Patient-derived tumoroid models of pulmonary large-cell neuroendocrine carcinoma: a promising tool for personalized medicine and developing novel therapeutic strategies.

Pulmonary large-cell neuroendocrine carcinoma (LCNEC), a disease with poor prognosis, is classified as pulmonary high-grade neuroendocrine carcinoma, along with small-cell lung cancer. However, given its infrequent occurrence, only a limited number of preclinical models have been established. Here, we established three LCNEC tumoroids for long-term culture. Whole-exome sequencing revealed that these tumoroids inherited genetic mutations from their parental tumors; two were classified as small-cell carcinoma (S-LCNEC) and one as non-small cell carcinoma (N-LCNEC). Xenografts from these tumoroids in immunodeficient mice mimicked the pathology of the parent LCNEC, and one reproduced the mixed-tissue types of combined LCNEC with a component of adenocarcinoma. Drug sensitivity tests using these LCNEC tumoroids enabled the evaluation of therapeutic agent efficacy. Based on translational research, we found that a CDK4/6 inhibitor might be effective for N-LCNEC and that Aurora A kinase inhibitors might be suitable for S-LCNEC or LCNEC with MYC amplification. These results highlight the value of preclinical tumoroid models in understanding the pathogenesis of rare cancers and developing treatments. LCNEC showed a high success rate in tumoroid establishment, indicating its potential application in personalized medicine.

Surgery versus radiotherapy for limited-stage small cell esophageal carcinoma: a multicenter, retrospective, cohort study in China (ChiSCEC).

BACKGROUND: There is no standard management for small cell esophageal carcinoma (SCEC). The purpose of this multicenter, retrospective study (ChiSCER) was to investigate the treatment, outcomes, and risk factors impacting survival endpoints in patients with limited-stage SCEC (LS-SCEC). MATERIALS AND METHODS: Consecutive patients with LS-SCEC from 14 institutions between 2000 and 2020 in China were enrolled. Survival curves were constructed using the Kaplan-Meier method and compared using a log-rank test. Univariate and multivariate Cox regression models and propensity score matching (PSM) analysis were adopted in the prognostic analysis. Results were reported as hazard ratio (HR), 95% confidence interval (CI), and P value. Statistical significance was set as P value <0.05 in a two-tailed test. RESULTS: Among 458 LS-SCEC patients, the median age was 63 [interquartile range (IQR), 57-68] years, and 318 (69%) were males. Eighty-four (18%), 167 (36%), and 207 (45%) patients received chemotherapy (CT) alone, CT plus definitive radiotherapy (CT+RT), and CT plus radical surgery (CT+S), respectively. With a median follow-up time of 58.7 (95% CI 48.9-68.6) months, the median overall survival (OS) and 3-year OS rate for all patients 24.3 (95% CI 21.6-27) months and 37.3% (95% CI 32.8-42.5%), respectively. Multivariate analysis indicated that treatment modes, Karnofsky performance status (KPS), TNM stage, and CT cycle were independent prognostic factors for OS ( P <0.05). Compared with CT alone, patients treated with CT+RT (HR 0.57, 95% CI 0.41-0.8, P =0.001) or CT+S (HR 0.59, 95% CI 0.42-0.82, P =0.002) had an improved OS, with no significant survival differences between CT+S and CT+RT groups after multivariate and PSM analyses ( P >0.05). Subgroup analysis indicated that compared with CT+RT, patients with tumor location at lower 1/3 (HR 0.59, 95% CI 0.37-0.93, P =0.03) or tumor length >5 cm (HR 0.52, 95% CI 0.3-0.9, P =0.02) could obtain significant OS benefit from CT+S. Patients with tumor location at middle 1/3 (HR 1.55, 95% CI 1.03-2.36, P =0.04) or tumor length ≤5 cm (HR 1.49, 95% CI 1.02-2.17, P =0.04) favored CT+RT. Distant metastasis accounted for 73.7% of all treatment failures after multidisciplinary treatments. CONCLUSION: Surgery and RT were equally effective local therapies for patients with LS-SCEC. The personalized decision of local therapy should be made after comprehensive considerations on tumor location, length, comorbidities, and organ preservation.

Clinical impact of mixed pulmonary carcinoma and carcinoid: the driver from their mono-clonal origin.

