:1112-7). In the proposed system, pT2 tumors were defined as those devoid of lymphovascular invasion (LVI) or perineural invasion (PNI), and were not poorly differentiated; whereas pT3 showed one or more of the following: LVI, PNI, and/or grade 3. 48 pT2/pT3 cases were included (AJCC, pT2: 27 and pT3: 21; Proposed, pT2: 22 and pT3: 26). The disease-free survival (DFS) and progression-free survival (PFS) did not differ between pT2 and pT3, following the current AJCC definitions (p = 0.19 and p = 0.10, respectively). When the pT2/3 stages were reconstructed using the modified criteria, however, a statistically significant difference was present in both DFS and PFS between pT2 and pT3 (p = 0.004 and p = 0.003, respectively). The proposed staging system has the potential to improve the prognostication of pT2/pT3 tumors in pSCC. Each of these histopathologic variables has been shown to have a significant association with outcomes in pSCC, which is an advantage. Further studies are needed to demonstrate the utility of this modified staging system in patient populations from other geographic regions.

Updates in staging of penile cancer: the evolution, nuances, and issues.

Staging based on the tumor (T), node (N), and metastasis (M) schema of the American Joint Committee on Cancer (AJCC) is usually the most important prognostic factor for any tumor type. Although a rare tumor, in penile cancers, this staging has evolved rapidly in the last two editions of the AJCC Cancer Staging manuals. These changes and updates are largely based on the advancement in our knowledge of the complex anatomy of the penis, the role of histopathological variables in disease biology, and the results of multicentric studies comprising large data sets. In this review, we present the evolution of the AJCC staging model from its inception to the present day. The evidence and data that entailed these changes are also discussed. We highlight a few issues with the current staging model and also briefly discuss the future perspectives and the road map which, with the help of global efforts, can further refine the staging models.

Predictors of Pelvic Lymph Nodal Metastasis in Penile Squamous Cell Carcinoma- Results From a Matched-Pair Analysis.

INTRODUCTION: Pelvic lymph node (PLN) metastasis has a worse prognosis in penile squamous cell carcinoma. This study sought to determine the predictors of PLN metastasis in penile SCC. MATERIALS AND METHODS: This retrospective study included primary penile resections with inguinal lymph nodes (ILN) and PLN dissections over 10 years (2007-2017). A subset of treatment naïve cases with PLN metastasis was matched for age and tumor size with another subset of cases having metastatic ILN and negative PLN. The variables were correlated with the PLN metastasis using appropriate statistical tests. Internal validation of the multivariate model was conducted by using 2000 bootstraps on the same cohort. The optimum cut-off for the number of positive ILN was obtained by plotting a receiver operating characteristic curve and using the highest Youden's index as a discriminator. RESULTS: A total of 56 cases (28 in each subset) formed the study cohort. On unadjusted analysis the size of the largest ILN (p=0.038), number of positive ILN (p=0.001), percentage of positive ILN (p=0.001), and laterality of ILN involvement (p=0.007) had a significant correlation with PLN metastasis. On adjusted analysis, the number of positive ILN (p=0.011) was the only statistically significant variable. Bootstrapping results indicated that this multivariate model represented the dataset adequately. The maximum Youden's index was obtained when ≥5 ILN were positive. CONCLUSIONS: The number of metastatic ILN is the most important predictor of PLN metastasis. A higher threshold of metastatic ILN for addressing PLN dissection can be investigated, particularly in a high disease burden setup.

Aliens in the thyroid gland: The secondary lesions.

BACKGROUND: A secondary lesion in the thyroid gland is a rare clinical scenario diagnosed preoperatively during the evaluation of a neck mass, postoperatively in a thyroidectomy specimen or in autopsy studies. Even though the thyroid gland is highly vascular, secondary malignant lesions are rare accounting for 0.2% of all thyroid malignancies. Thyroid gland secondary lesions are often metachronous in presentation as they are seldom evaluated in the initial diagnostic workup of the primary lesion. Fine-needle aspiration cytology (FNAC) is a useful modality for the diagnosis of secondary thyroid lesions. MATERIALS AND METHODS: A 6-year retrospective review (2016-2021) was carried out to assess the secondary lesions in the thyroid gland. Papanicolaou and field-stained FNAC smears of secondary thyroid lesions were reviewed. Ancillary techniques were performed on the cell block for differentiating from the primary thyroid gland lesions. RESULTS: There were 383 patients in our archives. There were only 18 cases (4.7%) that presented with secondary neoplastic lesions in the thyroid gland either by direct extension, metastases or as a hematolymphoid malignancy. There were 14 (77.7%) cases that presented with non-hematolymphoid secondary lesions while 4 (22.3%) cases presented with hematolymphoid malignancies. Thyroid secondaries were predominantly seen in female patients (female: male ratio of 1.5:1). Most of the cases presented with a synchronous secondary lesion (n = 14, 77.7%) and few metachronous secondary lesions were also noted (n = 4, 22.3%). CONCLUSION: Although exceedingly rare, the detection of secondary thyroid gland lesions is important for staging and planning treatment.

