Small Cell Carcinoma Of Cervix Research Articles

Abstract 5531: Loss of csf2(gm-csf) with cisplatin treatment decreases metastasis and improves survival in a hpv positive head and neck cancer murine model

Abstract Granulocyte macrophages colony stimulating factor (GM-CSF) also known as CSF2 is a popular cytokine responsible for homeostasis. According to TCGA databank CSF2 expression upregulated in human HPV+ (Human Papilloma Virus) Head and Neck Small Cell Carcinoma (HNSCC) compared to normal tissue. The mechanism of CSF2 in tumor progression and chemo resistance has not been well studied. Previously, our lab generated a murine model of HPV+ HNSCC that is partially responsive to cisplatin and radiation (like human disease). The role of our study is to evaluate the importance of Csf2 with cisplatin treatment (CT) in HPV + HNSCC in the murine model. Using CRISPR-Cas9 technology we knocked out the expression of the Csf2 ligand in our parental mEERL (murine E6 E7 Ras Luciferase) tumor cell line and implanted both the parental mEERL tumor and the Csf2 KO mEERL tumor in the oral cavity of C57BL6/J mice. When tumors reached a palpable size, we administered Cisplatin (20mg/m2, 3 doses total). We observed slow tumor growth in absence of Csf2 without treatment. On the other hand, we observed tumor regression in both tumor models with cisplatin treatment. Post treatment, mice with Csf2 KO tumors had a significantly prolonged rate of survival. To evaluate the role of Csf2 in the Tumor Microenvironment (TME), we collected the tumors 96 hours post CT and characterized the TME using multicolored flow cytometry. The results showed that post treatment mice with Csf2 KO tumors increased the number of the Natural Killer cell population and a surge of M-MDSC (Ly6Chi) population. The synergistic effect of knocking out Csf2 and cisplatin treatment in our tumor model appears to be driven by chemokine and cytokine changes in the TME. Simultaneously, we observed significantly lower levels of lung metastasis in Csf2 KO tumor bearing mice compared to those with parental mEERL tumors. Whereas we have seen increased metastasis in ipsilateral lymph node of Csf2 KO mice. This metastasis data mimics human disease where many patients have regional lymph node involvement, but few develop distant metastasis. These results indicate that GM-CSF (CSF2) in the TME could be an excellent target that would cause less metastasis and improved overall survival. Further investigations are needed to understand the underlying mechanism of immune response in the absence of CSF2 in the TME. Citation Format: Payal Ghosh, Craig Welbon, William C. Spanos. Loss of csf2(gm-csf) with cisplatin treatment decreases metastasis and improves survival in a hpv positive head and neck cancer murine model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5531.

Quantitative proteomics analysis in small cell carcinoma of cervix reveals novel therapeutic targets

BackgroundAs a rare pathologic subtype, small cell carcinoma of the cervix (SCCC) is characterized by extensive aggressiveness and resistance to current therapies. To date, our knowledge of SCCC origin and progression is limited and sometimes even controversial. Herein, we explored the whole-protein expression profiles in a panel of SCCC cases, aiming to provide more evidence for the precise diagnosis and targeting therapy.MethodsEighteen SCCC samples and six matched normal cervix tissues were collected from January 2013 to December 2017. Data independent acquisition mass spectrometry (DIA) was performed to discriminate the different proteins (DEPs) associated with SCCC. The expression of CDN2A and SYP in corresponding SCCC tissues was verified using immunohistochemistry. GO and KEGG enrichment analyses were used to identify the key DEPs related to SCCC development and tumor recurrence.ResultsAs a result, 1311 DEPs were identified in SCCC tissues (780 up-regulated and 531 down-regulated). In up-regulated DEPs, both GO analysis and KEGG analysis showed the most enriched were related to DNA replication (including nuclear DNA replication, DNA-dependent DNA replication, and cell cycle DNA replication), indicating the prosperous proliferation in SCCC. As for the down-regulated DEPs, GO analysis showed that the most enriched functions were associated with extracellular matrix collagen-containing extracellular matrix. KEGG analysis revealed that the DEPs were enriched in Complement and coagulation cascades, proteoglycans in cancer, and focal adhesion-related pathways. Down-regulation of these proteins could enhance the mobility of cancer cells and establish a favorable microenvironment for tumor metastasis, which might be accounted for the frequent local and distant metastasis in SCCC. Surprisingly, the blood vessels and circulatory system exhibit a down-regulation in SCCC, which might be partly responsible for its resistance to anti-angiogenic regimens. In the stratification analysis of early-stage tumors, a group of enzymes involved in the cancer metabolism was discriminated in these recurrence cases.ConclusionsUsing quantitative proteomics analysis, we first reported the whole-protein expression profiles in SCCC. Significant alterations were found in proteins associated with the enhancement of DNA replication and cellular motility. Besides the association with mitosis, a unique metabolic feature was detected in cases with tumor recurrence. These findings provided novel targets for disease surveillance and treatments, which warranted further validation in the future.

