Combined Small Cell Carcinoma Research Articles

Combined small-cell lung carcinoma.

Currently, studies assessing combined small-cell lung carcinoma (C-SCLC) are relatively scarce and limited. Indeed the clinicopathological features, treatment, and prognosis of patients with C-SCLC have not been fully determined. The incidence of C-SCLC ranges from 5%–28% in different studies, which is related to the specimen types used. The clinical features of C-SCLC are characterized by the higher proportion of peripheral locations, earlier stage, and more opportunity to experience surgery. Surgery is more important for earlier stage C-SCLC. There have been no recent changes in the chemotherapy of C-SCLC, which is recommended by the treatment guidelines for SCLC, neither showing survival benefit from the 3-agent regimen. Meanwhile, the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutated C-SCLC patients remains inconclusive. This review focuses on clinical and pathologic features, prognostic factors, and optimized treatment model in C-SCLC.

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

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

Clinical analysis of neuroendocrine carcinoma of the larynx

Objective:To evaluate the clinical manifestation, therapy and prognosis of neuroendocrine carcinoma of the larynx. Method:Twenty-six cases with neuroendocrine carcinoma of the larynx were analyzed retrospectively. Four pathological types were found in our series: typical carcinoid (1/26), atypical carcinoid (15/26), small cell carcinoma, neuroendocrine type (9/26) and combined small cell carcinoma, neuroendocrine type (1/26). In this series, 12 cases were received total laryngectomy, 2 cases supracricoid partial laryngectomy-cricohyoidopexy (SCPL-CHP), 4 cases horizontal partial laryngectomy, 5 cases vertical partial laryngectomy, 1 case transoral CO₂ laser microsurgery, and 2 cases radiotherapy and/or chemotherapy. Result:Three-year and five-year overall survival rates were 76.9% and 69.2% respectively. Conclusion:The neuroendocrine carcinoma of the larynx was rare, which was more common in the supraglottis. Atypical carcinoid was the most common pathological type. Compared to SCC, the clinical feature of neuroendocrine carcinoma of the larynx was non-specific. The clinical behavior, treatment,and prognosis were correlative to the tumor pathological.The diagnosis depended on comprehensive immunohistochemistry examination.

Combined small cell carcinoma with giant cell carcinoma component of the lung: A case successfully diagnosed by computed tomography-guided fine-needle aspiration cytology.

Combined small cell lung carcinoma (SCLC) is a rare variant of SCLC and is defined as a mixture of SCLC and non-SCLC components. Although any histopathological subtype may be present as a non-SCLC component, the presence of pleomorphic carcinoma components are extremely rare. The present report describes the first documented cytological features of combined SCLC with a giant cell carcinoma component. A 50-year-old Japanese female with a history of smoking presented with a mass lesion in the left lung. Computed tomography-guided fine-needle aspiration cytology and needle biopsy were performed, followed by a lobectomy. A Papanicolaou smear revealed the presence of two distinct neoplastic components in a necrotic background. One component was SCLC, which comprised small-sized neoplastic cells containing scant cytoplasm and round to oval nuclei with dispersed granular chromatin without nucleoli. The other component was giant cell carcinoma, which was composed of large-sized neoplastic cells containing irregular large hyperchromatic nuclei (approximately 7 to 10 times larger than those of SCLC). SCLC was demonstrated in the biopsy specimen, however no giant cell carcinoma component was present. Histopathological study of the lobectomy specimen verified a diagnosis of combined SCLC with giant cell carcinoma component. Both SCLC and giant cell carcinoma exhibit characteristic cytological features, therefore, albeit extremely rare, careful observation may lead to a correct diagnosis of combined SCLC in the cytological specimen.

