Immunohistochemical and ultrastructural study of mixed small cell/large cell carcinoma of the lung. Expression of Sialyl LeX-i antigens and scarcity of neuroendocrine characteristics.

The authors examined the immunohistochemical and ultrastructural characteristics of mixed small cell/large cell carcinoma (mixed subtype) of the lung which has been newly categorized as anaplastic small cell lung carcinoma. The 34 cases of small cell lung carcinoma examined consisted of 18 cases of pure small cell carcinoma (pure subtype), 12 cases of the mixed subtype and 4 cases of combined small cell carcinoma. Immunohistochemically, the number of immunoreactive tumor cells for chromogranin A was smaller (P less than 0.05) and that for creatine kinase BB was relatively larger in the mixed subtype. Sialyl LeX-i antigen (SLX), one of the SSEA-1 related carbohydrate antigens, was expressed specifically in the mixed subtype. Ultrastructurally, tumor cells in the mixed subtype had smaller amounts of neurosecretory granules and larger amounts of desmosomes than those in the pure subtype (P less than 0.05, P less than 0.005, respectively). These results suggest that the mixed subtype may show more epithelial than neuroendocrine differentiation and that SLX may be a specific marker for the mixed subtype to be used in pretherapeutic diagnosis.     

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.     

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.     

Squamous cell characteristics in small cell carcinoma of the uterine cervix: histological, immunohistochemical, and ultrastructural study in xenografted small cell carcinoma

Small cell carcinoma of the uterine cervix is a rare type of gynecological tumor that frequently expresses neuroendocrine differentiation. Its histological origin is unclear. We examined the histopathological characteristics of small cell cervical carcinoma in a patient with elevated serum adrenocorticotropin hormone. We then studied the morphological alteration in xenotransplanted tumors (passages 1–9) using immunohistochemistry and electron microscopy. The primary cervical tumor was characterized by a sheetlike arrangement of uniform small cells with hyperchromatic nuclei and a high nucleocytoplasmic ratio. A ribbon-like or trabecular pattern was also observed in a small area of the tumor. Neuron-specific enolase, chromogranin A, and S-100 were positive for the tumor cells, but cytokeratin was negative. Dense-core granules were detected by electron microscopy. In the xenografted tumor, a serial change from squamous cells to round-to-oval cells was observed. Cytokeratin was immunohistochemically stained in the squamous tumor cells but not in the other tumor cells. In contrast, chromogranin A was stained in some of the round-to-oval cells. Basal lamina underlaid the squamous tumor cells, and desmosome-like junctions were apparent. The cytoplasm was filled with well-differentiated organelles including electron-dense tonofilaments. Elliptical tumor cells resembled the primary carcinoma ultrastructurally. These findings suggest that small cell cervical carcinoma with neuroendocrine properties shares the characteristics of squamous cell carcinoma.This study was presented at the 24th Annual Meeting of the Clinical Electron Microscopy Society of Japan, Okayama, September 17, 1992.     

miR-210对肾透明细胞癌血管生成的影响

目的探讨miR-210对肾透明细胞癌血管生成的影响。方法检测40例肾透明细胞癌组织标本中miR-210的表达,并分析其与相应癌组织中微血管密度(MVD)的关系。通过miR-210反义寡核苷酸(miR-210-ASO)技术抑制肾透明细胞癌细胞系786-O细胞中miR-210表达,RT-q PCR检测转染效果。三维培养实验观察对照组、阴性对照组和miR-210-ASO组肿瘤细胞上清液对人脐静脉内皮细胞(HUVEC)管腔形成数量的影响。建立裸鼠移植瘤模型,应用endomucin免疫荧光染色于激光共聚焦显微镜下观察抑制miR-210对移植瘤生长,血管形成和VEGF表达的影响。结果肾透明细胞癌组织标本中miR-210的表达与微血管密度呈正相关(P0.05),经miR-210-ASO转染的786-O细胞其miR-210表达明显下降(P0.05)。miR-210-ASO组细胞上清液培养的HUVEC细胞管腔形成数量显著少于对照组和阴性对照组(P0.05)。miR-210-ASO组细胞形成的移植瘤体积小于对照组,且微血管数量和VEGF的表达量显著少于对照组(P0.05)。结论抑制miR-210可降低肾透明细胞癌中血管生成数量。     

