Small Cell Carcinoma Of Urinary Bladder Research Articles

Abstract 5434: Insulinoma-associated protein 1 (INSM1) expression in small cell neuroendocrine carcinoma of the urinary tract

Abstract Introduction Clinical guidelines including the American Urological Association (AUA) state that neoadjuvant chemotherapy should be administered prior to surgery in cases of muscle invasive urinary bladder small cell neuroendocrine carcinoma. Although the recently described marker insulinoma-associated protein 1 (INSM1) has been reported to be sensitive and specific for neuroendocrine differentiation in neuroendocrine tumors at several sites, its efficacy as a marker in urinary bladder small cell carcinoma has not been well established. This study aims to examine the immunohistochemical expression pattern of INSM1 on whole tissue sections of urinary bladder small cell neuroendocrine carcinoma and compare INSM1 expression to those of established markers of neuroendocrine differentiation. Methods Archived tissue from 32 cases of urinary bladder small cell neuroendocrine carcinoma were obtained from Rhode Island Hospital and The Miriam Hospital. Immunohistochemical stains for CD56, INSM1, synaptophysin, and chromogranin were performed. Staining was scored for intensity (0: no staining; 1: weak; 2: moderate; 3: strong) and proportion of cells stained (0: 0%; 1: >0 to 25%; 2: >25 to 50%; 3: >50 to 75%; 4: >75 to 100%). Results INSM1 was positive (intensity 1-3 or proportion 1-4) in 87% (28/32) of small cell neuroendocrine carcinoma cases (20 with intensity 2-3, 17 with proportion 3-4). CD56, synaptophysin, and chromogranin were positive in 75% (24/32), 60% (19/32), and 44% (14/32) of cases, respectively. While the rate of positivity was high, INSM1 was negative (n=4) or only showed weak intensity staining (n=7) in 34% (11/32) of cases. Conclusion INSM1 is a sensitive marker of small cell neuroendocrine differentiation of the urinary bladder. However, the findings in this study suggest that optimal utilization of INSM1 would be in a limited panel of stains rather than as a stand-alone screening marker given that it is negative or only shows weak intensity staining in a significant proportion of cases. StainNegative [n (%)]Positive [n (%)]INSM14 (13)28 (87)CD568 (25)24 (75)Synaptophysin13 (40)19 (60)Chromogranin18 (56)14 (44) Citation Format: Isaac E. Kim, Ali Amin, Li Juan Wang, Liang Cheng, Carmen M. Perrino. Insulinoma-associated protein 1 (INSM1) expression in small cell neuroendocrine carcinoma of the urinary tract [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5434.

Evaluation of metastases to the pancreas with fine needle aspiration: A case series from a single centre with review of the literature.

Fine needle aspiration (FNA) is a minimally invasive albeit highly effective modality used to detect solid and cystic pancreatic lesions. This manuscript aims to present our experience in diagnosing metastases to the pancreas and highlight the importance of immunocytochemistry in the diagnostic process. It also aims to provide a brief review of the literature on this topic. We retrospectively searched our archives for cases of metastatic deposits to the pancreas diagnosed with FNA over a 5-year period. We also reviewed the literature for such cases. We describe seven cases from our archives that metastasised to the pancreas. Three of them (43%) represented metastatic renal cell carcinoma while the rest four comprised deposits from a lung adenocarcinoma, a colon adenocarcinoma, an adrenal leiomyosarcoma, and a small cell carcinoma of the urinary bladder, respectively. History of primary malignancy was available for all seven patients. All diagnoses were confirmed with the use of immunostains. In our literature review, similar to our case series, renal cell carcinoma was the most common metastasis to the pancreas managed with FNA (around one out of three patients; 35%). Of interest, our endoscopic ultrasound-FNA case of pancreatic metastasis from urinary bladder small cell carcinoma is the first reported. As metastases to the pancreas are commonly accompanied by diverse prognostic signatures and management strategies compared to primary pancreatic malignancies, their accurate identification is imperative. Pancreatic FNA is a diagnostic modality that can confirm or exclude metastasis to the organ, especially when immunocytochemistry is applied.

