Argininosuccinate Synthetase-1 (ASS1) Loss in High-Grade Neuroendocrine Carcinomas of the Urinary Bladder: Implications for Targeted Therapy with ADI-PEG 20

High-grade neuroendocrine carcinomas (HGNECs) of the urinary bladder encompass small cell (SCNEC) and large cell neuroendocrine carcinomas (LCNEC). Currently, recommended initial management is with systemic chemotherapy, followed by consolidative therapy with either radical cystectomy or radiotherapy in patients with localized disease. Nevertheless, survival in this setting remains poor. We therefore evaluated the potential to modify arginine metabolism as an alternative, targeted therapy approach in these carcinomas. In humans, arginine is a semi-essential amino acid and its synthesis enzyme argininosuccinate synthetase (ASS1) represents the rate-limiting step in arginine biosynthesis. Neoplasms that show low to absent ASS1 expression require extracellular arginine for cancer cell survival, and thus can be targeted using arginine-degrading enzymes such as pegylated arginine deiminase (ADI-PEG 20). An initial study by our group of 19 patients demonstrated that a high percentage of SCNEC lack ASS1 expression. Herein, we evaluated an expanded cohort of 74 radical cystectomy patients with HGNEC, including 63 SCNEC, 5 LCNEC, and 6 mixed morphology HGNEC patients. ASS1 expression was assessed through immunohistochemistry. Fifty-eight (of 74, 78%) patients with HGNEC showed absent ASS1 expression, including all patients with LCNEC and mixed morphology (11 of 11, 100%). Ten-year survival from disease-specific death was not statistically significant between ASS1-expressing and ASS1-deficient cases (p?=?0.75). Our results show that HGNEC of the bladder may be candidates for arginine deprivation therapy using drugs such as ADI-PEG 20. Further studies are needed to validate these findings and to determine the therapeutic efficacy of such agents.     

Adenocarcinoma with neuroendocrine differentiation of the urinary bladder. Clinicopathologic, immunohistochemical, and ultrastructural study

We describe a primary mixed adenocarcinoma-neuroendocrine carcinoma of the urinary bladder of probable urachal origin. Neuroendocrine differentiation was confirmed by ultrastructural (neurosecretory granules) and immunohistochemical studies (chromogranin and neuron-specific enolase). Two local recurrences and multiple metastases consisted exclusively of the neuroendocrine component. The patient died 30 months after diagnosis with widely metastatic neuroendocrine carcinoma.     

Neuroendocrine carcinomas of the prostate and urinary bladder: a diagnostic and therapeutic challenge

This review addresses the various morphological, immunohistochemical and cell kinetic aspects of pure and mixed neuroendocrine carcinomas of the prostate and urinary bladder and of carcinomas with focal neuroendocrine differentiation. It is important that neuroendocrine tumours of the prostate and urinary bladder be clearly distinguished from their nonneuroendocrine counterparts because of differences in treatment and prognosis. In the case of high-grade neuroendocrine carcinomas, early diagnosis and initiation of appropriate chemotherapy may increase survival and potentially induce complete remission in individual cases.     

Large cell neuroendocrine carcinoma of the urinary bladder with lymphoepithelioma-like features

The group of undifferentiated carcinomas of the urinary bladder encompasses small cell undifferentiated carcinoma, giant cell carcinoma, lymphoepithelioma-like carcinoma (LELC), and large cell neuroendocrine carcinoma (LCNEC). These tumors are either pure or can be associated with other components, such as transitional cell carcinoma, squamous cell carcinoma, and adenocarcinoma. We report a case of LCNEC of the urinary bladder in a 54-year-old woman. Histologically, the tumor showed features of LELC; immunohistochemically, the tumor cells reacted to chromogranin A, NSE, and synaptophysin. In addition to these neuroendocrine markers, tumor cells were positive for cytokeratin CAM 5.2 and AE1/AE3, and there was focal positivity for vimentin. In situ hybridization for the detection of Epstein-Barr virus was negative. Despite radical cystourethrectomy and six courses of chemotherapy, the patient developed metastases invading the left inguinal lymph nodes 11 months postoperatively. Currently, 16 months postoperatively, the patient has developed metastases spreading into the lymph nodes of the right ischiorectal fossa; therefore, she is receiving a new cyclus of chemotherapy. There are only three previously reported cases of LCNEC of the urinary bladder, and the significance of neuroendocrine differentiation in non-small cell carcinomas at this location remains to be established. However, LELC appears to be a separate clinicopathological entity with sensitivity to chemotherapy and a relatively favorable prognosis. The differentiation between LELC and LCNEC with prominent inflammatory reaction could be of therapeutic relevance. However, in our case, this was possible using immunohistochemistry only.     

