Combined Small Cell Carcinoma Research Articles

Molecular profiling of small cell lung cancers in Japanese patients.

7599 Background: Molecular abnormalities discovered in the last decade have led to a paradigm shift in the diagnosis and treatment of lung adenocarcinoma. But there have been few reports about molecular profiling of small cell lung cancers (SCLC). We conducted the Shizuoka Lung Cancer Mutation Study to analyze driver mutations in patients with thoracic SCLC malignancies. Methods: We collected molecular profiling data of SCLC from the biobanking system in conjunction with the clinic, including the pathology lab, where 23 mutations in 9 genes (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN and HER2), EGFR, MET, PIK3CA, FGFR1 and FGFR2 amplifications, and EML4-ALK translocations were assessed using pyrosequensing plus capillary electrophoresis, qRT-PCR, and RT-PCR, respectively. To evaluate mutation status for SCLC patients, we collected patient characteristics data from medical records. Results: Between July 2011 and July 2012, fifty small cell lung cancer patients were assessed in our biobanking system. Patient characteristics were as follows: median age (range) 70 (43 - 82) years; male 82%; smoker 96%; limited disease/extended disease 56/44%; small cell carcinoma/combined small cell carcinoma with adenocarcinoma 94/6%; surgically resected snap-frozen samples 8, formalin-fixed paraffin-embedded samples 40 and pleural effusion 7. We detected driver mutations in 8 cases (16%). Mutations found: EGFR 1 (2%), KRAS 1 (2%), PIK3CA 2 (4%), AKT1 1 (2%), MET amplification 1 (2%), PIK3CA amplification 6 (12%). EGFR and KRAS mutation were found in combined small cell carcinoma with adenocarcinoma. No significant differences in age, sex, disease extent at diagnosis or smoking status were found between patients with mutations and those without mutations. But serum neuron-specific enolase (NSE) levels were significantly higher in patients without mutations (p=0.03). Conclusions: In our analysis, driver mutations were found in 16% of SCLC patients and PIK3CA amplification seemed to be relatively frequent in SCLC. Our results suggest that PIK3CA might become a target of treatment for SCLC patients.

Combined small cell carcinoma of the hypopharynx

We report an extremely rare case of combined small cell carcinoma (combined SmCC) of the hypopharynx. A 73-year-old male presented with multiple left neck swellings for 1 month. A tumorous lesion was found in the left pyriform sinus, and biopsy revealed that the lesion was squamous cell carcinoma (SqCC). Surgery was performed and pathological examination led to a diagnosis as combined SmCC, composed of SqCC and small cell carcinoma (SmCC). One month after surgery, a contrast-CT indicated metastases to the cervical lymph node (LN), mediastinum and liver. We performed 5 courses of chemotherapy with the use of cisplatin (CDDP) and irinotecan (CPT-11). The patient temporarily showed a favorable response to the chemotherapy; however, eventually he died of regrowth of the tumor. Combined SmCC is a disease with a poor prognosis. Although biopsy sometimes fails to detect the SmCC component, intensive diagnosis and treatment are necessary.

Combined small cell and squamous cell carcinoma of the larynx

A case of combined small cell and squamous cell carcinoma of the larynx in a male patient in the sixth decade of life is reported. The etiopathogenesis of this combined tumor remains unclear; however, a number of hypotheses were proposed in the past including the pivotal role of Kulchitsky, squamous cells and the glandular cells. The gene mutations may also play an important role in laryngeal carcinogenesis. This unusual type of laryngeal combined carcinoma has previously been reported worldwide in only 17 cases. This is an extremely rare tumor the histological nature of which makes the diagnosis more complicated than in other types of laryngeal cancers. The diagnosis of this carcinoma is based on light microscopy and should be supported by immunohistochemical studies. In our case, the tumor was growing in the left pyriform sinus. Metastatic neck lymph nodes were found on the left side, but no distant metastases were observed. Microscopic sections revealed a combined tumor composed of small cell carcinoma neuroendocrine type and non-keratinizing squamous cell carcinoma. Positive reaction to p16, bcl-2, thyroid transcription factor 1, synaptophysin and chromogranin A in the small cell neuroendocrine type carcinoma component was observed. The cells from squamous cell carcinoma component showed positive reaction to p63, high-molecular-weight cytokeratin and cytokeratin 5/6.