Demonstration of argyrophil granules in small cell carcinoma of the lung

Summary The Grimelius silver nitrate stain has enabled us to demonstrate the presence of tumor cells with argyrophil granules (argyrophil cells) in small cell carcinoma of the lung. Of the 22 tumors, 11 showed varying numbers of argyrophil cells. The occurrence of the cells differed in frequency among the subtypes of small cell carcinoma. The fusiform cell type showed the cells more frequently than the other types. Both tumors with numerous argyrophil cells belonged to the fusiform cell type.The number of positive cells seen under the light microscope did not correlate with the number of cells containing neurosecretory granules under the electron microscope, nor with the amount of either ACTH or serotonin in the tumor extracts.The demonstration of these cells in a pulmonary carcinoma may be of help in making correct histological diagnosis.Supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Education, Science and Culture, and the Ministry of Health and Welfare, Japan     

Primary gastric small cell carcinoma: report of a case and review of the literature

A 52-year-old man suffering from a pure-type primary gastric small cell carcinoma was treated with surgery and combination chemotherapy. The small cell carcinoma, approximately 6.5 cm in diameter, was situated in the posterior wall of the antrum and there were no distant metasatses. Total gastrectomy and regional lymph node dissection was carried out. Histological examination revealed a solid pattern of proliferation of small cells with hyperchromatic, round nuclei and scant cytoplasm. Neoplastic cells infiltrated into the subserosal layer with severe lymphatic and vascular invasion. Regional lymph node cells were mostly replaced by tumor cells that stained positive for Grimelius, neuron-specific enolase (NSE), and synaptophysin. Accumulations of electron-dense core granules in the small neoplastic cells were seen by electron microscopy. Following surgery, the patient was treated with adjuvant chemotherapy consisting of cisplatin and etoposide. The patient is alive and recurrence free 3 years after surgical operation. We review 107 published cases of primary gastric small cell carcinoma, an extremely rare disease first reported in 1976. Small cell carcinoma is an aggressive, malignant tumor. Intensive chemotherapy is essential for patient survival even when curative surgical resection is carried out.     

Extrapulmonary small cell carcinomas express K homology domain containing protein overexpressed in cancer, but carcinoid tumors do not

A number of malignancies, including high-grade neuroendocrine carcinomas of the lung, have been reported to express K homology domain containing protein overexpressed in cancer (KOC), a member of the insulin-like growth factor messenger RNA-binding protein (IMP) family also known as L523S and IMP3. KOC acts to promote tumor cell proliferation by enhancing insulin-like growth factor-II protein expression. This study aimed to examine KOC expression pattern in extrapulmonary neuroendocrine tumors. Seventy-five extrapulmonary neuroendocrine tumors that were surgically resected or had undergone biopsy, including 53 small cell carcinomas (uterine cervix, 21; bladder, 10; colorectum, 13; prostate, 7; stomach, 1; and esophagus, 1) and 22 carcinoid tumors (colorectum, 10; appendix, 5; ileum, 4; duodenum, 2; and stomach, 1), were immunohistochemically studied using a monoclonal antibody against KOC. Our results demonstrated that 47 small cell carcinomas (89%) showed moderate to strong positive staining for KOC, with 25 cases (53%) showing positivity in more than 90% of tumor cells and 22 cases (47%) in 40% to 80% of tumor cells. Three cases showed weak staining in 5% to 10% of the tumor cells. The remaining 3 cases (uterine cervix, 2; bladder, 1) showed completely negative immunoreactivity. No KOC immunostaining was detected in 22 carcinoid tumors. These findings indicate that KOC may play an important role in the regulation of biologic behavior of extrapulmonary small cell carcinomas. In addition, immunohistochemical detection of KOC expression may serve as a useful diagnostic tool in the distinction between small cell carcinoma and carcinoid tumor, particularly when the diagnostic material is a small biopsy with crushing artifact.     

