Small cell neuroendocrine carcinoma of the urinary bladder

Summary Small cell carcinoma with the histological appearance of pulmonary small cell carcinoma is a rare tumour in the urinary bladder. In previous case reports the neuroendocrine nature of small cell bladder carcinoma has been accepted, but on review the evidence for true neuroendocrine differentiation appears unsatisfactory. In this study the histological, immunohistochemical and ultrastructural characteristics of three cases of small cell carcinoma of the urinary bladder are described. Ultrastructurally, the cytoplasm of all three tumours contained neurosecretory-type granules and each of the tumours demonstrated positive immunoreaction for two or more neuroendocrine markers, from a panel including neuron-specific enolase, chromogranin A, Leu-7, bombesin and synaptophysin. Although the combination of ultrastructural and immunohistochemical examination obviously offers the strongest evidence in establishing neuroendocrine differentiation, it is argued that immunohistochemistry alone may also yield important information in demonstrating a neuroendocrine nature, provided that at least neuron-specific enolase and synaptophysin are included as markers. The clinical relevance of identifying neuroendocrine differentiation in small cell bladder carcinoma is suggested by the favourable response to combination chemotherapy in two of our cases.     

Expression of novel neuroendocrine marker insulinoma-associated protein 1 (INSM1) in genitourinary high-grade neuroendocrine carcinomas: An immunohistochemical study with specificity analysis and comparison to chromogranin,synaptophysin, and CD56

Confirmation of genitourinary high-grade neuroendocrine carcinomas (GU-HGNECs) often requires immunohistochemical staining. Here we evaluated a novel neuroendocrine marker, insulinoma-associated protein 1 (INSM1), in GU-HGNECs with comparison to chromogranin, synaptophysin and CD56. Immunohistochemical expression of INSM1, chromogranin, synaptophysin, and CD56 was evaluated in 39 GU-HGNECs using full tissue sections [4 in kidney, 28 in urinary bladder, and 7 in prostate; 31 small cell carcinomas (SmCCs), 6 large cell neuroendocrine carcinomas (LCNECs), 2 mixed SmCC-LCNECs]. In 33 SmCCs/components, INSM1 showed similar sensitivity (93.9 %) to chromogranin (87.8 %), synaptophysin (93.9 %) and CD56 (87.8 %), and stained a similar percentage of tumor cells (52 %) to chromogranin (49 %) and CD56 (52 %), but lower than synaptophysin (87 %) (p < 0.0001). In 8 LCNECs/components, INSM1 is similar to chromogranin, synaptophysin or CD56 in sensitivity (62.5 %, 62.5 %, 75 %, 62.5 %, respectively) and the mean percentage of positively stained tumor cells (21 %, 44 %, 48 %, 37 %, respectively). INSM1 is more sensitive for SmCCs than LCNECs (93.9 % vs. 62.5 %, p = 0.015). INSM1 showed 97.4 % specificity upon analyzing 273 genitourinary non-neuroendocrine tumors on tissue microarrays. Our study indicates that INSM1 is a sensitive marker for genitourinary HGNECs with high specificity. For genitourinary SmCCs, INSM1 shows similar sensitivity to chromogranin, synaptophysin and CD56 but stains a lower percentage of tumor cells than synaptophysin. For genitourinary LCNECs, INSM1 showed similar sensitivity to chromogranin, synaptophysin and CD56. INSM1 is more sensitive for genitourinary SmCCs than LCNECs. Our result and literature review indicate that whether INSM1 is more sensitive than conventional neuroendocrine markers for HGNECs depends on the tumor primary sites.     

Small cell carcinoma of the bladder: a contemporary clinicopathological study of 51 cases

AIMS: We present 51 cases of primary small cell carcinoma of the bladder in a clinicopathological study with emphasis on features that aid in the initial recognition and diagnosis of small cell carcinoma of the bladder. METHODS AND RESULTS: The patients were 40 men and 11 women between the ages of 39 and 87 years (mean age 67 years). Clinical data were available in 41 cases. The most common symptomatology was haematuria in 63% of the patients while dysuria was present in 12%. Thirty-eight patients were caucasians; seven patients were Hispanics; two patients were Asian; one patient was African-American; in the three additional patients no racial information was obtained. Biopsy material was obtained in all of the patients. Cystectomy was performed in 20 patients. At diagnosis, clinical stage was as follows: stage I in two (5%), stage II in 18 (44%), stage III in 10 (24%), and stage IV in 11 (27%). Histologically, urothelial carcinoma was present in 70% of the cases, adenocarcinoma in 8%, and squamous cell carcinoma in 10% of the cases. Small cell carcinoma was the only histology present in only 12% of the cases studied. Immunohistochemical studies using chromogranin, synaptophysin and chromogranin were positive in 30-70% of the cases. CONCLUSIONS: The present study highlights the unusual phenomenon of pure small cell carcinoma of the bladder and its association with other non-small cell carcinomas in that anatomical location. In addition, the study highlights the different modalities employed to treat patients in whom there is a component of small cell carcinoma of the bladder.     