The combination of neuroendocrine/non neuroendocrine lung tumors (CNNELT) mentioned in the last edition of the World Health Organization (WHO) of Thoracic Tumors refers to small cell carcinoma (SCLC) or large cell neuroendocrine carcinoma (LCNEC) mixed with any other non-small cell lung carcinoma (NSCLC). Typical Carcinoid (TC)/Atypical Carcinoid (AC) combined with NSCLC is not included among this category. However, case reports of TC/AC combined with NSCLC have been described. We previously reported 2 cases of lung adenocarcinoma (LUA) mixed with carcinoid sharing mutations in both components supporting the hypothesis of a clonal origin. We extended our analysis to other four cases of mixed NSCLC-carcinoid by performing targeted-DNA and RNA-based NGS analysis in both primary and their paired lymph nodes metastasis. In all cases, LUA and AC components shared at least 1 common mutation (KRAS driver mutation p.Gly12Val in cases 1 and 3, AKAP13-RET fusion in case 2, and missense KRAS driver mutation p.Gly12Ala in case 4, reinforcing the hypothesis of a clonal origin. Moreover, the same mutation was detected in the metastasis constituted only by AC (cases 2 and 4). Although it is a rare malignancy in the lung, mixed LUA and TC/AC could be included among the histotypes for which a deep molecular characterization of both components is needed to identify the presence of potential druggable genetic alterations.

A Population-Based Study of Patients With Small Cell Carcinoma of the Ovary, Hypercalcemic Type, Encompassing a 30-Year Period.

CONTEXT.­: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and lethal tumor, characterized by hypercalcemia and early onset and associated with germline and somatic SMARCA4 variants. OBJECTIVE.­: To identify all known cases of SCCOHT in the Slovenian population from 1991 to 2021 and present genetic testing results, histopathologic findings, and clinical data for these patients. We also estimate the incidence of SCCOHT. DESIGN.­: We conducted a retrospective analysis of hospital medical records and data from the Slovenian Cancer Registry in order to identify cases of SCCOHT and obtain relevant clinical data. Histopathologic review of tumor samples with assessment of immunohistochemical staining for SMARCA4/BRG1 was undertaken to confirm the diagnosis of SCCOHT. Germline and somatic genetic analyses were performed using targeted next-generation sequencing. RESULTS.­: Between 1991 and 2021, we identified 7 cases of SCCOHT in a population of 2 million. Genetic causes were determined in all cases. Two novel germline loss-of-function variants in SMARCA4 LRG_878t1:c.1423_1429delTACCTCA p.(Tyr475Ilefs*24) and LRG_878t1:c.3216-1G>T were identified. At diagnosis, patients were ages 21 to 41 and had International Federation of Gynecology and Obstetrics, or FIGO, stage IA-III disease. Outcomes were poor, with 6 of 7 patients dying of disease-related complications within 27 months from diagnosis. One patient had stable disease for 12 months while receiving immunotherapy. CONCLUSIONS.­: We present genetic, histopathologic, and clinical characteristics for all cases of SCCOHT identified in the Slovenian population during a 30-year period. We report 2 novel germline SMARCA4 variants, possibly associated with high penetrance. We estimate the minimal incidence of SCCOHT to be 0.12 per 1 million per year.

A dramatic response to checkpoint inhibitor in a woman with small cell carcinoma of the hypercalcemic type of the ovary.

OBJECTIVE: We present the rare case of a 21 year old woman with small cell carcinoma of the right ovary of the hypercalcemic type with dramatic response to checkpoint inhibitor. METHODS: Case report. RESULTS AND CONCLUSIONS: Our patient, a 22-year old woman with small cell carcinoma of the hypercalcemic type with hepatic metastases, is currently 43 months under treatment with pembrolizumab. Last MRI revealed no viable liver metastases nor other signs of recurrence. This is the longest survival of a patient with small cell carcinoma of the ovary under therapy with checkpoint inhibitors reported in the literature so far. With this report we emphasize the importance of immunohistological testing for PD-L 1. Treating clinicians should keep off-label use of immune checkpoint blockade in mind when treating this highly aggressive tumor if all other treatment options fail.

Clonal Origin and Lineage Ambiguity in Mixed Neuroendocrine Carcinoma of the Uterine Cervix.