中咽頭原発混合型小細胞癌の1例

小細胞癌は進行が早く，高率に遠隔転移を生じることから予後不良とされる。肺に好発するが，中咽頭の小細胞癌は極めてまれであり，治療法は確立していない。他の癌腫の成分が混在している場合は生検組織中には，小細胞癌の成分が見出されないこともある。今回われわれは，中咽頭側壁，扁桃原発の混合型小細胞癌・扁平上皮癌を経験したので報告する。われわれが検索し得た範囲では，中咽頭側壁原発の混合型小細胞癌・扁平上皮癌症例の報告はこれまでにない。

Small Cell Lung Carcinoma With Marked Bronchial Epithelial Involvement

Marked involvement of bronchial epithelium by malignant cells with a neuroendocrine immunophenotype was observed in a pulmonary lobectomy specimen containing combined small cell lung carcinoma (SCLC). Review of the medical literature reveals scant information on malignant neuroendocrine cells in bronchial epithelium accompanying SCLC and no documentation of an SCLC precursor. We discuss the possibility that the intraepithelial neoplastic lesion that we have described may be a primary lesion and possibly a precursor of SCLC and the alternative possibility that it represents invasion by underlying invasive SCLC. The need for further comprehensive study of the morphology and immunophenotype of bronchial mucosal abnormalities accompanying SCLC utilizing lung resection specimens is emphasized.

Combined small-cell carcinoma of the lung with quadripartite differentiation of epithelial, neuroendocrine, skeletal muscle, and myofibroblastic type

The combined variant of small-cell lung carcinoma (SCLC) refers to the variable admixture of small cell and non-small cell carcinoma, whereas the association with sarcoma or sarcoma-like elements is exceedingly rare. A 76-year-old Caucasian man underwent right upper lobectomy with regional lymphadenectomy because of a symptomatic 7cm-sized tumor mass. Formalin fixed-paraffin embedded material was used to highlight several differentiation cell lineages by means of immunohistochemistry, electron microscopy, and mutational assay. The tumor was discovered as being IIB stage (pT2b pN1(1/51) pM0) and featured biphasic appearance with close intermingling of SCLC (40%) and collagen-rich spindle cell sarcoma (60%). Epithelial (cytokeratins, TTF-1), neural (neurofilaments, GFAP), endocrine (chromogranin, synaptophysin, CD56), and skeletal muscle (desmin, sarcomeric actin, myogenin) markers were variably co-expressed by SCLC elements, whereas mesenchymal (vimentin), smooth muscle (actin, myosin, H-caldesmon, calponin), fibroblastic (CD10), and, more focally, skeletal muscle (desmin, sarcomeric actin and myogenin) markers were highlighted in the spindle cell sarcoma elements. TP53 codon V274F mutation in exon 8 was shared by either cell component. After undergoing adjuvant chemotherapy, the patient is currently alive and well at the 40-month follow-up. To the best of our knowledge, this is the first report of combined SCLC with quadripartite differentiation of epithelial, neuroendocrine, skeletal muscle, and myofibroblastic type, somewhere at the level of the same individual tumor cells. This tumor had probably derived for clonal evolution of a p53-mutated common ancestor lesion.

下咽頭混合型小細胞癌と考えられた１例

Combined small cell carcinoma (CSCC) involves small cell carcinomas and nonsmall cell carcinomas including squamous cell carcinoma (SCC). CSCC of the hypopharynx is extremely rare, with just 5 cases described to date in English literature. A 75-year-old man with CSCC of the hypopharynx seen for abnormal upper gastrointestinal endoscopic findings was found in video hypopharyngoscopy to have a right pyriform sinus tumor. Pathological biopsy findings showed SCC in situ (cTisN0M0). Radiotherapy with 70 Gy brought complete remission. A relapse three months later thought to be recurrent SCC (rT2N2cM0) at the tumor site necessitated total laryngopharyngectomy and bilateral neck dissection and free rectus abdominis flap reconstruction. Pathological findings showed small cell carcinoma. Most radiation-induced cancer arises 10 years later. We think the primary tumor was likely CSCC with SCC. After undergoing two chemotherapy courses (CBDCA+VP-16) for small cell carcinoma, the man died 4 months after surgery. We review the literature and discuss clinical features and management of this rare tumor.

Abstract B22: Is there a role of estrogen and progesterone receptors in differentiating primary neuroendocrinal lung tumors from metastatic adenocarcinoma?

