The present study demonstrates a high concordance between the immunohistochemistry (IHC) expression of HER2 and the RNA expression of ERBB2 in urothelial carcinoma. The genomic, transcriptomic, and ...immunologic landscapes of urothelial carcinoma based on ERBB2 expression were investigated. High-expressing ERBB2 tumors have an increased expression of antibody drug conjugate (ADC) target genes NECTIN4 and TACSTD2 versus the low-expressing ERBB2 tumor. Targeting ERBB2-high tumors with multiple ADCs should be investigated as a potential therapeutic strategy. Additionally, a positive association between ERBB2 expression and survival was observed and warrants further investigation. Background: Recent data suggests that HER2-targeted treatment is efficacious in urothelial carcinoma (UC). We investigated the genomic, transcriptomic, and immune landscapes and clinical outcomes in UC segmented by ERBB2 expression. Methods: NextGen DNA/RNA sequencing was performed for 4743 UC tumors. A total of 3% (124/4125) of tumors had HER2 IHC and whole transcriptome sequencing (WTS) data. ERRB2-high and -low tumors were defined by ≥75th and <25th percentiles of ERBB2 expression, respectively. PD-L1 (SP142) positive staining was defined as ≥2+ and ≥5%. HER2 (4B5) positive staining was defined as ≥3+ and >10% or 2+ and >10% with positive HER2 in situ hybridization (ISH). Results: Of the patients who were ERBB2-high, 79% (61/77) were HER2 positive via IHC. Tumors from lower tract UC had higher ERBB2 expression compared to upper tract UC (50 v 40 median TPM (mTPM), p < 0.001). ERBB2 expression was similar between primary and metastatic tumors (47 v 47 mTPM, p = 0.95). ERBB2-high tumors had a higher prevalence of pathogenic mutations in pTERT, ERBB2, and ELF3 versus ERBB2-low tumors, p < 0.001. ERBB2-high tumors had higher expressions of ADC target genes NECTIN4 (12 v 8 mTPM) and TACSTD2 (366 v 74 mTPM) versus ERBB2-low (p < 0.001), as well as better overall survival from time of tissue sampling than ERBB2-low (HR 1.71, p < 0.001). Conclusion: Our study demonstrated a high concordance between HER2 expression by IHC and ERBB2 gene expression by WTS in UC. Differences in ADC target expression between ERBB2-high vs. ERBB2-low UC may provide a rationale for combination treatment strategies with HER2-ADC. The association between high ERBB2 expression and survival advantage warrants further investigation.
We report a case of an isolated para-aortic retroperitoneal renal cell carcinoma (RCC) in the absence of a primary cancer in the kidney. Single case reports in the literature have described ...extra-renal RCC in different locations with no evidence of primary renal tumor. We present the initial presentation, diagnostic imaging, surgical treatment, and pathologic evaluation. Immunohistochemistry demonstrated positivity for TFE3 and TFEB, both of which are Microphthalmia associated transcription factors (MiT) associated with translocation RCCs. We hypothesize these few cases of extra-renal RCC represent rare forms of translocation RCC.
Aims
Formal depiction of granulomatous inflammation associated with renal neoplasms has mainly consisted of case reports. Herein, we investigate the clinicopathological features and potential ...significance of granulomas associated with renal tumours from a large multi‐institutional cohort.
Methods and results
One hundred and eleven study cases were collected from 22 institutions, including 57 partial nephrectomies and 54 radical nephrectomies. Patient ages ranged from 27 to 85 years (average = 60.1 years; male = 61%). Renal neoplasms included clear cell renal cell carcinoma (RCC; 86%), papillary RCC (8%), chromophobe RCC (3%), clear cell papillary RCC (1%), mixed epithelial stromal tumour (1%) and oncocytoma (1%). Granulomas were peritumoral in 36%, intratumoral in 24% and both in 40% of cases. Total granuloma count per case ranged from one to 300 (median = 15) with sizes ranging from 0.15 to 15 mm (mean = 1.9 mm). Necrotising granulomas were seen in 14% of cases. Histochemical stains for organisms were performed on 45% of cases (all negative). Sixteen cases (14%) had a prior biopsy/procedure performed, and eight patients had neoadjuvant immunotherapy or chemotherapy. Eleven patients (10%) had a confirmed diagnosis of sarcoidosis, including five in whom sarcoidosis was diagnosed after nephrectomy.
Conclusion
Based on this largest case‐series to date, peri−/intratumoral granulomas associated with renal neoplasms may be more common than initially perceived. The extent of granulomatous inflammation can vary widely and may or may not have necrosis with possible aetiologies, including prior procedure or immunotherapy/chemotherapy. Although a clinical association with sarcoidosis is infrequent it can still occur, and the presence of granulomas warrants mention in pathology reports.
