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Abstract Failure to maintain an appropriate balance between cell death and proliferation is partly due to derangements in the regulation of apoptosis. In this work, apoptosis and the expression of apoptosis regulating proteins were studied by 3' - end labeling of fragmented apoptotic DNA (TUNEL) and immunohistochemistry in a set of 147 tissue samples consisting of 44 biopsies of normal and dysplastic bronchial epithelium, and 103 non-small cell lung carcinomas. The quantity of apoptotic cells and bodies, apoptotic index (AI%), is defined as a percentage of apoptotic cells in the entire tumor cell population. Changes in the apoptotic activity were already seen in the metaplasia-dysplasia-carcinoma sequence of the lung, where the AI% increased gradually until moderate epithelial dysplasia but started to decrease after that. Thus, the AI% for invasive NSCLC (1.20 for squamous cell carcinoma and 1.24 for adenocarcinoma) was slightly lower than in premalignant bronchial epithelium (mean 1.50), but clearly higher than in normal tissue (0.20 for normal bronchial epithelium and 0.24 for lung interstitial cells). 53% of SQCCs and 50% of ACs showed p53 positive nuclei indicative of mutated p53 protein. The immunostaining of bcl-2, bax and mcl-1 revealed diffuse, cytoplasmic staining and was present in most tissues studied. No statistically significant associations between the extent of apoptosis and the expression of p53, bcl-2, bax, or mcl-1 could be found, although . The immunostaining for caspases 3, 6 and 8 was restricted to the tumor areas, reflecting increased apoptotic activity in them. The AI% was significantly higher in NSCLCs in which the single-cell staining pattern for caspase-8 was dominant (P = 0.017), whereas the expression of caspases 3 and 6 had no association with apoptosis. The number of apoptotic cells was significantly higher in NSCLC tumors with a high number of CD3+ and CD8+ T-lymphocytes (P = 0.01) and B-cells (P = 0.05). By multivariate analysis, enhanced apoptosis in NSCLC showed a 1.9-fold risk (95% CI 1.04–3.60; P = 0.04) and p53 positivity a 2.3-fold risk (95% CI 1.30–4.10; P = 0.005) for a shortened survival. Both factors appeared as independent prognostic variables. Apoptosis is clearly enhanced in premalignant and malignant lung tissue in comparison with normal tissue. Furthermore, the expression of the apoptosis-regulating genes is different in tumor tissue from that in normal tissue, and some of the changes in their expression can be seen even in the premalignant lesions of the bronchial epithelium. The expression of caspases seen only in tumor tissue implies the activation of the apoptotic mechanisms and, thus, the lowered treshold of tumor cells to undergo apoptosis. Even in the advanced stages of the disease, the immune defense is effective and the cytotoxic action of activated CD8+ T-cells clearly involves apoptosis. Based on these results it is concluded that alterations in the apoptotic activity and changes in the expression of apoptosis-regulating genes are associated with malignant transformation and growth in lung tissue.