Primary combined small cell carcinoma of larynx with lateralized histologic components and corresponding side-specific neck nodal metastasis: report of a unique case and review of literature

Combined small cell carcinoma (neuroendocrine) of the larynx has been rarely reported in the literature, and included in the current WHO classification. We hereby report an unusual case of combined carcinoma of the larynx; composed mainly of small cell neuroendocrine carcinoma nearly confined to the right side (mainly involving supraglottis extending to glottis) with synchronous minor in-situ and invasive squamous cell carcinoma component located on the left side of larynx (mainly glottis). Interestingly, this side-specific distribution of tumor was recapitulated in its metastatic nodal spread; so that right cervical lymph nodes showed only metastatic small cell carcinoma and left cervical lymph nodes only metastatic squamous cell carcinoma. To the best of our knowledge, the present case is the seventeenth reported case of a combined small cell carcinoma of larynx, second case in which individual tumor components were lateralized on either side of larynx, and the first case in which this side-specificity of tumor was reflected in its metastatic neck nodal spread. This report emphasizes the value of accurate pathologic diagnosis including diversity in differentiation and localization of laryngeal tumors, and underscores the need for thorough pathologic examination of bilateral laryngeal tumors. The pre-operative diagnostic yield of small cell carcinoma (pure or combined) can be enhanced by including deeper submucosal biopsies on laryngoscopy in all those cases in which the extent of disease on imaging is disproportionately larger than the apparent mucosal involvement on laryngoscopy. This approach can facilitate selection of neoadjuvant or palliative chemo-radiotherapy in large or unresectable tumors.     

Neuroendocrine small cell carcinoma of the breast: report of a case

A rare case of neuroendocrine small cell carcinoma (SmCC) of the breast is reported. A 51-year-old postmenopausal woman noticed a nodule approximately 3 cm in diameter in her right upper breast. Histologically, the tumor consisted of small ovoid to pleomorphic cells with hyperchromatic nuclei, and a large central area was occupied by acellular amorphous tissue. Extensive lymphatic permeation was seen around the tumor. Invasive and in situ ductal carcinoma foci were not observed in and surrounding the tumor. Immunohistochemically, estrogen and progesterone receptors and HER2/neu were all negative in the tumor cells. Synaptophysin and chromogranin A were diffusely positive in the tumor cells. Cytokeratin 8 was only positive in a few tumor cells. The labeling indices of Ki-67 and p53 were high in the tumor. Postoperatively, systemic studies including positron emission tomography were performed but failed to reveal any other possible primary sites, including lung. Based on these findings, the tumor was diagnosed as neuroendocrine primary SmCC of the breast. Postoperatively, the patient received a course of weekly paclitaxel. However, pelvic bone metastasis was identified on a bone scintigram 1 year after surgery. Mammary SmCC showing high Ki-67 and p53 index should be treated carefully because of their aggressive clinical behavior.     

Small cell (oat cell) carcinoma of the breast

A case of small cell (oat cell) carcinoma, which represents both the most dlstlnctlve and the least common type of mast carcinoma wtth neuroendocrine dlfterentiation and usually shows the most aggressive behavior, is described. Radlcal mastectomy was performed on a Wyearold female for a 10 cm tumor located in the outer part of the right breast with cutaneous ulceration Microscoplcally, the tumor predominantly consisted of a diffuse proliteration of small, round to ovoid cells with hyperchromatlc nuclei and ill-defined, scant cytoplasm that was reminiscent of oat cell carclnoma of the lung. There were foci of invasive ductal carcinoma and ductal carcinoma in situ . Small cell carcinoma areas constituted approximately 90% of the neoplasm. The patlent had axlllary lymph node metastasis. The small tumor cells were argyrophlllc and positive for CAM5.2, carclnoembryonic antigen, neuron-specific enolase, Leu-7, chromogranln A and synaptophysin. Flow cytometric analysis showed an aneuplold DNA content. The patient was alive and well without disease 4 years after surgery. Small cell carcinomas of the breast may exhibkt a spectrum of malignancy that is comparable to similar tumors at better known primary 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.     