PC 02.01 Thoracic Radiation - YES

Small cell lung cancer (SCLC) accounts for 15%–20% of all lung cancers, and the overwhelming majority (>95%) are associated with tobacco exposure. The incidence of all types of lung cancer, including SCLC, has been declining in the United States with the onset of tobacco smoking cessation programs, although this trend took nearly 20 years to become evident among men. Overall survival (OS) rates for patients with lung cancer have also increased by about 5% since the advent of low-dose spiral computed tomography (CT) scanning to detect early lung cancer. The prognosis for patients with SCLC continues to be poor but has improved with the advent of smoking cessation campaigns, more effective chemotherapy agents and radiation planning and delivery techniques, and the use of prophylactic cranial irradiation (PCI) for those who experience a complete response to therapy. Consolidation with chest radiotherapy has improved OS among patients with extensive-stage SCLC who achieved a complete response to chemotherapy. SCLC often presents as bulky symptomatic masses, and mediastinal involvement is common with or without pleural effusion and extrathoracic disease. Extrathoracic spread (i.e., extensive-stage disease) is also quite common, being present in 80%-85% of cases at diagnosis. Brain metastases are present in approximately 20% of patients at diagnosis; roughly half of these metastases are symptomatic and the other half are detected by imaging. Predictors of poor prognosis include poor performance status, older age, and being male. The pathologic subtypes of the disease (small cell carcinoma and combined small cell carcinoma) all carry a similarly poor prognosis. Current guidelines of the U.S. National Comprehensive Cancer Network recommend the use of positron emission tomography (PET), CT scanning, or fused PET/CT scanning of the chest, liver, adrenals, bone, and other areas of concern in the diagnosis and staging of SCLC (NCCN guideline-SCLC 2017). Thoracic radiotherapy has also become important for improving OS among patients with SCLC who achieved a complete response to chemotherapy. In one prospectively randomized study of 498 patients with extensive-stage SCLC (WHO performance status score 0-2) who achieved complete response to chemotherapy, patients who received consolidation thoracic radiotherapy (30 Gy in 10 fractions) had significantly better 2-year OS rates than did those who did not receive thoracic radiotherapy (13% vs. 3%, P=0.004). Thoracic radiotherapy further improved thoracic-only failure rates (19.8% vs. 46% without, P=0.001) (Slotman B et al, Lancet Oncol 2015;385:36-42). However, many patients with extensive-stage SCLC do not respond to the standard etoposide/cisplatin chemotherapy (Fig 1). Those patients may need to receive molecular-targeted therapies or immunotherapy with the consolidating thoracic radiotherapy. Several histologic and immunohistochemical markers have been evaluated for diagnosing or monitoring treatment response in SCLC, including transcription thyroid factor-1 (positive in >85% of SCLC cases); cytokeratin 7; deletions in chromosome 3; Leu-7; chromogranin A; synaptophysin; myc amplification; and p53 mutations (present in ∼75% of cases). Deletions in tumor-suppressor genes are also relatively common and include fragile histidine triad (FHIT) (80%); RAS effector homologue (RASSF1) (>90%); TP53 (>75%); retinoblastoma-1 (RB1) (>90%); and retinoic acid receptor-beta (72%). However, to date no biomarkers have been validated for use in diagnosing SCLC. Moreover, mutations that are often present in non-small cell lung cancer (such as epidermal growth factor receptor [EGFR] mutations and anaplastic lymphoma kinase [ALK]) are rare in SCLC. Several clinicopathologic features have been linked with worse prognosis, including poor performance status, significant weight loss, high lactate dehydrogenase levels, large numbers of metastatic sites, and the presence of paraneoplastic syndromes. Because SCLC has the among the highest rates of somatic driver mutations, and because more than 95% of patients with SCLC are former or current smokers, immunotherapy seems a reasonable approach, as high mutation burdens correlate with good response to chemoradiotherapy and sensitivity to immunomodulators (Peifer M et al., Nat Genet 2012;44(10):1104-10). At MD Anderson Cancer Center, an ongoing phase I/II study of patients with extensive-stage SCLC has been proposed to the NRG as a prospective randomized study (PI J Welsh) (Fig 2). Use of thoracic radiotherapy to consolidate a site at which SCLC is quite likely to recur is reasonable, given that recurrence considerably reduces quality of their life as well as OS. In summary, in most cases SCLC presents as extensive-stage disease, for which outcomes are very poor. Consolidation with thoracic radiotherapy for patients who achieve a complete response to chemotherapy can improve 2-year OS rates. However, less toxic and more effective systemic treatment is also required to derive the greatest benefit from consolidation thoracic radiotherapy. thoracic radiotherapy extensive small-cell lung cancer, immunotherapyFig 2View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Correlation between histone acetylation and expression of Notch1 in human lung carcinoma and its possible role in combined small-cell lung carcinoma