Survival of Contemporary Patients With Non-metastatic Small-cell Carcinoma of Urinary Bladder, According to Alternative Treatment Modalities.

The objective of this study was to test the effect of chemotherapy and/or radical cystectomy (RC) and/or radiotherapy (RT) on survival of patients with non-metastatic small-cell carcinoma of the urinary bladder (SCCUB). Within the Surveillance, Epidemiology, and End Results registry (2001-2016), we identified patients with non-metastatic (T1-4, N0, M0) SCCUB. Treatment was defined as: chemotherapy alone, chemotherapy+ RC, and chemotherapy+ RT. Temporal trends, cumulative incidence plots, and multivariable competing risks regression models were used. Of 595 patients with SCCUB, 230 (38.5%), 159 (27%), and 206 (34.5%) were treated with chemotherapy alone, chemotherapy+ RC, and chemotherapy+ RT, respectively. The rates of chemotherapy+ RC increased (estimated annual percentage changes [EAPC],+5.9%; P= .002). Conversely, chemotherapy alone (EAPC,-1.7%; P= .1) and chemotherapy+ RT rates decreased (EAPC:-2.2%; P= .08). Overall, 5-year cancer-specific mortality (CSM) rates were 44%, 29%, and 40% for patients treated with chemotherapy alone, chemotherapy+ RC, and chemotherapy+ RT, respectively (P= .004). Relative to chemotherapy alone, patients treated with chemotherapy+ RC experienced lower CSM (hazard ratio, 0.5; P< .001). Conversely, patients treated with chemotherapy+ RT did not exhibit any CSM benefit (hazard ratio, 0.8; P= .2), when compared with chemotherapy alone. In contemporary patients with SCCUB with non-metastatic disease, the rates of chemotherapy+ RC are increasing. Conversely, the rates of combined chemotherapy with RT and chemotherapy alone are decreasing. These patterns of treatment are in agreement with better cancer control in patients with SCCUB. In consequence, until more robust data become available, the combination of chemotherapy and RC should represent the recommended treatment strategy.

A Rare Presentation of Primary Small-cell Carcinoma of Urinary Bladder

Primary small cell carcinoma of urinary bladder is rare and aggressive neuroendocrine tumor. It is part of neuroendocrine tumor family that affects respiratory system, gastro intestinal tract and genitourinary system of male and female. We report a case of primary small cell carcinoma of urinary bladder treated with chemotherapy. Patient is 81 year old male who presented to emergency department with recurrent urinary retention associated with hematuria. Patient had cystoscopy and was diagnosed with small cell carcinoma of urinary bladder with no distant metastasis. Patient was treated with chemotherapy. Patient died with septic shock due to clostridium difficile colitis.

Clinicopathologic and Immunohistochemical Study of Combined Small Cell Carcinoma and Urothelial Carcinoma Molecular Subtype.

Muscle invasive bladder cancer, an aggressive disease with heterogeneous molecular profiles, has recently been subclassified into three major molecular subtypes -basal, luminal and "p53-like" urothelial carcinomas (UCas), which bear prognostic and therapeutic implication. Similar to breast cancer, basal and luminal subtype UCas are designated by basal (CK5/14) and luminal (CK20) markers. The "p53-like" subtype presents with wild-type p53 gene with upregulated p53 pathways and is implicated in chemoresistance. Urinary bladder is one of the most common primary sites of extrapulmonary small cell carcinoma (SmCC). Bladder SmCC frequently coexists with UCa; however, the relation of SmCC with specific UCa molecular subtypes has not been studied. The aim of this study is to investigate the clinicopathology and immunophenotypes of the combined SmCC and UCa molecular subtypes. A total of 22 combined SmCC and UCa cases were studied for the clinicopathology and immunohistochemical (IHC) profiles by luminal and basal cell markers as well as Her2/Neu and p53. Our results demonstrated that all the urinary bladder SmCCs were associated with high grade UCas. They were more commonly seen in older male patients with a smoking history and had a poor prognosis. Based on the reported molecular subtyping, the UCas could be immunohistochemically subclassified into luminal, basal, dual and null types, which showed different clinicopathologic and IHC features. Compared to non-SmCC associated UCa, the subtypes of UCa in the combined SmCCs and UCas were characterized by: 1) Although overall luminal type was still relatively more common in men, basal marker-expressing subtypes were significantly increased in incidence and were more common in women. 2) Her2/Neu overexpression was more commonly observed in luminal than basal cell marker-expressing UCas. 3) IHC overexpression of p53 was common in all the subtypes, with UCas and SmCCs sharing the same p53 expression pattern. Although limited by relatively a small number of cases, the results of this study will enhance our understanding of the combined SmCC and UCa entity and potentially lead to a future therapeutic management.