Primary large cell neuroendocrine carcinoma of the urinary bladder

Primary large cell neuroendocrine carcinomas (LCNEC) of the urinary bladder are rare. Reported herein is a case of a primary, pure LCNEC occurring in a man. The patient was a 32-year-old man who presented with hematuria of 1 week's duration. On cystoscopic examination, a solitary mass measuring 3 cm in diameter was detected protruding from the anterosuperior wall of the urinary bladder. Two months after the primary transurethral resection, significant regrowth of the remnant mass was noted on CT, and the patient underwent a partial cystectomy. A diagnosis of LCNEC was made based upon histological and immunohistochemical findings. Tumor cells were positive for synaptophysin, chromogranin A, CD56, epithelial membrane antigen, and cytokeratin. Histologically, the tumor penetrated the deep muscle and perivesical fat. In spite of three cycles of chemotherapy, the patient developed multiple metastases in the lung and liver 10 months postoperatively. LCNEC of the urinary bladder are uncommon entities, which have a possible fatal outcome.     

HPV infection and p16INK4A and TP53 expression in rare cancers of the uterine cervix

Cervix cancer remains among most commonly diagnosed cancer in developing countries. Except squamous cell carcinoma and adenocarcinoma, the etiopathology and oncogenic mechanisms of rare cancers remain largely unknown. The study was performed to investigate the value of HPV infection and the expression of p16^INK4A and TP53 in rare primitive cancers of the cervix.We conducted a retrospective study of rare primitive cancers of the cervix. Main clinicopathological features were reported. HPV infection was detected by in situ hybridization. Expression of p16^INK4A and TP53 was analyzed by immunohistochemistry.Overall, seven cases were identified, including basaloid squamous cell carcinoma (BSCC, n?=?2), small cell neuroendocrine carcinoma (SCNEC), granulocytic sarcoma without acute myeloid leukemia, leiomyosarcoma, primitive neuroectodermal tumor and botryoid-type embryonic rhabdomyosarcoma. The mean age of patients was 53.7 years. Four cancers were diagnosed at advanced stages. The prognosis was unfavorable and associated with patient death in five cases. HPV types 16/18 were detected in BSCCs and SCNEC. Strong and diffuse p16^INK4A overexpression was described in the nucleus and the cytoplasm of all tumor cells of BSCCs and SCNEC. The remaining cancers exhibited only scattered and focal p16^INK4A staining. Mutated TP53 protein was detected in BSCC (case 1) and GS.Rare cancers of the cervix are aggressive and associated with poor prognosis. In contrast to mesenchymal tumors, BSCCs and SCNEC are etiologically related to high-risk HPV infection and could be identified by block positive p16^INK4A overexpression as common cancers of the cervix. TP53 mutations are not a negligible genetic event in rare cervical cancers.     

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.     

Carcinosarcoma of the urinary bladder: A distinct variant characterized by small cell undifferentiated carcinoma with neuroendocrine features

Summary The clinicopathological features of two carcinosarcomas of the urinary bladder are reported. The tumours occurred in a 64- and a 66-year-old patient presenting with haematuria and both were polypoid. The epithelial component was consistent with small cell undifferentiated carcinoma with neuroendocrine differentiation, whereas the sarcomatous component did not display specific features. The carcinomatous component showed immunohistochemical reactivity for different epithelial markers as well as for chromogranin and neuron specific enolase. Conversely, the sarcomatous cells stained strongly for vimentin and in one case for muscle actin and smooth muscle actin. The differential diagnosis of biphasic tumours of the bladder is discussed and the literature reviewed.     