Combined small-cell lung carcinoma (cSCLC) is composed of small-cell lung carcinoma (SCLC) admixed with non-small-cell lung carcinoma (NSCLC). Evaluating the molecular differences between SCLC and NSCLC could lead to a better understanding of the pathogenesis of such neoplasms. Therefore, in this study, we investigated the correlation between histone acetylation and Notch1 expression in lung carcinoma. Using chromatin immunoprecipitation (ChIP) assay, we measured the level of acetylated histone H3 around the promoter region of Notch1 in SCLC and NSCLC cells. We then treated SCLC cells with trichostatin A (TSA) and characterized the level of histone H3 acetylation at Notch1. In addition, TSA-treated cells were injected into immune-compromised mice, for analysis of the ex vivo tumor xenograft phenotype. The level of acetylated histone H3 surrounding the Notch1 promoter was lower in lung cancer cells not expressing Notch1. Tumors originated from TSA-treated SCLC cells occasionally formed an epithelial-like glandular arrangement of cells; with Notch1 expression and decreased expression of neuroendocrine (NE) markers. Histone deacetylation around the promoter region of Notch1 inhibits Notch1 protein expression in SCLC and the restoration of Notch1 expression in SCLC leads to the concurrent appearance of epithelial-like areas within the SCLC, which could provide a possible mechanism for histogenesis of cSCLC.

Combined small cell lung carcinoma and giant cell carcinoma: a case report

BackgroundCombined small cell lung carcinoma (SCLC) is defined as SCLC combined with elements of non-small cell lung carcinoma (NSCLC), accounting for approximately 30% of cases of SCLC. However, combined SCLC and giant cell carcinoma (GC) is very rare.Case presentationA 50-year-old woman with a 45 pack-year smoking history was referred to our hospital for further investigation of an abnormal left hilar shadow. Chest computed tomography (CT) revealed a 28-mm solid pulmonary nodule in the left lower lobe and an enlarged left hilar lymph node adjacent to the left main pulmonary artery. CT-guided biopsy of the pulmonary nodule led to the diagnosis of high-grade neuroendocrine carcinoma. The preoperative clinical stage was defined as cT1bN1M0. Thus, the patient underwent left lower lobectomy with ND2a-2 lymph node dissection via thoracotomy. Pathological investigation revealed a 22-mm tumor and dense sheet-like growth of small tumor cells with scant cytoplasm and finely granular nuclear chromatin. Moreover, there was a sheet-like growth of bizarre, highly pleomorphic mono- or occasionally multinucleated giant cells, accounting for approximately 40% of the tumor. Both the small and giant cell components were thyroid transcription factor-1-positive and p40-negative and exhibited neuroendocrine differentiation, as indicated by positivity for synaptophysin and CD56 and negativity for chromogranin A. While the small cell component was E-cadherin-positive and vimentin-negative, the giant cell component was E-cadherin-negative and vimentin-positive, indicating an epithelial-to-mesenchymal transition. Only the small cell component was found within the mediastinal and hilar lymph nodes. The final pathological diagnosis was combined SCLC and GC, pT1bN2M0, and pStage IIIA. The patient received adjuvant chemotherapy with 4 cycles of cisplatin and irinotecan. No sign of recurrence has been noted for 1 year after the surgery.ConclusionsThis is the first detailed report of a unique case with combined SCLC and GC. The coexistence of SCLC and GC in the presented case might indicate several possibilities: (1) GC may arise from SCLC via epithelial-to-mesenchymal transition, (2) SCLC may arise from GC through phenotypic conversion, and (3) SCLC and GC may have derived from a common neuroendocrine origin. Further investigation is necessary to reveal the underlying pathological process.

The pitfalls in cytology diagnosis of poorly differentiated neuroendocrine carcinoma of lung and their treatment response.