Merkel cell carcinoma metastasizing to the kidney mimicking primary neuroendocrine renal cancer

A 56-year-old male with a history of cutaneous neuroendocrine (Merkel cell) carcinoma presented with a solid mass of the left kidney, measuring 10 cm in largest diameter. On histology, the tumour was composed of loosely packed uniform cells with round-to-oval nuclei and scant cytoplasm. Immunohistochemically, the tumour cells diffusely expressed pancytokeratin and neuroendocrine markers, such as chromogranin A, synaptophysin and CD56 (NCAM). Distinct paranuclear dot-like expression of cytokeratin 20 showed the lesion to be metastatic Merkel cell carcinoma. This is the first reported case of Merkel cell carcinoma metastatic to the kidney mimicking primary neuroendocrine renal cancer. We discuss the differential diagnosis of the tumour and perform a systematic literature review, including potential indications for renal tumour biopsy in patients with a history of nonrenal malignancy.     

Extrapulmonary small cell carcinoma of the liver: clinicopathological and immunohistochemical findings

Patients with primary small cell carcinoma of the liver have rarely been described in medical literature. Knowledge of clinical, pathological and immunohistochemical properties remains limited. We described an 82-year-old female patient with primary small cell carcinoma of the liver. Histologically, the tumor showed typical morphology of a pulmonary small cell carcinoma. Immunohistochemically, the tumor revealed neuroendocrine differentiation; positive reaction for chromogranin, synaptophysin, CD56, and neuron specific enolase. The tumor was also positive for TTF-1 and c-kit but completely negative for hepatocyte, carcinoembryonic antigen, cytokeratin 7; 19; and 20. Herein, we discussed the clinical, pathological and immunohistochemical findings of extrapulmonary small cell carcinoma of the liver and reviewed the relevant literature.     

CD56 expression in basaloid anal squamous cell carcinoma – A potential diagnostic pitfall

Anal squamous cell carcinoma (SqCC) is a morphologically heterogeneous entity. Basaloid and non-keratinizing anal SqCC may be confused with other tumors including neuroendocrine carcinoma due to morphologic overlap, and expression of neuroendocrine markers is not well-studied in anal SqCC. Prompted by a case of anal SqCC that was initially misdiagnosed as neuroendocrine carcinoma on the basis of morphology and CD56 expression, we retrospectively examined the expression of neuroendocrine markers CD56, synaptophysin, and chromogranin in 48 cases of basaloid anal SqCC, with clinicopathologic correlation. HPV16 was identified in 46 cases, HPV33 in one case, and one case was HPV-negative. Three (6.3%) cases demonstrated CD56 expression, including two with diffuse and one with focal expression. Two CD56-positive cases demonstrated basaloid morphology with peripheral palisading and the other demonstrated adenoid cystic/cylindroma-like morphology. None of the cases showed significant synaptophysin or chromogranin expression. The three cases expressing CD56 were HPV16-positive, and one demonstrated a CTNNB1 mutation. There was no difference in clinicopathologic features including stage, outcome, or HPV status, between CD56-positive and negative groups. Our findings support that CD56 expression is infrequently expressed in anal SqCC and is not indicative of neuroendocrine differentiation in the absence of expression of more specific neuroendocrine markers such as synaptophysin and chromogranin. Pathologists should be aware that CD56 expression may occur in basaloid anal SqCC and is a diagnostic pitfall due to morphologic overlap with neuroendocrine carcinoma and other tumors including basal cell carcinoma.     