易混淆的膀胱活检小细胞性浸润性尿路上皮癌的诊断与鉴别诊断：附1例报告

目的：探讨膀胱活检中小细胞性浸润性尿路上皮癌的病理形态学特征以及与其它小细胞性病变的鉴别诊断。方法：对北京中医药大学东直门医院1例膀胱黏膜活检的病理及临床资料进行回顾性分析,并对相关国内外文献进行复习。结果：患者,男性,82岁,膀胱镜下见：在膀胱颈部10~12点可见黏膜突起如蕈状,蒂不明显。活检组织光镜下见：1)尿路上皮下小细胞肿瘤细胞呈弥漫性及巢状分布,间质增生;2)瘤细胞体积小,呈短梭形或淋巴细胞样,胞浆极少,局部瘤细胞胞浆宽广透明;3)核为圆形、椭圆形或梭形,核深染且结构不清,部分核不规则,可见双核、核重叠及多核瘤巨细胞,核仁不明显;4)未见核分裂象;5)局部组织可见挤压现象及局灶凝固性坏死;6)可见脉管浸润;7)局部异型增生的尿路上皮基底层处与固有膜内的小细胞性肿瘤成分有移行。免疫组织化学结果显示免疫表型CK少数细胞弱(+),其余标记均(?),病理诊断为：小细胞低分化癌。临床行经尿道膀胱肿瘤电切术,未送病理,数月后发现肠系膜多个转移瘤结节,瘤细胞形态与活检相似,局部瘤细胞核偏位,可见核仁及病理性核分裂象,免疫组化显示上皮性标记、p63及CD44V6均(+),神经内分泌标记(?),综合考虑最后病理诊断为：膀胱小细胞性浸润性尿路上皮癌伴肠壁转移。结论：膀胱小细胞性浸润性尿路上皮癌在膀胱镜活检标本中诊断难度较大,应重视其病理特点,鉴别诊断需结合临床和免疫组化特征综合评价,当二者不能提供有价值的帮助时,确诊还需以HE切片形态学特征为主,同时在报告中加以注明。膀胱镜活检标本病理诊断尿路上皮癌核分裂象应是有或无。     

Undifferentiated small-cell carcinoma of the urinary bladder: Report of two cases with a primary urinary cytodiagnosis

Two undifferentiated small-cell carcinomas of the urinary bladder are reported. The patients, 68- and 55-yr-old men, respectively, presented with painless hematuria. In the first case, numerous small, lymphocyte-like cells with coarse chromatin, sometimes with small nucleoli, and high nuclear/cytoplasmatic ratios were found in cytologic urine specimens. A cytodiagnosis of undifferentiated small-cell cancer was made. In the second case, urine samples showed rare aggregates of small, undifferentiated cells in association with malignant urothelial cells. The cytodiagnosis of mixed tumor composed of undifferentiated small cell and transitional carcinoma was confirmed by histologic examination. The presence of focal reactivity with anti-chromogranin antibody and neurosecretory granules via electron microscopy supports a neuroendocrine differentiation for the small neoplastic cells. The patients died 13 and 8 mo after diagnosis, respectively. © 1995 Wiley-Liss, Inc.     

Small cell carcinoma of the urinary bladder: Distinctive cytological characteristics and Cyto-histologic correlation

Preoperative diagnosis in liquid-based cytology preparation in voided urine specimen and cyto-histologic correlation of small cell carcinoma of the urinary bladder has not been described in detail in the literature. A 79-year old male presented at our institution with gross hematuria. He was accurately diagnosed with small cell carcinoma of the bladder on liquid-based cytology in urine. The patient subsequently proceeded to transurethral resection of the bladder tumor, confirming the diagnosis. In this article, we present a detailed report of primary urothelial carcinoma with dominant neuroendocrine differentiation of the bladder describing the cytologic and histologic morphologic features, its differential diagnosis with a review of the literature.     

Fine-needle aspiration cytology of primitive neuroectodermal tumor of the urinary bladder: a case report

Primitive neuroectodermal tumors (PNETs) are malignant small round cell tumors, which exhibit a variable degree of neural differentiation. These tumors are usually found in the extraosseous soft tissue and rarely in bones. Occasional cases of PNETs of the urinary bladder have been reported on histopathology. However, to the best of our knowledge, none have been diagnosed on fine-needle aspiration cytology (FNAC). A patient presented to the out-patient department with complaints of a slowly progressive lump in the lower abdomen, which was diagnosed as PNET on FNAC. The smears showed a dispersed population and sheets of malignant small round cells with focal rosette formation and perivascular arrangement of tumor cells. Periodic acid-Schiff staining showed strong cytoplasmic positivity. Immunocytochemistry of the cytology smears also showed strong membrane positivity for CD99 (MIC-2), which was also confirmed on histopathological examination. PNET of the urinary bladder is a distinct entity, which can be diagnosed on FNAC and confirmed by immunohistochemistry. A diagnosis of PNET should be considered as a differential diagnosis in urinary bladder masses, especially in adolescents and young adults.     