Small-cell neuroendocrine carcinoma (SCNEC) of the cervix is a rare disease characterized by a high incidence of mixed tumors with other types of cancer. The mechanism underlying this mixed phenotype is not well understood. This study established a panel of organoid lines from patients with SCNEC of the cervix and ultimately focused on one line, which retained a mixed tumor phenotype, both in vitro and in vivo. Histologically, both organoids and xenograft tumors showed distinct differentiation into either SCNEC or adenocarcinoma in some regions and ambiguous differentiation in others. Tracking single cells indicated the existence of cells with bipotential differentiation toward SCNEC and adenocarcinomas. Single-cell transcriptional analysis identified three distinct clusters: SCNEC-like, adenocarcinoma-like, and a cluster lacking specific differentiation markers. The expression of neuroendocrine markers was enriched in the SCNEC-like cluster but not exclusively. Human papillomavirus 18 E6 was enriched in the SCNEC-like cluster, which showed higher proliferation and lower levels of the p53 pathway. After treatment with anticancer drugs, the expression of adenocarcinoma markers increased, whereas that of SCNEC decreased. Using a reporter system for keratin 19 expression, changes in the differentiation of each cell were shown to be associated with the shift in differentiation induced by drug treatment. These data suggest that mixed SCNEC/cervical tumors have a clonal origin and are characterized by an ambiguous and flexible differentiation state.

Case series of ovarian neuroendocrine carcinoma: overview of clinicopathological features.

BACKGROUND: Ovarian neuroendocrine carcinoma (O-NEC) is a relatively uncommon neoplasm, and the current knowledge regarding its diagnosis and management is limited. In this series, our objective was to provide an overview of the clinicopathological characteristics of the disease by analyzing clinical case data to establish a theoretical foundation for the diagnosis and management of O-NEC. CASE PRESENTATION: We included three patients in the present case series, all of whom were diagnosed with primary O-NEC based on pathomorphological observation and immunohistochemistry. Patient 1 was a 62-year-old patient diagnosed with small cell carcinoma (SCC) of the pulmonary type. Post-surgery, the patient was diagnosed with stage II SCC of the ovary and underwent standardized chemotherapy; however, imaging examinations conducted at the 16-month follow-up revealed the existence of lymph node metastasis. Unfortunately, she passed away 21 months after the surgery. The other two patients were diagnosed with carcinoid tumors, one at age 39 and the other at age 71. Post-surgery, patient 2 was diagnosed with a carcinoid in the left ovary, whereas patient 3 was diagnosed with a carcinoid in her right ovary based on clinical evaluation. Neither of the cases received adjuvant therapy following surgery; however, they have both survived for 9 and 10 years, respectively, as of date. CONCLUSION: Primary O-NECs are rare and of diverse histological types, each of which has its own unique biological features and prognosis. SCC is a neoplasm characterized by high malignancy and a poor prognosis, whereas carcinoid tumors are of lesser malignancy and have a more favorable prognosis.

Novel Mouse Cell Lines and In Vivo Models for Human High-Grade Neuroendocrine Lung Carcinoma, Small Cell Lung Carcinoma (SCLC), and Large Cell Neuroendocrine Carcinoma (LCNEC).

There is a clear need to expand the toolkit of adequate mouse models and cell lines available for preclinical studies of high-grade neuroendocrine lung carcinoma (small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC)). SCLC and LCNEC are two highly aggressive tumor types with dismal prognoses and few therapeutic options. Currently, there is an extreme paucity of material, particularly in the case of LCNEC. Given the lack of murine cell lines and transplant models of LCNEC, the need is imperative. In this study, we generated and examined new models of LCNEC and SCLC transplantable cell lines derived from our previously developed primary mouse LCNEC and SCLC tumors. RNA-seq analysis demonstrated that our cell lines and syngeneic tumors maintained the transcriptome program from the original transgenic primary tumor and displayed strong similarities to human SCLC or LCNEC. Importantly, the SCLC transplanted cell lines showed the ability to metastasize and mimic this characteristic of the human condition. In summary, we generated mouse cell line tools that allow further basic and translational research as well as preclinical testing of new treatment strategies for SCLC and LCNEC. These tools retain important features of their human counterparts and address the lack of LCNEC disease models.

Small Cell Neuroendocrine Carcinoma of the Parotid Gland: An Uncommon Example of Incompletely Encapsulated Tumor Including S100 Protein-Positive Clear Cells.