Frequent TMPRSS2-ERG rearrangement in prostatic small cell carcinoma detected by fluorescence in situ hybridization: the superiority of fluorescence in situ hybridization over ERG immunohistochemistry

Small cell carcinoma of the prostate is both morphologically and immunohistochemically similar to small cell carcinoma of other organs such as the urinary bladder or lung. TMPRSS2-ERG gene fusion appears to be a highly specific alteration in prostatic carcinoma that is frequently shared by small cell carcinoma. In adenocarcinoma, immunohistochemistry for the ERG protein product has been reported to correlate well with the presence of the gene fusion, although in prostatic small cell carcinoma, this relationship is not completely understood. We evaluated 54 cases of small cell carcinoma of the prostate and compared TMPRSS2-ERG gene fusion status by fluorescence in situ hybridization (FISH) to immunohistochemical staining with antibody to ERG. Of 54 cases of prostatic small cell carcinoma, 26 (48%) were positive for TMPRSS2-ERG gene fusion by FISH and 12 (22%) showed overexpression of ERG protein by immunohistochemistry. Of the 26 cases positive by FISH, 11 were also positive for ERG protein by immunohistochemistry. One tumor was positive by immunohistochemistry but negative by FISH. Urinary bladder small cell carcinoma (n = 25) showed negative results by both methods; however, 2 of 14 small cell carcinomas of other organs (lung, head, and neck) showed positive immunohistochemistry but negative FISH. Positive staining for ERG by immunohistochemistry is present in a subset of prostatic small cell carcinomas and correlates with the presence of TMPRSS2-ERG gene fusion. Therefore, it may be useful in confirming prostatic origin when molecular testing is not accessible. However, sensitivity and specificity of ERG immunohistochemistry in small cell carcinoma are decreased compared to FISH.

Small Cell Carcinoma of the Urinary Bladder—Histogenesis, Genetics, Diagnosis, Biomarkers, Treatment, and Prognosis

Small cell carcinoma of the urinary bladder is a rare but highly aggressive malignancy with a dismal prognosis. Most patients present with advanced disease at the time of diagnosis. Hematuria is the most frequent presenting symptom. Histologically, small cell carcinoma of the urinary bladder is indistinguishable from its pulmonary counterpart. Coexistence with other types of carcinoma is common. Histogenesis is uncertain; there are several competing theories, including origin from stem cells, from urothelial cells, and from neuroendocrine cells in normal or metaplastic urothelium. The molecular pathogenesis remains unclear. Immunohistochemical staining can be extremely helpful in establishing the diagnosis, and in investigating the use of potential therapeutic strategies. Currently, combinations of surgical resection, chemotherapy, and radiation therapy represent the main treatment options. The recent observation of c-kit and epidermal growth factor receptor expression in more than 25% of patients with urinary bladder small cell carcinoma opens new avenues for further investigation. Improvement in survival may depend upon the identification of new molecular markers to facilitate earlier diagnosis and the development of novel targeted therapies. In this paper, we review general aspects of small cell carcinoma of the urinary bladder, focusing on the ways in which our understanding of this entity has been positively influenced by studies of the histopathologic and immunohistochemical findings, and by investigations of genetic alterations in this disease.