Lung is the most common site of small cell carcinoma (SCLC) - a poorly differentiated neuroendocrine carcinoma (PDNEC). SCLC comprises 15-20% of the invasive cancers of the lung. This study was conducted to appraise the accuracy and pitfalls of the diagnosis of PDNEC on cytology along with treatment responses if available. Retrospective study for 2 years yielded 21 cases on cytology. Slides of fine-needle aspiration of lymph nodes, the tumor, bronchial brush, and bronchoalveolar lavage specimens were used. The histological correlation was obtained as were treatment responses. Eighteen SCLCs were confirmed on review. Of these, 13 initial reports were concordant and five, discordant. The rest three cases which initially reported as SCLC were found to be negative (2) and combined SCLC (1). One SCLC with concordant initial and reviewed diagnoses failed to confirm on histopathology. The patients, all heavy smokers, were predominantly males in the seventh to eighth decade age group. The sensitivity and specificity of reviewed diagnoses were better than that of the original. The difference between histopathology and cytology diagnoses (reviewed and original) was statistically insignificant. All patients were categorized as "extensive stage" by positron emission tomography-computerized tomography, and five were treated with etoposide and cisplatin with/without radiotherapy. Age group (61-70) and gender (males) distribution were statistically significant. Intermediate variants of SCLC may be misdiagnosed as adenocarcinoma. Similarly, combined SCLC may be missed on cytology if the observer does not sustain a high index of suspicion. Unequivocal cytology diagnosis opposed to negative histopathology report demands repeat biopsy.

頭頸部神経内分泌小細胞癌8症例の治療経験

Small cell neuroendocrine carcinoma of the head and neck is a rarely occurring poorly differentiated and high-grade malignant neoplasm characterized by highly active proliferation of neuroendocrine tumor cells. There are no established therapies for this disease. To clarify the clinical course and develop effective treatment(s) for the carcinoma, we reviewed the data of 8 patients of small cell neuroendocrine carcinoma of the head and neck treated by us between 2006 and 2014 at the Department of Otolaryngology, Gifu University School of Medicine and our affiliated hospitals. The patients consisted of 3 men and 5 women, ranging in age from 38 to 84 years old (mean : 60.9 years). The tumor arose from the nasal cavity or the paranasal sinuses in 3 cases, from the parotid grand in 2 cases, from the oropharynx in 2 cases, and from the hypopharynx in 1 case. The tumor that arose from the hypopharynx was a combined small-cell carcinoma with squamous cell carcinomas, and the one that arose from the oropharynx had already metastasized to the brain. Most of the patients were treated by chemotherapy and radiotherapy based on the treatment employed for small cell carcinoma of the lung. Only the patient in whom the tumor arose from a paranasal sinus was treated by surgery despite the definitive diagnosis of small cell carcinoma. We selected CPT-11 and a platinum agent for 4 patients, and VP-16 and a platinum agent for 3 patients as the first-line chemotherapy. Although two patients showed carcinoma-free survival, one died of recurrence of the regional lymph node metastases and five died of distant metastases despite the absence of locoregional recurrence. The 5-year survival rate was a dismal 25%, suggesting that we need to establish effective treatment(s) for the control of distant metastases in cases of the small cell neuroendocrine carcinoma of the head and neck.

Elucidating alternative pathways triggering small cell lung carcinoma tumor biology

In their recent perspective Ito et al . comprehensively reviewed the carcinogenesis of pure and combined small cell lung carcinoma (SCLC) (1) and we appreciate the explicit discussion of our article Meder et a l. “ NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas. ” (2).

Rare case of combined small cell lung cancer with adenocarcinoma and squamous cell carcinoma

Combined small cell lung cancer (cSCLC) is relatively unusual. We report a case of cSCLC in a 78-year-old man with no prior medical history who presented for evaluation of right upper lobe (RUL) lung mass. A CT scan showed a 3.0×2.5×2.3cm RUL lung mass with mildly prominent mediastinal and hilar lymphadenopathy. A right thoracotomy with right upper lobectomy and lymphadenectomy was performed. Histological examination and immunohistochemical stains confirmed the diagnosis of combined small cell lung carcinoma (SCLC) with adenocarcinoma (AC) and squamous cell carcinoma (SCC) components.While there are available guidelines for treating SCLC, the optimal treatment for cSCLC which will improve prognosis has not been adequately determined. We report a very rare category of primary lung malignant neoplasm to represent our institution's experience in diagnosing and managing this type of rare case.

Primary combined small and squamous cell carcinoma of the hypopharynx: A case report.