Genetics of a combined lung small cell carcinoma and large cell neuroendocrine carcinoma with adenocarcinoma

Combined nonneuroendocrine-neuroendocrine lung tumors are relatively infrequent and little is known as for their genetic basis. Here, we report the case of a 69-year-old male with a solitary neoplasm in the upper lobe of the right lung. At histological examination, the tumor showed two components. The main part was an adenocarcinoma of the acinar type. The second part showed morphological and immunohistochemical phenotype of a neuroendocrine carcinoma composed of a small cell lung carcinoma and a large cell neuroendocrine carcinoma. The aim of our study was to investigate the genetic relationship between neuroendocrine and nonneuroendocrine tumor components. To this purpose, we performed a loss of heterozygosity (LOH) analysis with 40 chromosomal microsatellite markers. Microallelotyping revealed a common genetic profile in the different tumor areas. In 9 of 30 informative regions analyzed, LOH involved the same allele in all components, regardless of their histological type and grade. These findings support the true combined nature of this exocrine-neuroendocrine carcinoma of the lung and suggest a common monoclonal origin from a pluripotent epithelial (alveolar or bronchial) precursor cell for the two different tumor components.     

43例食管基底样鳞状细胞癌临床病理分析

目的探讨食管基底样鳞状细胞癌（basaloid squamous cell carcinoma,BSCC）临床病理特点。方法对43例食管BSCC进行组织形态学及免疫组化观察,并对其临床病理特点及随访资料进行分析。结果BSCC由类似于鳞状上皮基底细胞样的细胞组成,细胞排列呈实性巢状、小梁状、假腺样或筛状结构,巢周边瘤细胞常呈栅栏状排列,巢中央可见粉刺样坏死。24例（55.8％）与普通鳞癌或腺鳞癌并存,11例（25.6％）出现局灶鳞化,28例（65．1％）见到脉管内癌栓。免疫组化染色CKpan、AE1、AE3均呈不同程度的阳性表达,p53、Ki-67、PCNA呈中至强阳性表达,Syn、CgA分别有1例呈弱阳性,S-100蛋白、SMA、CEA均为阴性。结论BSCC是食管一种少见的鳞状细胞癌变异型,具有独特的形态特点和明显的侵袭性行为,预后较差。免疫组化无特异性,诊断主要依靠形态学特点。     

Mucinous breast carcinoma and mixed mucinous-infiltrating ductal carcinoma: a comparative cytologic study

In its pure form, mucinous breast carcinoma (MC) has a much better prognosis than infiltrating ductal carcinoma (IDC). Mixed MC-IDC has the prognosis of IDC. We compared the fine-needle aspiration (FNA) cytology and histology of nine cases of pure MC with 13 cases of mixed MC-IDC. While typical of pure MC, abundant mucin (3+/3+) was noted in smears from three cases of mixed tumor and is thus necessary but not sufficient for a diagnosis of pure MC. Cellular pleomorphism has been said not to be a feature of MC; however, we found occasional large cells markedly different from the typical small uniform cells of MC in four pure and seven mixed tumors. Cytologic features indicative of a mixed tumor include one or more smears totally without mucin, scantly amounts of mucin, or necrosis. A combination of features indicative of pure mucinous carcinoma in FNA included abundant mucin on all smears, no pleomorphism, and no necrosis. Many cases will have smear patterns that are not typical of either profile and should probably be designated as carcinoma with a mucinous component.     