宫颈小细胞神经内分泌癌中人乳头瘤病毒的研究

目的探讨宫颈小细胞神经内分泌癌中高危型人乳头瘤病毒（humanpapillomavirus,HPV）感染情况。方法提取1例33岁宫颈小细胞神经内分泌癌患者手术切除组织癌变区域蜡块中的DNA,通过巢式PCR方法检测其中HPV感染情况。结果该患者肿瘤切除组织高危型HPV18型阳性。结论利用巢式PCR方法分型检测宫颈小细胞神经内分泌癌中的高危型HPV型别,其准确性及敏感性均较高。     

Neuroendocrine Tumors of the Urinary Bladder According to the 2016 World Health Organization Classification: Molecular and Clinical Characteristics

Neuroendocrine neoplasms of the urinary bladder are a rare type of tumor that account for a small percentage of urinary bladder neoplasms. These tumors of the urinary bladder range from well-differentiated neuroendocrine neoplasms (carcinoids) to the more aggressive subtypes such as small cell carcinoma. Despite the rarity of the neuroendocrine tumors of the bladder, there has been substantial investigation into the underlying genomic, molecular, and the cellular alterations within this group of neoplasms. Accordingly, these findings are increasingly incorporated into the understanding of clinical aspects of these neoplasms. In this review, we provide an overview of recent literature related to the 2016 World Health Organization Classification of Neuroendocrine Tumors of the Urinary Bladder. Particular emphasis is placed on molecular alterations and recently described gene expression. The neuroendocrine tumors of the urinary bladder are subdivided into four subtypes. Similar to their pulmonary and other extrapulmonary site counterparts, these have different degrees of neuroendocrine differentiation and morphological features. The clinical aspects of four subtypes of neuroendocrine tumor are discussed with emphasis of the most recent developments in diagnosis, treatment, and prognosis. An understanding of molecular basis of neuroendocrine tumors will provide a base of knowledge for future investigations into this group of unusual bladder neoplasms.     

Carcinosarcoma with a large cell neuroendocrine epithelial component: first report of an unusual biphasic tumour of the urinary bladder

This article describes the first reported case of carcinosarcoma of the urinary bladder with a large cell neuroendocrine epithelial component. A 61 year old man presented with gross haematuria and underwent resection of a biphasic bladder tumour. The malignant epithelial component showed large cell neuroendocrine differentiation with immunohistochemical reactivity for neurone specific enolase, synaptophysin, and chromogranin. The malignant mesenchymal component did not show specific differentiation by histological or immunohistochemical examination. The differential diagnosis of biphasic tumours in the urinary bladder is discussed, along with a review of the literature.     

Inverted papilloma of the urinary bladder with granular eosinophilic cells. An unusual neuroendocrine variant

We report the morphologic, immunohistochemical, and electron microscopic characteristics observed in a case of an inverted papilloma that contained neuroendocrine cells resected from the urinary bladder of a 77-year-old woman. Additionally, we evaluated the incidence of neuroendocrine cells in eight cases of inverted papillomas of the urinary bladder obtained from the files of the Armed Forces Institute of Pathology, Washington, DC. To our knowledge, an in-depth study of neuroendocrine cells in this neoplasm and a comparison of the same with neuroendocrine cells observed in other conditions in the lower genitourinary tract have not been previously published, prompting this report.     

Primary carcinoid tumor of the urinary bladder with prominent subnuclear eosinophilic granules

Primary carcinoid tumor of the urinary bladder is a very rare neoplasm. We report here a case of primary carcinoid tumor of the urinary bladder with an unusual cytological feature in a 72-year-old Japanese man. A bladder polypoid mass was incidentally found by ultrasonography during the follow-up of a benign prostate hyperplasia. Histological examination of the transurethrally resected tissue revealed that the upper part of the mass was a tumor showing tubuloglandular anastomosing structures. Most of the tumor cells had peculiar subnuclear eosinophilic granules. The features of the granules were reminiscent of those observed in neuroendocrine cells of the intestine. The tumor cells were immunohistochemically positive for chromogranin A and synaptophysin. The tumor was diagnosed as carcinoid tumor of pure form of the urinary bladder. The lower part of the mass showed the findings of glandular cystitis, as its coexistence with carcinoid tumors of the bladder has often been described in previous reports.     