Epidermal Growth Factor Receptor Protein Expression and Gene Amplification in Small Cell Carcinoma of the Urinary Bladder

Small cell carcinoma of the urinary bladder is a highly aggressive malignancy with an average life expectancy of only a few months. Epidermal growth factor receptor (EGFR) has been implicated in the pathogenesis and progression of many malignancies. This study was done to investigate EGFR protein expression and gene amplification in a large series of small cell carcinomas of the urinary bladder. Fifty-two cases of urinary bladder small cell carcinoma were included in this study. Immunostaining for EGFR was done on paraffin-embedded tissue sections, and gene amplification for EGFR was done by fluorescence in situ hybridization. EGFR expression was correlated with clinicopathologic characteristics and clinical outcome. All 52 patients, except 1, had advanced disease (T2 or above) at presentation. Immunohistochemically, positive EGFR expression was observed in 14 of 52 (27%) cases. No EGFR gene amplification was observed in any of 52 cases by fluorescence in situ hybridization. Forty cases had polysomy and the remaining 12 cases displayed disomy. No correlation between EGFR protein expression and gene amplification was shown. There was no correlation between EGFR expression and clinicopathologic characteristics. EGFR is expressed in a subset of urinary bladder small cell carcinomas; however, expression of EGFR does not correlate with clinicopathologic variables. At the molecular level, EGFR overexpression in small cell carcinoma of the urinary bladder does not seem to be caused by gene amplification. The expression of EGFR raises the possibility that EGFR may be a potential therapeutic target in the treatment of this malignancy.

Molecular Genetic Evidence for a Common Clonal Origin of Urinary Bladder Small Cell Carcinoma and Coexisting Urothelial Carcinoma

In most cases, small-cell carcinoma of the urinary bladder is admixed with other histological types of bladder carcinoma. To understand the pathogenetic relationship between the two tumor types, we analyzed histologically distinct tumor cell populations from the same patient for loss of heterozygosity (LOH) and X chromosome inactivation (in female patients). We examined five polymorphic microsatellite markers located on chromosome 3p25-26 (D3S3050), chromosome 9p21 (IFNA and D9S171), chromosome 9q32-33 (D9S177), and chromosome 17p13 (TP53) in 20 patients with small-cell carcinoma of the urinary bladder and concurrent urothelial carcinoma. DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-assisted microdissection. A nearly identical pattern of allelic loss was observed in the two tumor types in all cases, with an overall frequency of allelic loss of 90% (18 of 20 cases). Three patients showed different allelic loss patterns in the two tumor types at a single locus; however, the LOH patterns at the remaining loci were identical. Similarly, the same pattern of nonrandom X chromosome inactivation was present in both carcinoma components in the four cases analyzed. Concordant genetic alterations and X chromosome inactivation between small-cell carcinoma and coexisting urothelial carcinoma suggest that both tumor components originate from the same cells in the urothelium.

Small Cell Carcinoma of the Urinary Bladder

Objective: To investigate the morphological diagnostic criteria and biology of the urinary bladder small cell carcinoma (SCC). Methods: Study of 23 cases of bladder SCC, looking for the clinical presentation, pathological features and evolution, and review of 134 previously published cases. Results: The SCC is infrequent (0.48–1%), 50% of them have areas of transitional cell carcinoma, supporting the metaplastic theory. The classic small cell morphology is the best diagnostic criterion. The neurone–specific enolase and chromogranin A are good markers, but not indispensable. An early metastatic incidence (56%) with a high mortality rate (68.7%), mostly before 2 years after the diagnosis, is the typical evolution. Only the patients with additional cis–platinum–based chemotherapy have better prognosis. Conclusion: The pathologist should watch out for the presence of SCC and the urologist should consider the possibility of combined treatment for these cases.