Immunoreactivity for epithelial and neuroendocrine antibodies are useful in the differential diagnosis of lung carcinomas

The histologic classification of pulmonary neoplasms can have important implications regarding appropriate management of patients. Although the histologic classification of lung tumors is predominantly based on morphology, ancillary studies such as immunohistochemistry can be used in difficult cases, and the diagnosis of large cell neuroendocrine carcinoma requires confirmation of neuroendocrine differentiation by immunohistochemistry or electron microscopy. We immunostained 142 lung tumors for B72.3, keratin 34betaE12, keratin 7, keratin 14, keratin 17, synaptophysin, and chromogranin to determine the utility of neuroendocrine markers and epithelial markers in the differential diagnosis. Among neuroendocrine carcinomas (small cell carcinoma and large cell neuroendocrine carcinoma), 84% (37 of 44) were chromogranin positive, 64% (21 of 36 small cell, 6 of 6 large cell neuroendocrine) were synaptophysin positive, 5% (2 of 43) were keratin 34betaE12 positive, 9% (4 of 44) were keratin 7 positive, and 5% (2 of 37) of small cell carcinomas and 50% (3 of 6) of large cell neuroendocrine carcinomas were B72.3 positive. Among non-neuroendocrine carcinomas, 5% (5 of 98) were chromogranin positive, 3% (3 of 96) were synaptophysin positive, and 97% (95 of 98) were positive for either keratin 34betaE12 or keratin 7 and 99% (97 of 98) were positive for either keratin 34betaE12, keratin 7 or B72.3. An antibody panel consisting of keratin 7, keratin 34betaE12, chromogranin, and synaptophysin separated 132 of 141 tumors (94%) into distinct groups. We conclude that immunostaining with both neuroendocrine markers and epithelial markers can be useful in the differential diagnosis of lung neoplasms.     

Frequent presence of neuroendocrine small cells in thymic carcinoma: a light microscopic and immunohistochemical study

AIMS: Neuroendocrine differentiation has been described in conventional carcinomas of various organs. Small cells postulated to be neuroendocrine cells were observed previously in some thymic carcinomas. This study was conducted to confirm and characterize the presence of neuroendocrine small cells in thymic carcinomas by light microscopy and immunohistochemistry. METHODS AND RESULTS: Twenty-two thymic carcinomas were studied by light microscopy to detect the presence of small neuroendocrine-like cells. They were found in four of 10 squamous cell carcinomas (SCC) and seven of eight adenosquamous carcinomas (ASC). No small cells were observed in three lymphoepithelioma-like carcinomas (LELC) and one adenocarcinoma. The small cells were located within the tumour nests and constituted less than 1% of the entire tumour. In one case, small cells also extended outside the tumour nests. Rosette formation was seen in three cases. They were proved to be neuroendocrine cells by their immunoreactivity to neuron-specific enolase, chromogranin A, and/or synaptophysin. A few scattered neuroendocrine small cells were found only by immunohistochemistry in one case each of SCC, ASC, and LELC. The small cells were also strongly positive for cytokeratin (CK) 8 and CK18 but negative for CK19 and CK20. The predominant carcinoma cells other than the neuroendocrine small cells also displayed neuroendocrine markers in 68% of the cases studied. CONCLUSIONS: Neuroendocrine small cells can be recognized by light microscopic examination in approximately 61% of thymic SCC and ASC. Neuroendocrine markers, CK8 and CK18 can aid in confirming their presence. The neuroendocrine small cells present in thymic carcinomas are different from the main carcinoma cells displaying immunohistochemical neuroendocrine markers. The presence of neuroendocrine small cells could be an useful marker for the differentiation of thymic carcinomas from thymomas and carcinomas of other sites.     

CD44 expression is a feature of prostatic small cell carcinoma and distinguishes it from its mimickers

Small cell neuroendocrine carcinoma of the prostate is a rare variant of prostatic cancer that shares morphologic similarity with prostatic adenocarcinoma of Gleason 5 pattern. It has also been considered morphologically and immunohistochemically indistinguishable from small cell neuroendocrine carcinomas of other origins. CD44 is a cell-surface molecule proposed to identify cancer stem/progenitor cells in prostate cancer. We performed immunohistochemical study for CD44 expression in 11 cases of prostatic small cell neuroendocrine carcinoma and compared its patterns of expression with 73 cases of prostatic adenocarcinoma and 47 cases of small cell neuroendocrine carcinomas of other organs. Strong and diffuse membrane staining for CD44 was observed in 100% of the prostatic small cell neuroendocrine carcinomas. In conventional adenocarcinomas of the prostate, positive staining was only seen in rare, scattered tumor cells; and CD44 staining was negative in most of the small cell neuroendocrine carcinomas of nonprostate origin. The difference in CD44 expression between small cell neuroendocrine carcinomas of the prostate and those of other organs are statistically significant (P < .001). Our study demonstrates the utility of immunohistochemical staining for CD44 in distinguishing prostatic small cell neuroendocrine carcinoma from its mimickers including prostatic adenocarcinoma of Gleason 5 pattern and small cell neuroendocrine carcinomas of other organs. CD44 is the first marker that shows a high degree of tissue/organ specificity for small cell neuroendocrine carcinomas. Because CD44 is a putative marker of prostate cancer stem cells, the strong and diffuse expression of CD44 and the lack of expression of prostate luminal differentiation markers androgen receptor and prostatic specific antigen in prostatic small cell neuroendocrine carcinomas suggest that the tumor cells may retain cancer stem cell features.     