Head and neck small-cell carcinoma: A multicenter study of 39 cases from 10 institutions.

Basal information of head and neck small-cell carcinoma (HNSmCC) including epidemiology, primary site, treatment, and prognosis remains sparse due to its rarity. We report here a multicenter retrospective study on the diagnosis, treatment, and outcomes of patients with HNSmCC. This study involved 47 patients with HNSmCC from 10 participating institutions. Eight patients were excluded for whom no pathological specimens were available (n = 2) and for discrepant central pathological judgements (n = 6). The remaining 39 patients were processed for data analysis. As pretreatment examinations, computed tomography (CT) was performed for the brain (n = 8), neck (n = 39), and chest (n = 32), magnetic resonance imaging (MRI) for the brain (n = 4) and neck (n = 23), positron emission tomography-CT (PET-CT) in 23 patients, bone scintigraphy in 4, neck ultrasonography in 9, and tumor markers in 25. Primary sites were oral cavity (n = 1), nasal cavity/paranasal sinuses (n = 16), nasopharynx (n = 2), oropharynx (n = 4), hypopharynx (n = 2), larynx (n = 6), salivary gland (n = 3), thyroid (n = 2), and others (n = 3). Stages were II/III/IV-A/IV-B/IV-C/Not determined = 3/5/16/6/5/4; stage IV comprised 69%. No patient had brain metastases. First-line treatments were divided into 3 groups: the chemoradiotherapy (CRT) group (n = 27), non-CRT group (n = 8), and best supportive care group (n = 4). The CRT group included concurrent CRT (CCRT) (n = 17), chemotherapy (Chemo) followed by radiotherapy (RT) (n = 5), and surgery (Surg) followed by CCRT (n = 5). The non-CRT group included Surg followed by RT (n = 2), Surg followed by Chemo (n = 1), RT alone (n = 2), and Chemo alone (n = 3). The 1-year/2-year overall survival (OS) of all 39 patients was 65.3/53.3%. The 1-year OS of the CRT group (77.6%) was significantly better compared with the non-CRT group (31.3%). There were no significant differences in adverse events between the CCRT group (n = 22) and the Chemo without concurrent RT group (n = 9). Neck and chest CT, neck MRI, and PET-CT would be necessary and sufficient examinations in the diagnostic set up for HNSmCC. CCRT may be recommended as the first-line treatment. The 1-year/2-year OS was 65.3%/53.3%. This study would provide basal data for a proposing the diagnostic and treatment algorithms for HNSmCC.

Small Cell Carcinoma of the Head and Neck: Update on the University of Florida Experience

We updated the University of Florida experience treating head and neck small cell carcinoma. Eight patients received a median of 67.7 Gy between 1989 and 2017. The 2-year rates of local, regional, distant, and disease control were 73, 60, 33, and 13%, respectively. The 2-year overall survival rate was 38%; median survival was 1.4 years. The longest disease-free period was 9.5 years after treatment with no evidence of disease. Radiotherapy is an acceptable treatment for these patients, who tend to have poor outcomes and distant metastatic disease. Superior systemic chemotherapy may improve outcomes and decrease the likelihood of distant recurrence.

Optimal treatment strategies for small cell carcinoma of the uterine cervix: A retrospective multi-center study (KROG 19-03)

ObjectiveThis multi-institutional study aimed to identify the optimal treatment strategy for small cell carcinoma of the cervix. Study designWe retrospectively collected the medical records of 166 patients diagnosed with small cell carcinoma of the uterine cervix from January 2000 to December 2015 from 13 institutions of the Korean Radiation Oncology Group. After excluding 18 (10.8 %) patients who initially had distant metastasis, the treatment outcomes of 148 patients were analyzed. ResultsAfter a median 46.4 (1.4–231.9) months of follow-up, the 5-year progression-free survival (PFS) and overall survival (OS) rates of all patients were 45.9 % and 63.5 %, respectively. Distant metastasis was the dominant pattern of failure occurring in 67 patients (45.3 %). We stratified the patients according to the primary local treatment: primary surgery (n = 119), primary radiotherapy (RT) (n = 26), and no local treatment group (n = 3). Although the primary RT group had advanced disease (FIGO stage ≧ IIB) more frequently than the primary surgery group (80.8 % vs. 47.9 %), the PFS and OS did not differ between the groups in multivariate analysis. ConclusionDefinitive RT is a reasonable local treatment option for small cell cervical cancer, particularly for advanced cases. Given the high rates of distant relapse, an effective systemic therapy protocol is warranted for small cell cervical cancer patients.