Solitary pancreatic metastasis of occult pulmonary small cell carcinoma diagnosed by EUS-FNA cytology: a case report

A 74-year-old man presented with symptoms suggestive of acute pancreatitis, and a mass lesion measuring 25 mm was detected in the pancreatic head. Cytological and histopathological examinations of EUS-FNA specimens taken from the lesion demonstrated small cell (neuroendocrine) carcinoma. Tumor cells were immunoreactive for cytokeratin, synaptophysin, chromogranin A, CD56, and TTF-1, and PET-CT of the chest revealed a small tumor in the upper lobe of the left lung. Pulmonary carcinoma, particularly small cell carcinoma, infrequently presents with a solitary metastatic lesion in the pancreas as an initial manifestation and clinically simulates a primary pancreatic neoplasm. Because primary small cell carcinoma of the pancreas is very uncommon, metastasis from the lung should always be considered when evaluating pancreatic neoplasms showing a “small cell” morphology. Immunohistochemistry for TTF-1 is useful for determining the pulmonary origin of this type of neoplasm, and its application to cytology specimens is recommended.     

手术切除肺神经内分泌癌的临床特征与预后因素

目的:探讨手术切除肺神经内分泌癌的临床特征与预后因素.方法:回顾性分析65例手术切除肺神经内分泌癌患者的临床特征、基因状态,用Kaplan-Meier方法计算生存率,其显著性检验分析用Log-rank法,单因素和多因素分析用COX风险比例回归模型.结果:65例肺神经内分泌癌患者的临床特征差异无统计学意义(P>0.05),基因状态改变以PIK3CA基因突变为主,小细胞癌(26.7个月)、大细胞神经内分泌癌(30.4个月)和类癌中位生存时间(未达到)差异有统计学意义(P=0.039);小细胞癌单因素分析基因类型、癌症分期,差异具有统计学意义(P<0.05).结论:肺神经内分泌癌基因状态改变少见,以PIK3CA基因突变为主,肺神经内分泌癌分子表达谱种类丰富且不同亚型表达谱不同,类癌生存明显高于肺大细胞神经内分泌癌和小细胞癌.     

成纤维细胞生长因子受体1阳性肺鳞状细胞癌临床病理特征

目的 通过观察成纤维细胞生长因子受体1(FGFR1）蛋白在肺鳞状细胞癌(SCCL)组织中的表达，探讨FGFR1阳性病例的临床病理特征以及免疫组织化学（IHC）方法在筛查肺鳞状细胞癌FGFR1阳性病例中的意义。 方法 应用组织芯片技术制备208例SCCL组织微阵列；应用IHC检测FGFR1蛋白表达，结果与临床病理参数比较分析。 结果 208例SCCL患者中FGFR1阳性13例，阳性率为6.3%。FGFR1阳性组中肿瘤大于5cm患者比例明显高于FGFR1阴性组（P<0.05）；淋巴结转移组FGFR1阳性率较无淋巴结转移组明显增高（9.7% 比 2.9%，P<0.05）； Ⅲ、Ⅳ期患者FGFR1阳性率较Ⅰ、Ⅱ期患者明显增加（13.1% 比 1.6%，P<0.01）。吸烟患者较不吸烟患者FGFR1阳性率差异不明显(P>0.05)，但随吸烟指数的增加，有增高的趋势。结论 FGFR1阳性表达与SCCL患者肿瘤体积较大、淋巴结转移以及临床分期较晚相关；与年龄、性别、肿瘤部位、分化程度及吸烟等无明显相关。     

Dual differentiation in small cell carcinoma (oat cell carcinoma) of the lung

Two cases of small cell “undifferentiated” carcinoma (oat cell carcinoma) of the lung with dual neurosecretory and squamous differentiation are reported. One was treated with various regimens of chemotherapy and radiotherapy; the other was untreated at the time of biopsy. By electron microscopy, the same tumor cells showed membrane-bound, dense-core, neurosecretory-type granules and bundles of tonofibrils denoting squamous differentiation. This dual differentiation underlies the difficulty of ascribing an exclusively neural histogenesis to small cell carcinomas with neurosecretory-type granules. It is possible that entoderm-associated neuroectodermal tumors develop features of autochthonous entodermal tumors as a result of microenvironmental influences. An alternative hypothesis would be that small cell tumors are derived from basal reserve bronchoepithelial cells with pluripotentialities.