Small cell (neuroendocrine) carcinoma of the vagina

We report a case of vaginal small cell (neuroendocrine) carcinoma. Immunostaining for neuron-specific enolase, PGP 9.5, chromogranin, synaptophysin, Leu 7 and cytokeratin was positive. Neurosecretory granules were found by electronmicroscopy. There was local recurrence and regional lymph node metastases. The patient survived for 10 months following local surgical therapy only.     

Small cell type neuroendocrine carcinoma colliding with squamous cell carcinoma at esophagus

Collision tumor is an extremely rare tumor which defined as the concrescence of two distinct primaries neoplasms. We report here a case of collision tumor at lower third esophagus composed of small cell type neuroendocrine carcinoma (NEC), which is an very rare, highly aggressive and poorly prognostic carcinoma and squamous cell carcinoma (SqCC). In our case, pathologically, the small cell carcinoma display the characteristic of small, round, ovoid or spindle-shaped tumor cells with scant cytoplasm, which colliding with a moderately differentiated squamous cell carcinoma. Immunohistochemical staining demonstrated positive activities for CD56, synaptophysin, 34βE12, CK 5/6, ki-67 (70%-80%), but negative for CD99, chromogranin A, and TTF-1. Accurate diagnosis was made base on these findings.     

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.     

Ureteral small cell carcinoma

Ureteral small cell carcinoma is very rare; only eight cases have been reported in the literature. In this article, we report the ninth case of ureteral small cell carcinoma. A 79-year-old Japanese man presented with asymptomatic macrohematuria, and left nephroureterectomy was performed. The nonpapillary and broad-based tumor, which measured 3.7 × 3.7 × 2.0 cm, was seen in the lower portion of the left ureter just above the ureteral orifice. Microscopically, the tumor was composed of urothelial carcinoma and small cell carcinoma. Immunohistochemically, neoplastic cells of small cell carcinoma were focally positive for chromogranin A. In the normal ureteral mucosa adjacent to the tumor, some endocrine cells positive for chromogranin A and synaptophysin were identified. In conclusion, we suggest that endocrine cells in the ureteral urothelial epithelium may be precursor cells of ureteral small cell carcinoma.     

Solid variant of mammary "adenoid cystic carcinoma with basaloid features" merging with "small cell carcinoma"

We describe a rare case of a solid variant of a mammary adenoid cystic carcinoma with basaloid features (sbACC) and its coexistence with a "small cell" carcinoma (SCC), identified and confirmed by histological and immunohistochemical observations: the absence of glandular structures and PAS-positive globules, positivity for neuroendocrine markers (NSE, synaptophysin and chromogranin), and negativity for 34betaE12 and SMA actin were the aspects suggesting the presence of SCC. Furthermore, positivity for CD10 was found both in sbACC and in SCC, supporting the hypothesis that the two components share the same histogenetic myoepithelial origin and represent an example of dedifferentiation along neuroendocrine phenotype lines occurring in a multipotential neoplastic stem line, already committed towards a myoepithelial phenotype. To our knowledge, this is the first reported case of a solid basaloid adenoid cystic carcinoma merging with an SCC carcinoma. Furthermore, it is the first study in which CD10 was used to investigate the histogenesis of the two neoplastic components.     

Small cell carcinoma of the urinary bladder

Primary small cell carcinoma of the urinary bladder is very rare; only several studies have been reported in the English literature. A 62-year-old woman was admitted to our hospital because of hematuria and dysuria. Bladder endoscopy revealed a large polypoid tumor at the bladder base. Transurethral bladder tumorectomy (TUR-BT) was performed. Many TUR-BT specimens were obtained. Histologically, the bladder tumor was pure small cell carcinoma. Immunohistochemically, the tumor cells were positive for cytokeratin (CK) AE1/3, CK CAM5.2, CK8, CK18, neurone-specific enolase, chromogranin, NCAM (CD56), synaptophysin, Ki-67 (labeling=100%), p53, KIT (CD117), and platelet-derived growth factor receptor-α (PDGFRA). The tumor cells were negative for CK5/6, CK 34BE12, CK7, CK14, CK19, CK20, p63, CD45, and TTF-1. A molecular genetic analysis using PCR-direct sequencing showed no mutations of KIT (exons 9, 11, 13 and 17) and PDGFRA (exons 12 and 18) genes. No metastases were found by various imaging techniques. The patient is now treated by cisplatin-based chemotherapy.     