Small cell carcinoma is rare in salivary glands and has recently been termed small cell neuroendocrine carcinoma. We herein describe an uncommon example arising in the parotid gland. The patient was a 75 yearold Japanese male who had swelling in the right parotid area. He underwent a superficial lobectomy and, after a histological diagnosis was made, a total parotidectomy. Histologically, the tumor had a thick hyalinized capsule that was incomplete, beyond which the tumor invaded into the surrounding parotid parenchyma. The tumor consisted of typical small basophilic cells intermingled with bland clear cells, between which a gradual transition was observed both inside and outside the capsule. Small basophilic cells were immunoreactive for chromograninA as well as synaptophysin, while clear cells were positive for S100 protein. The Ki-67 labeling rate reached 30-40% at the high points of small basophilic cells, but clear cells were minimally labelled. The present case was considered a dedifferentiated carcinoma of the parotid gland, possibly with acinic cell carcinoma as a precursor. This tumor could also be considered a "mixed exocrine-endocrine carcinoma," which may explain the histogenesis of neuroendocrine carcinomas in non-endocrine organs that are not included in the diffuse (dispersed) neuroendocrine system, such as the parotid gland.

[Small cell neuroendocrine carcinoma of the endometrium]. / Melkokletochnaya neiroendokrinnaya kartsinoma endometriya.

The article describes a rare case of small cell neuroendocrine carcinoma of the endometrium in a 67-year-old woman. According to the literature, only about 90 such observations have been described worldwide. Histological examination revealed three necessary features: the small-cell nature of the tumor, the presence of epithelial and neuroendocrine markers. An IHC study revealed a positive expression of Syn, Chrom A, CD56, CK AE1/AE3 markers; the proliferative activity index was 70%.

Metastatic Small Cell Carcinoma of a Male Breast: A Case Report and Review of the Literature.

Neuroendocrine breast cancers are rare tumors that were recognized as a distinct entity by WHO classification in 2003. It is much rarer in male breast cancer. Diagnosis is based on immunochemical analysis in which the expression of at least one neuroendocrine marker is required, associated with the exclusion of another primary site of the tumor. These tumors have a worse long-term outcome compared to other breast cancers. Small cell carcinoma of the breast is a high-grade subtype, presents with more advanced disease, and has a poorer prognosis compared with other neuroendocrine breast subtypes. A proper therapeutic strategy is still not well established. In the herein reported case, a 62-year-old male patient was diagnosed with small cell neuroendocrine carcinoma of the breast, metastatic to the liver, lung, bone and lymph node, and was treated with a first-line Platinum-Etoposide chemotherapy combination with a good clinical and radiological response. Only four previous cases of male small cell breast carcinoma were reported. Keywords: Neuroendocrine Breast Carcinoma, Small Cell Carcinoma, Diagnosis, Prognosis, Treatment.

The prognosis of patients with small cell carcinoma of the cervix: a retrospective study of the SEER database and a Chinese multicentre registry.

BACKGROUND: Small cell carcinoma of the cervix is a rare but poor prognosis pathological type of cervical cancer, for which advice in clinical guidelines is unspecific. We therefore aimed to investigate the factors and treatment methods that affect the prognosis of patients with small cell carcinoma of the cervix. METHODS: In this retrospective study, we collected data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries cohort and a Chinese multi-institutional registry. The SEER cohort included females diagnosed with small cell carcinoma of the cervix between Jan 1, 2000, and Dec 31, 2018, whereas the Chinese cohort included women diagnosed between Jun 1, 2006, and April 30, 2022. In both cohorts, eligibility was limited to female patients older than 20 years with a confirmed diagnosis of small cell carcinoma of the cervix. Participants who were lost to follow-up or those for whom small cell carcinoma of the cervix was not the primary malignant tumour were excluded from the multi-institutional registry, and those with an unknown surgery status (in addition to those for whom small cell carcinoma of the cervix was not the primary malignant tumour) were excluded from the SEER data. The primary outcome of this study was overall survival (length of time from the date of first diagnosis until the date of death from any cause, or the last follow-up). Kaplan-Meier analysis, propensity score matching, and Cox-regression analyses were used to assess treatment outcomes and risk factors. FINDINGS: 1288 participants were included in the study; 610 in the SEER cohort and 678 in the Chinese cohort. Both univariable and multivariable Cox regression analysis (SEER hazard ratio [HR] 0·65 [95% CI 0·48-0·88], p=0·0058; China HR 0·53 [0·37-0·76], p=0·0005) showed that surgery was associated with a better prognosis. In subgroup analyses, surgery remained a protective factor for patients with locally advanced disease in both cohorts (SEER HR 0·61 [95% CI 0·39-0·94], p=0·024; China HR 0·59 [0·37-0·95]; p=0·029). Furthermore, the protective effect of surgery was observed among patients with locally advanced disease after propensity score matching in the SEER cohort (HR 0·52 [95% CI 0·32-0·84]; p=0·0077). In the China registry, surgery was associated with better outcomes in patients with stage IB3-IIA2 cancer (HR 0·17 [95% CI 0·05-0·50]; p=0·0015). INTERPRETATION: This study provides evidence that surgery improves outcomes of patients with small cell carcinoma of the cervix. Although guidelines recommend non-surgical methods as first-line treatment, patients with locally advanced disease or stage IB3-IIA2 cancer might benefit from surgery. FUNDING: The National Key R&D Program of China and the National Natural Science Foundation of China.