Light chain amyloidosis of the urinary bladder. A site restricted deposition of an externally produced immunoglobulin

AIMS:To identify the amyloid protein in a patient with amyloidosis localised to the urinary bladder, and to see whether subtyping of the protein by sequence analysis increases the understanding of the selection of the urinary bladder as the site of amyloid deposition. METHODS:A patient with gross haematuria and a congophilic mass in his urinary bladder was evaluated further. Characterisation of the amyloid protein was performed using conventional histological and immunohistochemical methods. Determination of the N-terminal amino acid sequence of the amyloid protein was performed using protein sequencers. RESULTS:The patient's history, physical examination, and laboratory evaluation excluded the involvement of other organs, justifying a diagnosis of amyloidosis localised to the urinary bladder. Histological and immunological studies showed that the amyloid protein deposited in the urinary bladder of the patient was probably of the amyloid light chain type. No plasma cells or lymphocytes were seen in sections of the urinary bladder and lower ureter adjacent to the amyloid deposits. Molecular analysis showed the sequence NFMLTQPHSISGSPG, which assigned the amyloid protein to either the Vlambda(I) or the Vlambda(VI) immunoglobulin (Ig) light chain families. CONCLUSIONS:The findings suggest that the amyloid protein in this patient originated outside the urinary bladder. The heterogeneity of the Ig proteins in known cases of amyloidosis of the lower urinary tract suggests that the amino acid residues, which determine the Vlambda subtyping, have no major role in restricting the deposited protein to the urinary bladder.     

Primary large cell neuroendocrine carcinoma of the urinary bladder

Reports of primary large cell neuroendocrine carcinomas of the urinary bladder are few; we identified only 2 cases in the literature. Both of these cases involved male patients with rapid progression of disease culminating in death with widespread metastases. We report a case of primary large cell neuroendocrine carcinoma of the bladder, with an admixed minor element of adenocarcinoma, in an 82-year-old man. This solitary lesion arose in a bladder diverticulum lateral to the left ureteric orifice. Two attempts at transurethral resection were unsuccessful at achieving local control. The patient underwent a partial cystectomy with left-sided pelvic lymphadenectomy following preoperative staging investigations that found no metastatic disease. Pathologically, the tumor invaded into the deep aspect of the muscularis propria, without extension into perivesical fat. The lateral resection margin was microscopically positive for tumor, but no malignancy was found in the pelvic lymph nodes. The adenocarcinoma comprised less than 5% of total tumor volume, and areas of transition between the neuroendocrine and adenocarcinoma components were apparent. The patient developed a local recurrence 8 months postoperatively, which was managed by a combination of transurethral resection and radiation therapy. Currently, the patient has no evidence of local or metastatic disease 2 years after initial diagnosis.     

Primary and secondary prostatic adenocarcinoma of the urinary bladder

Urinary bladder involvement by prostatic adenocarcinoma (PAC) is not well characterized in the literature. Fifteen consecutive cases of PAC diagnosed in the urinary bladder over a period of 10 years were reviewed. All bladder and prostate slides from each patient were evaluated. Eleven patients (group A) had synchronous PAC in the prostate. In these patients, bladder PAC occurred 2 to 11 years after the initial diagnosis of PAC in the prostate and tended to have a higher Gleason score than the original prostatic PAC. Four cases of bladder PAC in group A had areas with features of urothelial carcinoma, with focal positive immunoreactivity for thrombomodulin in 2 cases. Two patients (group B) had undergone radical prostatectomy for PAC 15 years earlier. The lesions in the urinary bladder in both cases showed histopathologic features similar to those seen in the previous prostatic malignancies. Two patients (group C) had histories of previously resected urothelial carcinoma. Bladder PAC was diagnosed at routine follow-up, and repeated prostate biopsy up to 2 years after the diagnosis of bladder PAC showed no evidence of prostatic PAC. PAC in the urinary bladder may be either primary or secondary. Secondary PAC is usually associated with high-grade and high-stage carcinoma in the prostate and may mimic transitional cell carcinoma. Primary bladder lesions may or may not be associated with a history of PAC in the prostate. The prognosis of patients with the primary carcinoma is favorable. HUM PATHOL 32:434-440.