We herein report a very rare case of combined small-cell carcinoma (SmCC) of the hypopharynx, with a squamous cell carcinoma (SqCC) element. A 74-year-old man presented with a 3-month history of throat pain and hoarseness. On hypopharyngoscopy, a tumor was identified in the right anterior wall of the piriform sinus and, following examination of a biopsy sample, the lesion was diagnosed as SqCC. Total laryngectomy with bilateral neck dissection was performed and the malignancy was diagnosed as combined SmCC. One month after surgery, concomitant chemoradiotherapy with cisplatin and etoposide was administered. Immunohistochemically, the SmCC element was positive for CD56 and Ki-67 (50.2%), whereas the SqCC element was positive for cytokeratin 34βE12 and Ki-67 (47.5%). Furthermore, the SmCC element was positive for KIT and platelet-derived growth factor α (PDGFRα), while the SqCC element was positive for epidermal growth factor receptor (EGFR) and PDGFRα. By genetic analysis, a silent mutation in the PDGFRα gene was recognized. The expression of KIT, PDGFRα and EGFR in this case provided evidence that combined SmCC may be a candidate for molecular-targeted therapy, although further investigations are required.

ゲフィチニブ投与にて病勢の進行を緩和し得た非喫煙者の<i>EGFR</i>遺伝子変異陽性混合型小細胞肺癌の1例

症例．74歳の女性．胸部X線異常陰影の精査目的で当院紹介受診となった．全身精査の結果，小細胞肺癌（cT2N3M0，Stage IIIB，限局型）と診断され，同時放射線化学療法（カルボプラチン＋エトポシドを6コースと胸部放射線治療45 Gy/30 Fr）が施行され，治療効果はSDであった．その後は病勢コントロールされていたが，1年後に多発脳転移で再燃し当科入院となった．全脳照射（30 Gy/10 Fr）施行後，全身化学療法（カルボプラチン＋エトポシド）を施行したが，抗癌剤の副作用と原病進行のためPS 1から4まで悪化し，全身状態悪化を認めた．非喫煙者の小細胞癌で，初診断時の病理組織標本にて腺腔構造の形成が認められたことから，EGFR遺伝子検索を行ったところ活性型EGFR遺伝子変異（Exon21：L858R）が陽性であり，混合型小細胞肺癌の診断でゲフィチニブ内服治療が開始された．治療後PS 4から2に改善がみられ，退院が可能となった．最終的に原病の進行に伴う呼吸不全のため，ゲフィチニブ治療開始約2ヶ月後に死亡した．結論．ゲフィチニブ投与にて病勢の進行を緩和し得た非喫煙者のEGFR遺伝子変異陽性混合型小細胞肺癌の1例を経験した．全身化学療法施行困難なPS不良のEGFR変異陽性混合型肺小細胞癌において，ゲフィチニブは治療選択肢の一つとなり得る可能性が示唆された．

Implementing amplicon-based next generation sequencing in the diagnosis of small cell lung carcinoma metastases

Small cell lung carcinoma (SCLC) is the most aggressive entity of lung cancer. Rapid cancer progression and early formation of systemic metastases drive the deadly outcome of SCLC. Recent advances in identifying oncogenes by cancer whole genome sequencing improved the understanding of SCLC carcinogenesis. However, tumor material is often limited in the clinic. Thus, it is a compulsive issue to improve SCLC diagnostics by combining established immunohistochemistry and next generation sequencing.We implemented amplicon-based next generation deep sequencing in our routine diagnostics pipeline to analyze RB1, TP53, EP300 and CREBBP, frequently mutated in SCLC. Thereby, our pipeline combined routine SCLC histology and identification of somatic mutations. We comprehensively analyzed fifty randomly collected SCLC metastases isolated from trachea and lymph nodes in comparison to specimens derived from primary SCLC.SCLC lymph node metastases showed enhanced proliferation and frequently a collapsed keratin cytoskeleton compared to SCLC metastases isolated from trachea. We identified characteristic synchronous mutations in RB1 and TP53 and non-synchronous CREBBP and EP300 mutations.Our data showed the benefit of implementing deep sequencing into routine diagnostics. We here identify oncogenic drivers and simultaneously gain further insights into SCLC tumor biology.