A Clinicopathological Analysis of Molecular Subtypes of Breast Cancer using Immunohistochemical Surrogates: A 6-Year Institutional Experience from a Tertiary Cancer Center in North India.

Puneet Kaur SomalObjective Classification of breast cancer into different molecular subtypes has important prognostic and therapeutic implications. The immunohistochemistry surrogate classification has been advocated for this purpose. The primary objective of the present study was to assess the prevalence of the different molecular subtypes of invasive breast carcinoma and study the clinicopathological parameters in a tertiary care cancer center in rural North India. Materials and Methods All female patients diagnosed with invasive breast cancer and registered between January 1, 2015, and December 31, 2020, were included. Patients with bilateral cancer, missing information on HER2/ER/PR receptor status, absence of reflex FISH testing after an equivocal score on Her 2 IHC were excluded. The tumors were classified into different molecular subtypes based on IHC expression as follows-luminal A-like (ER- and PR-positive, Her2-negative, Ki67 < 20%), luminal B-like Her2-negative (ER-positive, Her2-negative and any one of the following Ki67% ≥ 20% or PR-negative/low, luminal B-like Her2-positive (ER- and HER2-positive, any Ki67, any PR), Her2-positive (ER- and PR-negative, Her2-positive) and TNBC (ER, PR, Her2-negative). Chi square test was used to compare the clinicopathological parameters between these subtypes. Results A total of 1,625 cases were included. Luminal B-like subtype was the most common (41.72%). The proportion of each subtype was luminal A (15.69%), luminal B Her2-negative (23.93%), luminal B Her2-positive (17.78%), Her2-positive (15.26%), TNBC (27.32%). Majority of the tumors were Grade 3 (75.81%). Nodal metastases were present in 59%. On subanalysis of the luminal type tumors without Her2 expression (luminal A-like and luminal B-like (Her2-negative), luminal A-like tumors presented significantly with a lower grade ( p < 0.001) and more frequent node-negative disease in comparison to luminal B-like (Her2-negative) tumors. In comparison to other subtypes, TNBC tumors were more frequently seen in the premenopausal age group ( p < 0.001) and presented with node-negative disease ( p < 0.001). Conclusion This is one of the largest studies that enumerates the prevalence of various molecular subtypes of breast cancer in North India. Luminal B-like tumors were the most common followed by TNBC. TNBC tumors presented more commonly in premenopausal age group and with node negative disease in comparison to other subtypes.

Challenges Encountered and Pattern-Based Analysis of Bone Marrow Biopsy in Lymphomas: An Institutional Experience.

Objective The evaluation of bone marrow (BM) status is an integral part of the initial workup of patients diagnosed with lymphoma as it plays an important role in staging and predicting prognosis in these patients. This article determines the incidence and pattern of BM involvement in lymphoma cases and distinguishes benign from malignant lymphoid aggregates in BM biopsies. Materials and Methods The study group included 121 cases of Hodgkin and non-Hodgkin lymphomas for which BM biopsies were performed, fixed in acetic acid-zinc formalin solution, decalcified using 10% formic acid, and subjected to hematoxylin and eosin and immunohistochemistry. Results The overall incidence of BM biopsy involvement in our study was 31.4% (37/118), including 34.7% (35/101) in cases of B cell lymphomas, 25% (2/8) in cases of T cell lymphomas, and no involvement in Hodgkin lymphoma. The predominant histological pattern of BM involvement was diffused (14/37; 37.8%), followed by interstitial (10/37; 27.1%). Five cases revealed benign nonparatrabecular lymphoid aggregates which could be confused with lymphomatous involvement, especially in low grade lymphomas. Conclusion A careful examination of the BM biopsies along with clinical history, peripheral blood examination, flow cytometry, and immunohistochemistry will help in arriving at the correct diagnosis.

Early endometrial carcinoma: Experience and outcomes.

Aim: Endometrial carcinoma (EC) data from India are very sparse. We did a retrospective analysis of our patients registered at this peripheral cancer center based in rural Punjab and studied their outcome. Materials and Methods: Ninety-eight Stage I and II EC patients with endometroid histology registered at our institute from January 2015 to April 2020 were studied for demography, histopathology, treatment received, and outcomes. FIGO 2009 staging and new European Society for Medical Oncology (ESMO) risk group classification was used. Results: Our patients had a median age of 60 years (range 32-93 years). There were 39 (39.8%), 41 (42.0%), 4 (4.1%), 12 (12.2%) patients in the low risk, intermediate risk (IR), high intermediate risk, and high risk groups, respectively, as per new ESMO risk classification. Two (2.0%) patients had incomplete information to assign them to a particular risk group. Fifty (46.7%) patients underwent complete surgical staging and 54 (50.5%) patients received adjuvant RT. With a median follow-up of 27.0 months, there were 1 locoregional and 2 distant recurrences. There were 8 deaths in total. Three-year overall survival for the entire group is 90.6%. Conclusions: The risk group determines adjuvant treatment in endometrial cancer. Patients operated at dedicated cancer center tend to have better surgical staging and thus better outcome because of better risk stratification and grouping for adjuvant therapy. IR histology was more common in our group of patients, which is variable as compared to available literature.