Neuroendocrine tumors of the cervix are extremely rare. Women diagnosed with small cell neuroendocrine carcinoma of the cervix have a higher frequency of metastases in the lymph nodes, lymphovascular invasion, recurrence and worse prognosis compared to those with other types of cervical neoplasia. We report the case of a 58-year-old female, with a history of six years of postmenopausal irregular vaginal bleeding, in addition to symptoms related to chronic anemia. Gynecological examination showed a tumor of 4 cm that occupied the upper third of the vagina and protruded through the cervix initially diagnosed as an abortifacient myoma, and sent to histopathology study. 90% of the tumor was small cell neuroendocrine carcinoma grade III, and the remaining 10% was squamous cell carcinoma. The patient underwent into a radical hysterectomy plus bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymphadenectomy. Histopathologic examination of the surgical specimen found endometrium and myometrium compromised by malignancy. Parametrium, annexes and lymph nodes were free of neoplasia. At microscopy, the result was a grade III neuroendocrine carcinoma (small cell carcinoma, infiltrating), with extensive lymphovascular emboli. The immune-histochemical study showed synaptophysin positive in areas with neuroendocrine differentiation. / Los tumores neuroendocrinos de cuello uterino son extremadamente raros. Las mujeres con diagnóstico de carcinoma neuroendocrino de células pequeñas del cuello uterino tienen mayor frecuencia de metástasis en los ganglios linfáticos, invasión linfovascular, recurrencia y peor pronóstico en comparación con aquellos con otros tipos de neoplasias cervicales. Se presenta el caso de una mujer de 58 años, con un tiempo de enfermedad de seis años antes del ingreso, caracterizado por sangrado vaginal irregular posmenopáusica, además de sintomatología relacionada a anemia crónica. En el examen ginecológico, se evidenció tumoración de 4 cm que ocupaba tercio superior de vagina y protruía por el cérvix. Fue diagnosticado como mioma abortivo y enviada a estudio anatomopatológico. El resultado fue carcinoma neuroendocrino de células pequeñas grado III en el 90% y carcinoma epidermoide en el 10%. La paciente fue sometida a histerectomía radical más salpingo-ooferectomía bilateral y linfadenectomía pélvica bilateral y para-aortica. El estudio anatomopatológico de la pieza quirúrgica encontró endometrio y miometrio comprometido por neoplasia maligna. Parametrios, anexos y ganglios linfáticos se encontraron libres de neoplasia. A la microscopía el resultado fue carcinoma neuroendocrino grado III (carcinoma de células pequeñas, infiltrante), con extensa embolia linfovascular. El estudio de inmunohistoquímica arrojó sinaptofisina positivo en las áreas con diferenciación neuroendocrina.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18869号 / 医博第3980号 / 新制||医||1008(附属図書館) / 31820 / 京都大学大学院医学研究科医学専攻 / (主査)教授 武田 俊一, 教授 小西 郁生, 教授 小松 賢志 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Prostate cancer is among the most common malignancies in males in the United States and adenocarcinoma accounts for 95% of all malignancies of prostate. Rarely prostate cancer can also present as small cell carcinoma. Pure small cell carcinoma is rare at time of initial diagnosis (<2%) however neuroendocrine differentiation into small cell carcinoma may emerge in men who have had previous treatment with ADT for prostate adenocarcinoma. These tumors, sometimes called treatment-related neuroendocrine prostate cancers or aggressive-variant prostate cancers, are increasingly recognized in the castration-resistant phases of disease progression. They account for less than 1% of all prostate cancers. A 73-year-old otherwise male had routine health screening in May 2018. Prostate specific antigen (PSA) level was elevated at 9.53 ng/mL. He had not had a screening PSA for at least two prior years but this was a significant change from prior levels. Patient was asymptomatic however the abnormal laboratory evaluation prompted consultation with Urology. Biopsy of prostate gland confirmed prostatic adenocarcinoma with Gleason's score of 5+ 4 = 9 with bilateral gland involvement. Imaging studies including CT scan of abdomen and pelvis, a bone scan and a PET scan showed no clear evidence of metastatic disease. Patient's clinical stage was determined to be IIIC with T2c N0 M0 disease. Patient began treatment with androgen deprivation therapy and received definitive radiation treatment with external bean radiation therapy from July to September 2018. PSA was 0.08 ng/ml at the end of radiation treatment. Patient did well for about 15 months, after which he had multiple hospital admissions for dyspnea, fluid retention and lower extremity edema. He was also found to have refractory hypokalemia. Patient underwent MRI brain which revealed numerous small enhancing calvarial and skull base lesions consistent with bony metastasis in the skull. Patient also underwent PET/CT scan which showed numerous thoracic spine bony lesions, numerous to count bony metastasis throughout the lumbar spine and pelvis, as well as multiple hepatic lesions. Patient underwent biopsy of right hepatic lobe lesion and pathology was consistent with small cell carcinoma with positive neuroendocrine markers including CD56, synaptophysin and TTF-1. Interestingly patient’s PSA was only 0.09ng/dL. Given refractory hypokalemia, paraneoplastic syndrome was suspected and further work-up was initiated. Serum cortisol levels were elevated at 119.6 mcg/dL (3.7-19.4) and ACTH level was 333 pg/mL (7.2 - 63.3). Aldosterone level was <1 ng/dL (0 - 30.0). Patient was diagnosed with paraneoplastic Cushing syndrome. Given aggressive nature of this small cell transformation, patient was started on treatment with systemic chemotherapy with Carboplatin/Etoposide during the hospital stay, with stabilization of potassium levels. Prostate small cell carcinoma poses a challenge for diagnosis and treatment. In contrast to adenocarcinoma of the prostate, serum prostate-specific antigen (PSA) is not predictive of disease severity, nor is it a useful tumor marker for monitoring progression or surveillance. Patients with prostate small cell cancer presents with more diverse symptoms than any other prostate cancer since it tends to metastasize early. Also paraneoplastic syndromes are more common in prostate small cell cancers as well.