Clinicopathological characteristics, treatment and prognosis of head & neck small cell carcinoma: a SEER population-based study

BackgroundTo investigate the clinicopathological characteristics of head and neck small cell carcinoma (H&NSmCC) and identify prognostic factors on the basis of the Surveillance, Epidemiology and End Results (SEER) database.MethodsTotal of 789 primary cases from 1973 to 2016 were included. Univariate and multivariate analyses were performed to identify independent prognostic indicators. An H&NSmCC-specific nomogram was constructed and compared with the AJCC staging system by calculating the time-dependent area under the curve (AUC) of the receiver operating characteristic (ROC) curves.ResultsThe incidence of H&NSmCC peaked during the period of 50 to 70 years old, and the most frequent location was the salivary gland. The 5-year disease specific survival (DSS) was 27%. In the multivariate survival analysis, AJCC III + IV stage [HR = 2.5, P = 0.03, I + II stage as Ref], positive N stage [HR = 1.67, P = 0.05, negative N stage as Ref], positive M stage [HR = 4.12, P = 0.000, negative M stage as Ref] and without chemotherapy [HR = 0.56, P = 0.023, received chemotherapy as Ref] were independently associated with DSS. The H&NSmCC-specific nomogram was built based on the independent prognostic indicators. The nomogram demonstrated better predictive capacity than the AJCC staging system for 5-year DSS [(AUC: 0.75 vs 0.634; Harrell’s C-index (95% CI): 0.7(0.66–0.74) vs 0.59(0.55–0.62), P < 0.05].ConclusionN stage, M stage, AJCC stage and chemotherapy were independent prognostic indicators included in the prognostic nomogram model, which can better predict the survival of H&NSmCC than the AJCC staging system.

Small Cell Carcinoma of the Cervix: A Retrospective Clinicopathologic Analysis Over a Period of 3 Years in a Referral Laboratory in India

Small cell neuroendocrine carcinoma of the cervix is rare, constituting less than 2% of all invasive cervical malignancies. It has a poor prognosis due to aggressive clinical course with high propensity for nodal and distant metastasis leading to mortality. Although it is known to be a chemosensitive tumor, till date no definite treatment modality has been entirely successful. Six cases diagnosed as small cell carcinoma of cervix over a period of 3 years were included in the study. Formalin-fixed paraffin-embedded tissue was subjected to hematoxylin and eosin (H&E) staining and microscopic examination. This was followed by a panel of immunohistochemical markers including synaptophysin, chromogranin, non-specific enolase (NSE), cytokeratin (CK), CD56 and Ki67 essential for diagnosis. The clinical and morphological profile in all the cases was then evaluated. Out of total 265 cervical malignancies reported, six cases (2.3%) were diagnosed as small cell carcinoma. The median age at the time of diagnosis was 49 years (range 28–67 years). All patients presented with irregular vaginal bleeding, with or without lower abdominal pain. Radiological scans revealed a mass in the cervix. Histopathological examination revealed a tumor arranged in diffuse sheets exhibiting high N/C ratio and stippled chromatin. Immunohistochemical markers employed were positive for CK, synaptophysin, chromogranin and NSE and negative for p40, CK5/6 and CD45 in all the cases. Small cell carcinoma of cervix is a rare malignancy. Because of the high rates of nodal involvement even with early-stage disease, multimodality treatment with radiotherapy and chemotherapy should be considered.

Two cases of recurrent small-cell carcinoma of the uterine cervix treated with amrubicin as salvage chemotherapy

Small-cell carcinoma of the cervix (SCCC) is a rare and aggressive tumor; however, no definitive treatment guidelines for SCCC exist. A review of case series revealed that the most frequently used first-line chemotherapy regimen is combination etoposide and cisplatin, which is also used for small-cell lung cancer (SCLC). For recurrent SCLC, the utility of amrubicin (AMR) has recently been reported. However, optimal second-line chemotherapy for recurrent SCCC has remained unclear. Herein the authors report their experience using AMR as salvage chemotherapy for two patients with recurrent SCCC. AMR resulted in disease stabilization in both patients, with relatively long progression-free survival (PFS) of five and 14 months for platinum-refractory and -sensitive disease, respectively. No severe (grade &gt;3) hematological or non-hematological toxicities were observed. In conclusion, AMR may be as effective and safe for recurrent SCCC as it is for recurrent SCLC. To further evaluate the efficacy and safety of AMR for recurrent SCCC, it is necessary to collect additional case studies or conduct a phase II trial.