PAX8 and PAX2 are cell-lineage-specific transcription factors that are essential for the development of Wolffian and Müllerian ducts and have recently emerged as specific diagnostic markers for ...tumors of renal or Müllerian origin. Little is known about their expression in the Wolffian duct-derived human male genital tract. We report our findings of PAX8 and PAX2 expression in the epithelium of the normal male genital tract and in epithelial tumors derived therefrom using immunohistochemistry (IHC). We found that PAX8 and PAX2 were expressed in the epithelium of the male genital tract from the rete testis to the ejaculatory duct. Rare glands in the prostatic central zone, a tissue of purported Wolffian duct origin, were focally positive for PAX2, but no PAX8 was detected in this area, a finding that may warrant further study. We found diffuse expression of PAX8 and PAX2 in 1 case each of serous cystadenoma of the epididymis, carcinoma of the rete testis, Wolffian adnexal tumor of the seminal vesicle, and endometrioid carcinoma of the seminal vesicle. Neither PAX8 nor PAX2 was detected in the seminiferous tubules and interstitium of the normal testis, nor in Leydig cell tumors (n=6), Sertoli cell tumors (n=2), or 48 of 49 germ cell tumors. One pediatric yolk sac tumor showed focal and weak staining for PAX8. Tumors of mesothelial origin, that is, adenomatoid tumors (n=3) and peritoneal malignant mesotheliomas (n=37) in men, were negative for PAX2 and PAX8. Neither PAX2 nor PAX8 was present in other areas of the prostate. Expression of PAX8 and PAX2 in these primary epithelial neoplasms of the male genital tract is due to their histogenetic relationship with Wolffian or Müllerian ducts. PAX8 and PAX2 IHC may facilitate the diagnosis of these tumors and should be included in the differential diagnostic IHC panel.
Purpose
We aimed to determine incidence, pathologic findings, prognostic factors and clinical outcomes for patients with clinically localized papillary RCC.
Methods
Demographic, clinical and ...pathologic findings were collected on all patients with PRCC undergoing surgery at four academic medical centers. The primary endpoint was cancer-specific survival (CSS). Relapse-free survival (RFS) and overall survival (OS) were secondary endpoints. Kaplan–Meier estimates were obtained, and Cox proportional hazard regression models were used to assess predictors of mortality and relapse.
Results
We identified 626 PRCC, of which 373 (60 %) were type 1 and 253 (40 %) were type 2, with three-quarters of all tumors being pT1. Compared to patients with type 1, those with type 2 were older (mean age: 63 vs 61;
p
= 0.02), presented more commonly with symptoms (13 vs 7 %;
p
= 0.02) and had larger mean tumor size (5.2 vs 4.3 cm;
p
= 0.001). With a median follow-up of 41 months (IQR: 16–68), 92 patients had died of PRCC (15 %), 48 (8 %) experienced relapse, and 101 died from all causes (16 %). The estimated 5-year CSS, RFS and OS were 83, 91 and 82 %, respectively. In multivariable analysis, older age, T stage and nodal status were predictors of CSS and OS. However, PRCC subtype was not a predictor of CSS, RFS or OS.
Conclusion
While patients with type 2 PRCC appear to present with more advanced disease than patients with type 1, PRCC subtype does not appear to be an independent predictor of CSS, RFS or OS for treated localized disease.
Thyroid dyshormonogenesis continues to be a significant cause of congenital hypothyroidism. Over time, forms of thyroid dyshormonogenesis can result in goiter, which can lead to difficult management ...decisions as the pathologic changes can both mimic or lead to thyroid cancer.
Herein we describe the cases of two brothers diagnosed with congenital hypothyroidism, with initial findings consistent with thyroid dyshormonogenesis. One brother eventually developed multinodular goiter with complex pathology on biopsy, resulting in thyroidectomy.
Whole exome sequencing revealed the brothers carry a novel frameshift mutation in thyroperoxidase; the mutation, while not previously described, was likely both deleterious and pathogenic. Conlcusions: These cases highlight the complex pathology that can occur within thyroid dyshormonogenesis, with similar appearance to possible thyroid cancer, leading to complex management decisions. They also highlight the role that a genetic diagnosis can play in interpreting the impact of dyshormonogenesis on nodular thyroid development, and the need for long-term follow-up in these patients.
* Context.--Specimens from the prostate and bladder are commonly encountered by the general surgical pathologist. Emphasis is usually placed on neoplasms of the bladder and prostate, particularly if ...malignant, owing to their therapeutic consequences. A good command of benign lesions occurring in the bladder and prostate, and knowledge of their preneoplastic potential will help pathologists confidently diagnose malignancy versus its benign mimickers and guide the urologists in choosing the appropriate therapy and follow-up for the patient. (Arch Pathol Lab Med. 2012; 136:721-734; doi: 10.5858/arpa.2011-0584-RA)
Carcinoid tumors are neuroendocrine tumors that typically arise in the gastrointestinal tract. We present the case of a 74-year-old woman with a primary carcinoid tumor in an ileal conduit urinary ...diversion who presented with gross hematuria. We also provide a brief review of relevant reports. The patient subsequently underwent resection and replacement of her ileal conduit.
Extrarenal clear cell renal cell carcinoma (eccRCC) is a rare type of RCC that arises in areas other than the kidney. Given its rarity, consensus guidelines for optimal treatment of eccRCC have not ...been established, and the literature is lacking any reports of patient response to systemic therapy and any reports of administration of immunotherapy to patients with ecRCC. Here, we present the case of a patient in their 60s with eccRCC arising in the spleen. The patient underwent splenic resection and then received systemic therapy, due to disease recurrence, with a combination of immunotherapy (IO) and tyrosine kinase inhibitor targeted therapy (VEGF-TKI). The patient had an excellent and durable response to this therapeutic regimen with minimal adverse effects, completing 2 years of therapy of nivolumab and cabozantinib. At the time of this report, the disease remains stable. This case demonstrates that combination therapy with IO+VEGF-TKI represents a reasonable and well-tolerated treatment option with activity in eccRCC and reveals interesting correlative data, including nests of stem-like CD8+T-cell infiltration in tumor tissue, which provide important biological context to this patient's exceptional therapeutic response.