Accurate diagnosis of small‐cell carcinoma of the lung (SCLC) is clinically important because of the therapeutic implications. SCLC must be distinguished from non‐small‐cell carcinoma (NSCLC) and lymphoma. Paranuclear blue inclusions (PBIs) were recently described as a feature of metastatic SCLC on air‐dried Wright‐stained bone marrow aspirate smears. To determine the utility of PBIs in distinguishing SCLC from NSCLC and lymphoma, we evaluated air‐dried Diff‐Quik‐stained smears from 103 fine‐needle aspiration (FNA) specimens and 14 touch imprint specimens. PBIs were identified in 24 (89%) of 27 cases of SCLC, in 6 (9%) of 64 non‐small‐cell carcinomas (P < 0.00001), and in two (8%) of the 26 lymphoma cases (P < 0.00001). No PBIs were seen on any of the alcohol‐fixed Papanicolaou or hematoxylin‐eosin (HandE) stained smears examined. In conclusion, PBIs appear to be a feature of SCLC on air‐dried cytologic material stained with Romanowsky type stains. In the presence of cytologic features of SCLC, the identification of PBIs provides a useful diagnostic feature for diferentiating between SCLC and NSCLC carcinomas, and between SCLC and lymphomas in FNA specimens and touch imprints from surgical specimens.

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.

abstract: Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) is a rare and highly aggressive ovarian cancer that affects children and young women at a mean age of 24 years. Most SCCOHT patients are diagnosed at an advanced stage and do not respond to chemotherapy. As a result, more than 75% of patients succumb to their disease within 1-2 years. To provide insights into the biological, diagnostic, and therapeutic vulnerabilities of this deadly cancer, a comprehensive characterization of 22 SCCOHT cases and 2 SCCOHT cell lines using microarray and next-generation sequencing technologies was performed. Following histological examination, tumor DNA and RNA were extracted and used for array comparative genomic hybridization and gene expression microarray analyses. In agreement with previous reports, SCCOHT presented consistently diploid profiles with few copy number aberrations. Gene expression analysis showed SCCOHT tumors have a unique gene expression profile unlike that of most common epithelial ovarian carcinomas. Dysregulated cell cycle control, DNA repair, DNA damage-response, nucleosome assembly, neurogenesis and nervous system development were all characteristic of SCCOHT tumors. Sequencing of DNA from SCCOHT patients and cell lines revealed germline and somatic inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 79% (19/24) of SCCOHT patients in addition to SMARCA4 protein loss in 84% (16/19) of SCCOHT tumors, but in only 0.4% (2/485) of other primary ovarian tumors. Ongoing studies are now focusing on identifying treatments for SCCOHT based on therapeutic vulnerabilities conferred by ubiquitous inactivating mutations in SMARCA4 in addition to gene and protein expression data. Our characterization of the molecular landscape of SCCOHT and the breakthrough identification of inactivating SMARCA4 mutations in almost all cases of SCCOHT offers the first significant insight into the molecular pathogenesis of this disease. The loss of SMARCA4 protein is a highly sensitive and specific marker of the disease, highlighting its potential role as a diagnostic marker, and offers the opportunity for genetic testing of family members at risk. Outstanding questions remain about the role of SMARCA4 loss in the biology, histogenesis, diagnosis, and treatment of SCCOHT. / Dissertation/Thesis / Doctoral Dissertation Molecular and Cellular Biology 2014

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