Differential expression of neuroendocrine markers, TTF-1, p53, and Ki-67 in cervical and pulmonary small cell carcinoma.

Small cell carcinoma (SCC) is a highly malignant neuroendocrine tumor that may occur in many anatomic sites of the body.In this study, we compared the different expression of neuroendocrine markers, thyroid transcription factor 1 (TTF-1), p53, and Ki-67 in 23 cases of cervical SCC and 56 cases of pulmonary SCC using immunohistochemistry.Our study showed that cervical SCC had a younger onset age than pulmonary counterpart. Although both had the similar morphological features, different immunohistochemical expression panel was observed in this study. As neuroendocrine tumors, SCC of cervix and lung had similar immunoreactive staining for CD56 and chromogranin A, but the expression of the synaptophysin in cervical SCC was significantly higher than that in pulmonary SCC (P = .007). The TTF-1 expression of pulmonary SCC illustrating diffuse and strong positivity in tumor cell nuclei was significantly higher than that of the cervical SCC (P = .003). There was only 1 case showing p53 protein over-expression in the 23 cases of cervical SCC, and p53 over-expression was observed in 42.9% of pulmonary SCC (P = .001). Only 9 cases of cervical SCC showed ≥80% of the Ki-67 proliferation index, while it was found in 94.6% of pulmonary SCC (P < .001).The different immunohistochemical expressions of these 2 kinds of SCCs may be related with their pathogenetic mechanism, and these differences may be helpful in the identification of the origins of the metastatic SCC with unknown primary site.

Clinicopathological features of small cell carcinoma of the uterine cervix in the surveillance, epidemiology, and end results database.

To investigate the clinicopathological characteristics and survival of small cell carcinoma of the cervix using Surveillance, Epidemiology, and End Results database. Patients with a diagnosis of small cell carcinoma of the cervix were included between 1988 and 2012. Kaplan-Meier method and Cox regression models were used. A total of 487 patients were included. Of the patients with known International Federation of Gynecology and Obstetrics stage and tumor grade, the stage IV disease was diagnosed in 37.9% patients, and 98.5% patients had poorly or undifferentiated histology. The 5-year cause specific survival and overall survival were 33.0% and 29.4%, respectively. In multivariate analysis, increasing age, advanced stage, and treatment by primary radiotherapy were associated with worse survival outcomes. Small cell carcinoma of the cervix is a rare disease with aggressive characteristics and prone to metastasize and is dismal in prognosis. Reduced survival was associated with increasing age, advanced stage, and treatment by primary radiotherapy.

DAPK and P16 Methylation and HPV and EBV Infection in Small Cell Carcinoma of Cervix: A Case Report

Purpose: Small cell carcinoma (SMCC) of the cervix is rare and aggressive tumor, often diagnosed in an advanced stage and their prognosis is generally poor. A case of SMCC showing Human Papillomavirus (HPV) and Epstein barr virus (EBV) infection and Death-associated protein kinase (DAPK) and p16 genes methylation is presented. A 74-year-old woman was diagnosed as having stage IB2 of SMCC. Methods: HPV and EBV infection and DAPK and p16 gene methylation were found using molecular approaches. Results: The sample was positive for HPV and EBV infection and showed DAPK and p16 promoter regions methylated Conclusion: Methylation of DAPK and p16 gene could be used as a molecular marker in cervical cancer.

Small cell carcinoma of cervix: Rare and enigmatic

Small cell carcinoma of the cervix is a rare, poorly differentiated neuroendocrine tumor of cervix showing a high propensity to spread to lymph nodes as well as distant metastasis. Earlier considered to be a variant of squamous cell carcinoma, it is now acknowledged as a distinct entity showing markers of neuroendocrine differentiation. Because of the dismal prognosis, it is important to make early diagnosis and to differentiate it from a small cell variant of squamous cell carcinoma and other differentials. We present a case of a 45-year-old female who presented with cervical growth.

Radiation sensitivity assay with a panel of patient-derived spheroids of small cell carcinoma of the cervix.