Abstract Background: The distinction between primary lung carcinoma and metastatic tumors is essential for patient management and treatment. However for metastatic tumors, a wedge resection is often the procedure of choice, whereas for primary pulmonary neoplasms the standard treatment is to perform at least a lobectomy with mediastinal lymph node sampling. Computed tomography scans, histology and immunohistochemical stains still have some limitations in differentiating primary neuroendocrinal lung tumors and metastatic adenocarcinoma. Estrogen and progesterone receptors, although more frequently immunoreactive in breast carcinomas and gynecologic tumors than in primary lung tumors, can be positive in metastatic pulmonary adenocarcinoma. Objective: To assess estrogen and progesterone receptor expression in primary pulmonary neuroendocrine tumors. Design: Fifty seven neuroendocrine lung neoplasms including small cell carcinomas (25), carcinoids (19), large cell neuroendocrine carcinomas (6), and combined small cell carcinomas (7) were evaluated in this cross-sectional study for estrogen and progesterone receptors. Lung metastasis from gynecologic tumors (27) and non-small cell lung carcinomas (30) were also stained for comparison. Settings: Chest and gynecology departments of Assuit and Woman's Health University hospitals. Results: Neuroendocrine primary lung neoplasm demonstrated focal to diffuse estrogen and progesterone expression. There was no correlation with the size of the tumor, the sex or the age of the patients. In comparison with neuroendocrine lung carcinomas, lung metastasis from gynecologic adenocarcinomas (20 endocervical cancer, 7 endometrial cancer) expressed estrogen and progesterone receptors more frequently (p<0.7). Non-small cell carcinomas had less immunoreactivity for estrogen and progesterone than primary neuroendocrinal lung tumors and gynelogic lung metastasis (p<0.4). Conclusions: Although estrogen and progesterone receptor staining is frequently associated with gynecologic tumors, it can also be observed in “nontarget” organs. Therefore, presence of estrogen and progesterone expression in lung metastasis from gynecologic adenocarcinomas should not exclude a primary pulmonary neoplasm. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B22.

Defining Genomic Alteration Boundaries for a Combined Small Cell and Non-small Cell Lung Carcinoma

In the rare case of a male patient presenting with a combined small cell lung carcinoma (SCLC), large cell neuroendocrine carcinoma and adenocarcinoma, we used whole genome analysis by tiling-path array comparative genomic hybridization to evaluate the clonal relationship between nodules. In two areas of SCLC distinguishable by divergent neuroendocrine marker expression (CD56 and chromogranin-A), the presence of identical genomic breakpoints and rearrangements indicated a common origin, with the presence of additional distinct genomic alterations in these two components indicating diverging clonal evolution. The absence of shared genome alteration features for the adenocarcinoma and large cell neuroendocrine carcinoma components suggested that these tumors evolved independently from the SCLC. Taken together, the array comparative genomic hybridization data demonstrate the development and evolution of three independent primary lung cancers in close proximity to each other to form a combined carcinoma. Application of whole genome analysis shows the potential utility of high resolution molecular tools in resolving the origin and delineating the clonal relationships of a tumor that contains heterogeneous histologic components leading to an ambiguous histogenesis.

Immunohistochemical Expression of Estrogen and Progesterone Receptors in Primary Pulmonary Neuroendocrine Tumors

Lung and breast carcinomas are among the most prevalent cancers. Advances in cancer therapies can provide survival benefit and be potentially curative, even in metastatic disease. Due to the high prevalence of these carcinomas, it is not unusual to encounter lung nodule(s) in a patient with breast carcinoma, and distinguishing between primary and metastatic disease is critical for management/treatment. Occasionally neuroendocrine differentiation is present in breast carcinoma, making its distinction from pulmonary/nonpulmonary neuroendocrine tumors in the lung difficult. To assess estrogen and progesterone receptor expression in the entire spectrum of pulmonary neuroendocrine tumors. Seventy-one neuroendocrine neoplasms including typical carcinoids (42), atypical carcinoids (7), small cell carcinomas (14), large cell neuroendocrine carcinomas (2), and combined small cell carcinomas (6) were evaluated for estrogen and progesterone receptors. Mammary and non-small cell lung carcinomas were also stained for comparison. The entire spectrum of neuroendocrine neoplasms demonstrated focal to diffuse estrogen (typical carcinoid, 23; atypical carcinoid, 6; small cell carcinoma, 8; large cell neuroendocrine carcinoma, 2; combined small cell carcinoma, 4) and progesterone (typical carcinoid, 11; atypical carcinoid, 2; small cell carcinoma, 7; large cell neuroendocrine carcinoma, 0; combined small cell carcinoma, 2) expression. There was no correlation between sex and estrogen/progesterone status. Estrogen and progesterone staining were also noted in endothelial cells. Relative to neuroendocrine carcinomas, mammary carcinomas expressed estrogen and progesterone more frequently. Non-small cell carcinomas had greater and similar immunoreactivity for estrogen and progesterone, respectively. Although estrogen and progesterone receptor staining is frequently associated with breast and gynecologic primaries, it can also be observed in "nontarget" organs. Therefore, presence of estrogen and/or progesterone expression in neuroendocrine tumors involving the lung should not exclude a primary pulmonary neoplasm.