Case Report: Combined Small Cell Lung Cancer in a Lung Transplant Recipient

Lung transplantation confers an increased risk of lung cancer, especially for single lung transplant recipients, due to both the epidemiologic risk factors associated with the patient population and the posttransplantation immunosuppression required. We report what we believe to be the first case of combined small cell lung carcinoma identified in the native lung of a single lung transplant recipient. Combined small cell lung cancer is an increasingly recognized subtype of small cell carcinoma, and its possible presence is an important consideration in the interpretation of fine-needle aspiration biopsies. In our case, initial fine-needle aspiration suggested squamous cell carcinoma, and it was only after lobectomy that the diagnosis of small cell carcinoma was made. The case highlights the increased risk of malignancy in lung transplant recipients and suggests a role for adaptation of lung cancer screening guidelines to address this high-risk population.

Combined small cell carcinoma of the sinonasal tract associated with syndrome of inappropriate secretion of antidiuretic hormone: A case report.

Combined small cell carcinoma (SmCC) and squamous cell carcinoma (SqCC) is a rare malignant neoplasm in the head and neck. This study presents the first reported case of combined SmCC and SqCC originating from the sinonasal tract accompanied by syndrome of inappropriate secretion of antidiuretic hormone (SIADH). An 80-year-old female presented with a four-week history of right nasal discharge, nasal obstruction and left neck swelling. Imaging studies revealed a tumorous lesion in the maxillary sinus encroaching upon the right nasal cavity and left cervical lymph node (LN) swelling. An incisional biopsy carried out from the right maxillary sinus and LNs resulted in a diagnosis of combined SmCC with SqCC, staged as T4aN2cM0. Clinical examination revealed a sustained increase of antidiuretic hormone, hyponatremia with urinary sodium increase, and serum hypo-osmosis, resulting in SIADH. Water restriction to <1,000 ml/day was effective in improving sodium and osmotic imbalance. Curative treatment for the tumor was not prescribed due to the poor condition of the patient. Palliative treatment was administered and the patient succumbed to cachexia five months after histological diagnosis. The presence of SIADH may have marked implications for the treatment and prognosis of this disease.

Combined small cell lung cancer originated from small pure ground-glass nodule—Long-term observation after computed tomography screening

Abstract Combined small cell lung cancer is relatively rare. We report a case of combined small cell lung carcinoma that was suspected to originate from a small pure ground-glass nodule; the tumor was detected during a computed tomography (CT) health screening and observed periodically over 4 years. Surgical resection was performed; histology showed features of both adenocarcinoma and small cell carcinoma. The tumor histogenesis was interesting. Our result suggested that if a solid component appeared as a pure ground-glass nodule, clinicians should pay attention to both the CT -value and the doubling time. Not miss the timing of surgical resection considering of possibility of combined small cell lung carcinoma.

Combined high‐grade neuroendocrine carcinoma of the lung: Clinicopathological and immunohistochemical study of 34 surgically resected cases

To understand the pathogenesis of high-grade neuroendocrine carcinoma (HGNEC), we examined the histopathology and immunoreactivity against adenocarcinoma (AD), squamous cell carcinoma (SQ), and neuroendocrine markers in 34 cases with combined HGNEC. The 5 year overall survival rates of patients with combined small cell carcinoma (SCC) (n = 9) and combined large cell neuroendocrine carcinoma (LCNEC) (n = 25) were 33% and 75%, respectively (P = 0.011). Most of the patients were male (94%), smokers (94%), and had tumors located in the peripheral (94%) and upper lobe (65%) of the lung. Histopathologically, non-HGNEC components were predominantly ADs (65%) followed by SQs (26%). In combined HGNEC and AD, a lepidic AD component was found in 12 cases (48%). For the HGNEC components of combined HGNEC and AD, the incidence of positivity of thyroid transcription factor-1 (TTF-1) (8G7G3/1) and TTF1 (SPT24) were 64% and 91%, respectively. For HGNEC components of combined HGNEC and SQ, the incidence of positivity of 34βE12 and p63 were 22% and 11%, respectively. In conclusion, 48% of combined HGNEC and AD cases had a lepidic AD component, suggesting that HGNEC can develop in association with pre-existing AD. AD markers, but not SQ markers, were frequently retained through development of the HGNEC component.

篩骨洞原発混合型小細胞癌の1例

篩骨洞原発混合型小細胞癌の1例

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.