Small cell carcinoma of the uterine cervix (SCCC) is a rare cancer with a poor prognosis for which no standard treatment exists. Here, we successfully established panels of patient-derived spheroid cultures from six SCCC patient samples by cancer tissue-originated spheroids (CTOS) method. To assess the intrinsic radiosensitivity and mechanism of radioresistance in individual SCCC patients, we further developed an in vitro sensitivity assay for radiation. Radiation sensitivity in the CTOS assay varied among individual cases and was consistent with in vivo radiation sensitivity using CTOS-derived xenograft tumors in the examined cases. Furthermore, by comparing gene expression in CTOSs with different radiosensitivity, we found that expression of hypoxia-inducible factor-1α (HIF-1α) target genes was upregulated in resistant CTOSs. HIF-1α protein levels increased several hours after irradiation. In a radioresistant CTOS, an inhibitor of heat shock protein 90 (HSP90) suppressed radiation-induced HIF-1α expression. Suppression of HIF-1α by small hairpin RNA significantly enhanced the effect of radiation, at least in part by promoting radiation-induced apoptosis. HSP90 inhibitor also increased radiation sensitivity. Our results indicate that radiation-induced HIF-1α upregulation was one mechanism of radioresistance in a radioresistant SCCC CTOS. Accumulating CTOS lines may provide a good platform to study characters of rare cancers like SCCC.

Small cell carcinoma of the uterine cervix in a pregnant patient diagnosed with liquid based cytology and cell block immunocytochemistry.

Definitive cytomorphologic diagnosis of small cell carcinoma of the uterine cervix is possible but can be challenging in routine cervicovaginal cancer screening specimens. Several small series of reported cases of cervical small cell carcinoma have shown this uncommon malignancy to represent fewer than 2% of all invasive cervical cancers. This tumor type is associated with poor prognosis and rapid disease progression and can develop to an advanced stage in the interval between screening visits. Only rare case reports of small cell carcinoma arising in gravid cervices are known. In the current case a 29-year-old, gravida 6, para 2, pregnant (10-week gestation) female presented with postcoital bleeding. A definitive diagnosis of small cell carcinoma of the cervix was made possible by liquid based Pap testing with ancillary cell block preparation allowing for immunocytochemical characterization of the lesional cell population.

Small cell neuroendocrine carcinoma of the uterine cervix presenting with syndrome of inappropriate antidiuretic hormone secretion

Small cell carcinoma of the uterine cervix is rare. It is estimated that 10% of patients with small-cell lung cancer have syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and hyponatremia has been reported to be significantly associated with a poor prognosis. A proportion of small cell carcinoma of the uterine cervix exhibit neuroendocrine characteristics as revealed by immunohistochemistry, However, cases presenting typical symptoms due to SIADH are extremely rare. This report of the SIADH of the uterine cervix is a rare case in the small cell carcinoma of the cervix presenting with tumor-associated paraneoplastic syndrome.

A literature review of small cell carcinoma of the cervix

Case summary A 97-year-old lady had a cervical biopsy for a fungating mass. The specimen showed fragments of poorly differentiated carcinoma characterised by sheets of tightly packed small cells with hyperchromatic nuclei, nuclear moulding, fine granular chromatin and scanty cytoplasm. There was no glandular or squamous differentiation. Subjacent to the tumour, there was a full thickness dysplasia consistent with cervical intraepithelial neoplasia (CIN) 3. The tumour stained for neuroendocrine markers comprising of chromogranin, synaptophysin and NSE. It was also positive for polyclonal CEA. The squamous epithelium with CIN3 stained for p16-INK4. The findings support small cell carcinoma of cervical origin. Discussion Small cell carcinoma accounts for 1–6% of cervical carcinoma. Overexpression of p16-INK4 and the presence of HPV18 E7 have been previously reported in small cell carcinoma of the uterine cervix. Therefore, inactivation of RB protein by HPV18 E7 protein is associated with carcinogenesis of small cell carcinoma. It is clinically aggressive and frequently presents with parametrial invasion and pelvic lymph node metastases. The reported 5 year survival rate is 14–39%.