Immunohistochemical Expression of Estrogen and Progesterone Receptors in Primary Pulmonary Neuroendocrine Tumors

Abstract Context.—Lung and breast carcinomas are among the most prevalent cancers. Advances in cancer therapies can provide survival benefit and be potentially curative, even in metastatic disease. Due to the high prevalence of these carcinomas, it is not unusual to encounter lung nodule(s) in a patient with breast carcinoma, and distinguishing between primary and metastatic disease is critical for management/treatment. Occasionally neuroendocrine differentiation is present in breast carcinoma, making its distinction from pulmonary/nonpulmonary neuroendocrine tumors in the lung difficult. Objective.—To assess estrogen and progesterone receptor expression in the entire spectrum of pulmonary neuroendocrine tumors. Design.—Seventy-one neuroendocrine neoplasms including typical carcinoids (42), atypical carcinoids (7), small cell carcinomas (14), large cell neuroendocrine carcinomas (2), and combined small cell carcinomas (6) were evaluated for estrogen and progesterone receptors. Mammary and non–small cell l...

Combined Large Cell Neuroendocrine Carcinoma and Papillary Serous Carcinoma of the Endometrium With Pagetoid Spread

Neuroendocrine carcinomas of the endometrium are rare tumors that can be pure, combined with endometrioid adenocarcinoma, or a component of malignant mixed müllerian tumor. Recently, a case of combined small cell carcinoma and papillary serous carcinoma of the endometrium was described for the first time. We report the first case, to our knowledge, of combined large cell neuroendocrine carcinoma and papillary serous carcinoma of the endometrium, with an unusual pagetoid spread of the neuroendocrine component into normal endometrial and endocervical glands. The endometrial carcinoma had a small serous component, but most of the tumor was characterized by solid sheets of medium to large cells with abundant mitotic figures, numerous apoptotic bodies, and foci of necrosis. This component was diffusely positive for neuroendocrine markers. Following surgery, the patient was treated with radiation therapy and chemotherapy. She was without evidence of progression at 5 months of follow-up.

Combined Large Cell Neuroendocrine Carcinoma and Papillary Serous Carcinoma of the Endometrium With Pagetoid Spread

Neuroendocrine carcinomas of the endometrium are rare tumors that can be pure, combined with endometrioid adenocarcinoma, or a component of malignant mixed mullerian tumor. Recently, a case of combined small cell carcinoma and papillary serous carcinoma of the endometrium was described for the first time. We report the first case, to our knowledge, of combined large cell neuroendocrine carcinoma and papillary serous carcinoma of the endometrium, with an unusual pagetoid spread of the neuroendocrine component into normal endometrial and endocervical glands. The endometrial carcinoma had a small serous component, but most of the tumor was characterized by solid sheets of medium to large cells with abundant mitotic figures, numerous apoptotic bodies, and foci of necrosis. This component was diffusely positive for neuroendocrine markers. Following surgery, the patient was treated with radiation therapy and chemotherapy. She was without evidence of progression at 5 months of follow-up.

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.

Epidermal growth factor receptor mutation status and clinicopathological features of combined small cell carcinoma with adenocarcinoma of the lung

In lung cancer, somatic mutations of epidermal growth factor receptor (EGFR) are concentrated in exons 18-21, especially in adenocarcinoma (Ad), but these mutations have rarely been reported in small cell lung carcinoma (SCLC). Combined SCLC is rare, and the EGFR mutation status and its relationship to the clinicopathological features of this tumor type have not yet been elucidated. We retrospectively studied six patients with combined SCLC with Ad components among 64 consecutive patients who underwent resection of SCLC. The clinicopathological features of each patient were reviewed, especially for the distribution pattern of the Ad component and lymph node metastases. EGFR mutations were screened by high-resolution melting analysis in each case, and were confirmed by sequencing of each mutation in the microdissected SCLC or Ad components. Regarding EGFR, no specific mutation was detected in five of the six patients, whereas one female patient who had never smoked had a missense mutation. In this case, both the SCLC and Ad components shared the same mutation in exon 21 (L858R). We identified a patient with combined SCLC with Ad sharing an identical EGFR mutation in both the SCLC and Ad components. In addition to the clinicopathological characteristics of this rare histological type of lung cancer, these findings provide useful information for better understanding the biology, natural history and clinical management of SCLC.