Clear cell ductal adenocarcinoma of pancreas: a case report and review of the literature

We present a unique carcinoma of the pancreas with predominantly clear cell morphology (>95% clear cells). Mucicarmine stain revealed abundant intraluminal and intracytoplasmic mucin. Immunohistochemically, the cells were positive for the epithelial markers cytokeratin 7 and CAM 5.2, and were focally positive for cytokeratin 20. These cells also expressed monoclonal carcinoembryonic antigen. Stains for the neuroendocrine markers synaptophysin and chromogranin were negative, as were stains for vimentin, p53, HMB-45, and CD10. An additional outstanding feature was the presence of dense intraluminal and intracytoplasmic hyaline globules, which were immunohistochemically positive for alpha1-antitrypsin. Sequencing of the K-ras oncogene revealed a point mutation in codon 12, providing molecular evidence of ductal origin. In the proper morphologic context supported by immunohistochemistry, clear cell carcinoma can be regarded as a rare variant of ductal adenocarcinoma.     

Small cell carcinoma of the kidney: a clinicopathologic study of 14 cases

Small cell carcinoma of the kidney is distinctively rare. We searched pathology files in 2 institutions and found 14 cases of renal small cell carcinoma. The patients' mean age at diagnosis was 59 years (range, 22-75 years); 8 were women, and 6 were men. Patients usually presented with hematuria (n = 6) and abdominal pain (n = 5). The mean tumor size was 7.1 cm (range, 3.5-14.0 cm). The small cell carcinoma was pure in 9 cases and mixed with high-grade urothelial carcinoma in 5 cases. None was associated with any type of renal cell carcinoma. Tumor necrosis was present in all cases, and lymphovascular invasion was identified in 6 cases. The tumor invaded the perinephric adipose tissue in 13 cases and was confined to the kidney in only 1 case. Lymph node metastases were identified in all patients who underwent lymph node dissection (5/5). On immunostains, the small cell carcinoma cells were positive for pancytokeratin (11/12), chromogranin (6/9), and synaptophysin (8/9). Follow-up data were available for 13 patients, and 11 died of small cell carcinoma at a mean of 15 months (range, 4-31 months) after diagnosis. Of the 2 surviving patients, 1 was alive at 5 months after diagnosis, and the other, whose disease was confined to the kidney, was alive with no evidence of disease at 137 months. In summary, renal small cell carcinoma is a highly aggressive disease that often presents at an advanced stage with widespread metastases. Patients usually have a poor clinical outcome despite multimodal therapy. The frequent coexistence of small cell carcinoma with urothelial carcinoma suggests that renal small cell carcinomas may evolve from a preexisting urothelial carcinoma.     

Adenoid squamous cell carcinoma of the oral cavity

Because immunohistochemical features of adenoid squamous cell carcinoma (AdSCC) of the oral cavity is unclear, the author reports herein AdSCC in the gingival with an emphasis on immunohistochemical features. A 73-year-old woman presented with a left lower gingival tumor. The tumor was mildly elevated tumor measuring 1.5 x 1.5 x 0.5 cm. Dentist's diagnosis was granulation tissue, and a biopsy was taken. The biopsy showed proliferation of carcinoma cells arranged in cords, and squamous and tubular differentiations were noted in places. The biopsy diagnosis was adenosquamous carcinoma. Tumor excision with resection of mandibular bone was performed. The resected tissue showed a mixture and squamous cell carcinoma and tubular formation. Gradual merges between the two and acantholytic features of the squamous cell carcinoma element were seen. Both components were free from mucins. Both components were positive for pancytokeratins (AE1/3, CAM5.2) +++, cytokeratin (CK) 5/6 +, CK34βE12 ++, CK7 +, CK14 +++, CEA +, CA19-9 +, CA125 +, p53 +++, p63 +++, KIT + and MUC1 ++. Both components were negative for CK8, CK18, CK19, CK20, EMA, vimentin, TTF-1, desmin, myoglobin, S100 protein, melanosome, smooth muscle actin, CD34, CDX2, CD10, chromogranin, synaptophysin, NSE, CD56, lysozyme, CD68, MDM2, PDGFRA, MUC2, MUC5AC, and MUC6. Since both components were positive for squmaous cell carcinoma markers (CD5/6, CK34βE12, and p63) and adenocarcinoma markers (CEA, CA19-9, CA125, MUC1), this case of AdSCC appears an intermediate form between adenocarcinoma and squamous cell carcinoma. The margins were negative. No metastasis was found by imaging techniques. The patient is now free from tumor and is followed up carefully.