Small Cell Carcinoma of the Uterine Cervix Misdiagnosed as Squamous Cell Carcinoma

Small cell carcinoma of the uterine cervix is a rare tumor. It presents clinical and biological features of both cervical neoplasm such as local aggressiveness, and small cell cancer such as early spread and metastases. To date, an effective treatment protocol is not well established. Case: On March 2009, a 44-year-old pregnant woman with small cell carcinoma of the cervix misdiagnosed initially as squamous cell carcinoma, was treated with chemoradiation followed by surgery and brachytherapy. Twenty-three months later, she experienced brain metastases. A metastasectomy lead to an accurate diagnosis. Palliative whole brain radiotherapy was conducted. The patient died of evolutive disease on August 2012. Conclusion: The optimal therapeutic approach of small cell carcinoma of the cervix is still to define. Further studies regarding multimodal treatment are necessary to achieve a significant survival benefit.

Advances in study of cervical small cell carcinoma

Small cell carcinoma of cervix (SCCC) is a rare and high malignant neuroendocrine tumor.Because of its strong invasion,metastasis in early stage and easy recurrence,the prognosis is poor.Its diagnosis is based on pathomorphology,and immune-histochemistry biomarkers can improve its diagnosis.Combined therapy is recommended.Postoperative platinum/etoposide (PE),vincristine/adriamycin/cyclophosphamide (VAC) or taxel/carboplatin(TP) chemotherapy can improve the prognosis. Key words: Uterine cervical neoplasms; Surgical procedures,operative; Drug therapy; Radiotherapy

Clinicopathological features and prognosis of small cell carcinoma of the cervix

Small cell carcinoma of cervix (SCCC) is a rare disease with highly aggressive behaviour and is pathologically hard to diagnose. In this study, the clinicopathological features, diagnosis, treatment and prognosis of the condition were examined. Clinical records and follow-up data of 7 cases of SCCC were retrospectively studied. Our results showed that five non-recurrent cases initially presented irregular vaginal bleeding or increased apocenosis of varying degrees. Pathological examination revealed that the stroma was diffusely infiltrated with small monomorphous cells ranging from round to oval shape. Three cases were immunohistochemically confirmed. One case was accompanied with squamous cell cancer. Of the 7 cases, one case was classified as stage I b1, two stage I b2, one stage IIa, one stage IIb, and one stage IIIb. On the basis of their stages of condition, one subject with stage III b underwent chemotherapy, and one with stage Ib2 received extensive hysterectomy plus pelvic lymphadenectomy, while the other 5 cases were treated by extensive hysterectomy and pelvic lymphadenectomy in combination with pre- and/or post-operative adjuvant chemotherapy and radiotherapy. Of the 7 patients, 4 had relapse-free survival of 14, 14, 16 and 28 months respectively. It is concluded that SCCC is an aggressive tumor with propensity for early pelvis lymph node metastases. Early-stage patients should be treated by extensive hysterectomy and pelvic lymphadenectomy in combination with pre- and/or post-operative adjuvant chemotherapy and radiotherapy.

Small cell carcinoma of the cervix in liquid‐based Pap test: Utilization of split‐sample immunocytochemical and molecular analysis

Small cell (neuroendocrine) carcinoma of the uterine cervix (SMCC) is a rare, highly aggressive malignant neoplasm. Both conventional and liquid-based cytology (LBC) cervical smears have low sensitivity in diagnosing SMCC, requiring immunocytochemical (ICH) confirmation. We present the first series of SMCC primarily diagnosed in cytology specimens, and ICH studies performed on the residual LBC specimens with subsequent confirmation of the diagnosis on surgical pathology specimens. Immunocytochemical stains for keratin, p16INK4, and neuroendocrine markers (synaptophysin, chromogranin, CD56) were performed on additional ThinPrep slides. HPV test used chromogenic in situ hybridization high risk HPV DNA probe. The Pap smears in all three specimens were highly cellular with a mixture of squamous cells and numerous well-preserved single or small cohesive clusters of malignant epithelial cells. Tumor cells were small, monomorphic with minimal cytoplasm and high nuclear/cytoplasmic ratio. There was significant nuclear overlap, but no nuclear molding, or smudging of nuclear chromatin. The chromatin pattern was stippled. A background tumor diathesis was prominent. Atypical squamous cells of undetermined significance (ASCUS) were noted in one case, and markedly abnormal squamous cells were seen in another case. The main cytology differential diagnoses included high-grade squamous intraepithelial lesion and an endometrial adenocarcinoma. Immunocytochemical positivity for the neuroendocrine markers supported the diagnoses of SMCC in all three cases. The morphologic features of the concurrent surgical pathology specimens were typical of SMCC. The tissue diagnoses were also confirmed by immunohistochemistry. Our study allows us to conclude that SMCC can be primarily diagnosed in LBC specimens using a panel of immunocytochemical stains.