Combined small cell carcinoma with pulmonary blastoma and adenocarcinoma: Case report and clonality analysis

We describe a rare tumor occurring in the left pulmonary lobe of a 71-year-old Japanese man. The tumor, which was resected by left lower lobectomy, measured 65×50×50 mm. Histologic examination revealed papillary adenocarcinoma in small cell carcinoma, and chondrosarcoma. Also, the blastemal cells were located between the small cell carcinoma and the chondrosarcoma, and intermingled with both components. In blastemal cells, some glands resembled a well-differentiated fetal adenocarcinoma. The tumor was diagnosed as combined small cell carcinoma with pulmonary blastoma and papillary adenocarcinoma according to the 2004 WHO classification. Immunohistochemically, the small cell carcinoma expressed TTF-1, pancytokeratin, CD56, synaptophysin, and S100 protein, while blastemal cells expressed vimentin, desmin, smooth muscle actin, CD56, and S100 protein. To investigate whether the tumor was clonal or not, p53 gene mutation of each tumor component was analyzed by laser-captured microdissection, polymerase chain reaction-single-strand conformation polymorphism and direct sequencing. Despite the histologic complexity, all components showed the same mutation at exon5 of the p53 gene. These results indicate that the tumor was clonal and arose from a relatively primitive cell, and that p53 mutation occurred before histologic metamorphosis or differentiation.

A Rare Case of Combined Small-Cell Lung Cancer with Unusual Soft Tissue Metastasis

Combined small-cell lung carcinoma (SCLC) is a rare tumor. We report a case of combined SCLC of the lung, including adenocarcinoma and spindle-shaped cell tumor, with an unusual initial presentation. The patient suffered from a right shoulder mass, subsequently undergoing biopsy. A lung nodule was noted later after complete examination. The diagnosis turned out to be combined cell carcinoma with three different components (small-cell carcinoma, adenocarcinoma, and spindle-shaped cell tumor) after examination upon total removal of the lung nodule by lobectomy. In addition to the rarity of the three components in such a tumor, soft tissue metastasis also made it an unusual case.

Primary combined squamous and small cell carcinoma of the larynx: report of two cases and discussion of treatment modalities

Combined small cell carcinoma (SMCC) of the larynx consists of SMCC admixed with a component of squamous cell carcinoma or adenocarcinoma. These tumors are very rare and, to date, only a few cases have been fully described. This points out the lack of information available about the correct management of these patients. Here, we describe two additional cases of combined SMCC of the larynx that illustrate the difficulties that we can encounter to diagnose correctly these patients and, by consequence, to treat them adequately.

Histologically unique case of combined small cell and squamous cell carcinoma in a polypoid bronchial tumor

Presented herein is a case of combined small cell and squamous cell carcinoma in a polypoid bronchial tumor, showing a histologically unique progression, in a 76-year-old Japanese man. A bronchofiberscopic examination revealed that the bronchus (left B3) was occluded by the polypoid tumor. Biopsies were performed, and the pathological diagnosis was poorly differentiated squamous cell carcinoma. The patient consequently underwent a left upper lung lobectomy. The surgical specimen was described as a 24 x 8 x 8 mm soft tumor, emanating from the bronchial wall (left B3). Histologically, the tumor had two distinct components: (i) nearly the entire tumor was composed of atypical small round cells, with a high nuclear-cytoplasmic ratio, in the lamina propria, under the basement membrane; and (ii) the surface of the tumor was composed of poorly differentiated squamous cell carcinoma that had proliferated primarily above the basement membrane but there was also some proliferation, seen as island-like formations, below the basement membrane. The histological diagnosis was combined small cell and squamous cell carcinoma. It was suspected that poorly differentiated squamous cell carcinoma, generated in the bronchial epithelium, had caused small cell carcinoma resulting from neuroendocrine differentiation during its invasion into the lamina propria.

Combined small‐cell carcinoma of the stomach: p53 and K‐ras gene mutational analysis supports a monoclonal origin of three histological components

Primary small-cell carcinoma (SmCC) is extremely rare in stomach. We reported an autopsy case of combined gastric SmCC with p53 and K-ras mutational analysis. Histologically, the tumour was composed of well-differentiated adenocarcinoma surrounding the central dominant SmCC component with scattered nests of squamous cell carcinoma. Immunohistochemically, all the neoplastic components revealed strong expression for p53 protein. Based on these findings, we hypothesized that these histologically different components originated from a same progenitor cell that possessed p53 mutation. Using Laser-capture microdissection technique and mutational analysis, we identified the same point mutations of p53 gene (A-->G transversion in codon 239) and K-ras gene (G-->A transversion in codon 13) in all the neoplastic components, but not in the adjacent normal gastric epithelium. Our results strongly support a hypothesis that the combined SmCC of stomach in this case was of monoclonal origin.