Primary Ovarian Small Cell Carcinoma of Pulmonary Type: Analysis of 6 Cases and Review of 31 Cases in the Literatures.

Objective Primary ovarian small cell carcinoma of pulmonary type (SCCOPT) is a rare ovarian tumor with a poor prognosis. The platinum-based chemotherapy is the standard treatment. However, there is little research on the clinical characteristics of SCCOPT and the potential benefits of other treatments due to its low incidence. The study aims to investigate clinicopathological characteristics and treatment of SCCOPT.Methods We summarized the clinical, imaging, laboratorical and pathological characteristics of 37 SCCOPT cases, in which 6 cases were admitted to the Gansu Provincial Hospital from the year of 2008 to 2022 and 31 cases reported in 17 English and 3 Chinese literatures.Results The median age of the studied SCCOPT cases (n=37) was 56.00 (range, 22-80) years. Almost 80% of them had a stage Ⅲ or Ⅳ tumor. All patients underwent an operation and postoperative chemotherapy. Nevertheless, all cases had a poor prognosis, with a median overall survival time of 12 months. Immunohistochemically, the SCCOPT of all patients showed positive expressions of epithelial markers, such as CD56 and sex-determining region of Y chromosome-related high-mobility-group box 2 (SOX-2), and negative expressions of estrogen receptor, progesterone receptor, vimentin, Leu-7, and somatostatin receptor 2. The tumor of above 80% cases expressed synaptophysin. Only a few cases expressed neuron-specific enolase, chromogranin A, and thyroid transcription factor-1. Conclusions SCCOPT had a poor prognosis. SOX-2 could be a biomarker to be used to diagnose SCCOPT.

Undifferentiated component of dedifferentiated endometrial carcinoma presenting as a "small round cell" malignancy in a mediastinal lymph node, mimicking small cell carcinoma.

Undifferentiated/dedifferentiated endometrial carcinoma is an uncommon malignant neoplasm of the endometrium that can present as a diagnostic challenge, especially in a metastatic setting. We present a case of a 70-year-old woman with a prior endometrial biopsy diagnosed as endometrioid carcinoma, FIGO Grade 2. Chest computerized tomography showed moderate to severe centrilobular emphysema with a 3 mm nodule in the right upper lobe and posterior mediastinal lymphadenopathy. Fine needle aspiration smears of the mediastinal lymph node showed predominantly single and loosely cohesive tumor cells with scant basophilic cytoplasm, prominent nuclear streaking, and molding. Inconspicuous nucleoli and mitotic figures were present. Immunohistochemical (IHC) stains showed the tumor cells were positive for CD56 and synaptophysin but negative for AE1/AE3, CAM5.2, CK7, CK20, TTF-1, INSM1, chromogranin, CD99, HMB45, SOX10, EBV-LMP1, and desmin. Flow cytometry was negative for lymphoma. Based on the overall cytologic findings and significant smoking history, a small cell carcinoma could not be excluded. Similar morphologic findings were identified on the corresponding lymph node biopsy. Because of the history of endometrial carcinoma, additional IHC stains (PAX 8, ER, and EMA) were done but were negative. However, the mismatch repair proteins revealed loss of MLH1 and PMS2 with retained MSH2 and MSH6 nuclear expression. Hence, a metastatic undifferentiated component of a dedifferentiated carcinoma from the patients' endometrial primary was favored and subsequently confirmed on the hysterectomy specimen.

Desmoplastic Small Round Cell Tumor Involving Serous Fluid: Cytologic Features and Diagnostic Pitfalls: A Series of 8 Cases.

OBJECTIVES: When desmoplastic small round cell tumor (DSRCT) is present in serous fluid, the cytomorphology can be diverse and can mimic metastatic carcinomas and thus present a diagnostic challenge. The aim of this study was to evaluate the cytomorphologic and immunocytochemical features of this rare tumor in serous effusion specimens. METHODS: Demographic, clinical, radiologic, and pathologic information from patients who had a DSRCT diagnosis on body fluid specimens was collected and cytologic slides were reviewed. RESULTS: Nine specimens were identified (5 pleural fluid and 4 ascitic fluid specimens) from 8 patients (5 male and 3 female). The mean patient age at diagnosis was 26 years. The most common symptoms were abdominal distension and pain, with 5 patients having abdominal masses. Other findings included peritoneal carcinomatosis, liver masses, ascites, and pleural nodules. The predominant cytomorphology was loose cellular clusters, followed by tight clusters of small cells with scant occasional vacuolated cytoplasm and a sphere-like pattern. CONCLUSIONS: Serous fluid may be the first available specimen to diagnose DSRCT. In young patients with no history of malignancy and radiologic finding of peritoneal implants, DSRCT should be considered a possibility in the differential diagnosis, and sensitive markers should be used for accurate diagnosis.

Systemic treatment for neuroendocrine non-small cell lung carcinoma: A cases series and a systematic review of the literature.

INTRODUCTION: Neuroendocrine lung cancer constitutes a continuum from carcinoid tumours (CT) to large cell neuroendocrine (LCNEC) and small-cell carcinomas (SCLC). Except for SCLC, there is no consensual agreement on systemic therapy. The aim of this study is to review our clinical experience among patients with CT and LCNEC in the light of a systematic review of the literature. METHODS: A retrospective study of all patients with CT and LCNEC receiving a systemic therapy at Institut Jules Bordet and Erasme Hospital between 01/01/2000-31/12/2020. A systematic review of the literature was performed in Ovid Medline. RESULTS: 53 patients (21 CT and 32 LCNEC) were included. Despite limited response rates, patients with CT receiving a "carcinoid-like" 1st-line regimen (somatostatin analogues (SSA), everolimus, peptide receptor radionuclide therapy (PRRT)) had a numerically longer survival compared to those receiving other type of regimens (median 51.4 vs 18.6 months, respectively; p = 0.17). We observed a similar survival between 1st line "SCLC-like" vs "non-small cell lung cancer (NSCLC)-like" schemes in LCNEC (median 11.2 vs 12.6 months, respectively; p = 0.46). The systematic review identified 23 studies (12 prospective, 15 and 8 for CT and LCNEC respectively). For CT, everolimus and SSA led to prolonged disease control with an acceptable toxicity profile, while higher response rates but lower tolerance were associated with PRRT and chemotherapy regimens including oxaliplatine and dacarbazine. For LCNEC, no difference emerged when comparing "SCLC-like" and "NSCLC-like" regimens considering response rate, progression-free or overall survival. CONCLUSIONS: SSA, everolimus and PRRT present a good therapeutic index for CT, while the role of chemotherapy remains limited to aggressive and rapidly evolving CT. The best type of chemotherapy regimen remains an open question in LCNEC.

Primary Cilia Are Frequently Present in Small Cell Lung Carcinomas but Not in Non-Small Cell Lung Carcinomas or Lung Carcinoids.

Most human malignant neoplasms show loss of primary cilia (PC). However, PC are known to be retained and involved in tumorigenesis in some types of neoplasms. The PC status in lung carcinomas remains largely uninvestigated. In this study, we comprehensively assessed the PC status in lung carcinomas. A total of 492 lung carcinomas, consisting of adenocarcinomas (ACs) (n = 319), squamous cell carcinomas (SCCs) (n = 152), and small cell lung carcinomas (SCLCs) (n = 21), were examined by immunohistochemical analysis using an antibody against ARL13B, a marker of PC. The PC-positive rate was markedly higher in SCLCs (81.0%) than in ACs (1.6%) and SCCs (7.9%). We subsequently performed analyses to characterize the PC-positive lung carcinomas further. PC-positive lung carcinomas were more numerous and had longer PC than normal cells. The presence of PC in these cells was not associated with the phase of the cell cycle. We also found that the PC were retained even in metastases from PC-positive lung carcinomas. Furthermore, the hedgehog signaling pathway was activated in PC-positive lung carcinomas. Because ARL13B immunohistochemistry of lung carcinoids (n = 10) also showed a statistically significantly lower rate (10.0%) of PC positivity than SCLCs, we searched for a gene(s) that might be upregulated in PC-positive SCLCs compared with lung carcinoids, but not in PC-negative carcinomas. This search, and further cell culture experiments, identified HYLS1 as a gene possessing the ability to regulate ciliogenesis in PC-positive lung carcinomas. In conclusion, our findings indicate that PC are frequently present in SCLCs but not in non-SCLCs (ACs and SCCs) or lung carcinoids, and their PC exhibit various specific pathobiological characteristics. This suggests an important link between lung carcinogenesis and PC.