Polygonal Cell Type Research Articles

Recurrent KRAS, KIT and SF3B1 mutations in melanoma of the female genital tract

BackgroundMalignant melanoma of the female genital tract is relatively uncommon and accounts for 3–7% of all melanoma localizations. This study aimed to identify driver genes in melanoma of the female genital tract with the purpose of enhancing understanding of disease pathogenesis and identifying potential new therapeutic targets to develop effective therapies.MethodsKIT (CD117) and BRAF expression were detected immunohistochemically. Polymerase Chain Reaction (PCR) and Sanger sequencing techniques were performed to identify the mutational status of BRAF, NRAS, KRAS, NF1, KIT, PDGFRA and SF3B1 on 19 melanomas of the female genital tract, paired with 25 cutaneous melanomas, 18 acral melanomas and 11 melanomas of nasal cavity.ResultsSomatic variant analysis identified KRAS (6/19; 32%) as the most commonly mutated gene, followed by KIT (4/19; 21%), SF3B1 (3/19; 16%) and NRAS (1/19; 5%). None of the cases were found to harbor BRAF, NF1 and PDGFRA mutations in melanomas of the female genital tract. However, none of the cases were found to harbor SF3B1 and KIT mutations in cutaneous melanomas, acral melanomas and melanomas of nasal cavity. Recurrent KIT mutations, as well as mutations in the less frequently mutated genes NRAS and SF3B1, were exclusively detected in vulvovaginal melanomas, but not in tumors arising in the cervix. However, recurrent KRAS mutations were detected in similar frequencies in tumors of the vulva, vagina, and cervix. Additionally, recurrent KRAS and KIT mutations occurred predominantly in polygonal and epithelioid cell types of melanoma in the female genital tract. Immunohistochemistry revealed moderate or strong cytoplasmic CD117 expression in 6 of the 19 cases (31.6%).ConclusionsWe observed that gynecologic melanoma harbored distinct mutation rates in the KIT, BRAF, SF3B1, KRAS, and NRAS genes. Our findings support the notion that gynecologic melanoma is a distinct entity from non-gynecologic melanoma, and these findings offer insights into future therapeutic options for these patients.

EGFR mutational status of primary Lung Adenocarcinoma in an Indian cohort based on 2015 WHO classification of lung tumors

Background: Epidermal growth factor receptor (EGFR) mutations have been known to be associated with adenocarcinoma, women, non- smokers and East-Asian ethnicity. This study was aimed to characterize the frequency of EGFR mutations and their association with histologic subtypes in primary lung adenocarcinoma in an Indian cohort. Methods: Two seventy-four cases were categorized using 2015 WHO classification of lung tumors. The frequency of each histologic subtype and cell type was correlated with EGFR exon sequences in a subset of 120 cases using polymerase chain reaction (PCR) gene sequencing. Results: The predominant biopsy categories in 274 cases were acinar 167(61%), solid 63(23%), mucinous 19(7%), lepidic 11(4%) and others 14(5%). EGFR mutations were detected in 49/120 (40.8%) including 3/5(60%) lepidic, 4/9(44.4%) papillary, 29/68(42.7%) acinar, 10/24(41.7%) solid and 1/13(7.7%) mucinous subtypes and were significantly associated with the cuboidal cell type (p=0.01). These mutations were common in women and non-smokers, although not statistically significant. Exon 19 mutations predominated in 36/49(73.4%). The majority, 213/263 (81%), were thyroid transcription factor 1(TTF-1) positive. The polygonal cell type and the solid subtype were frequent amongst stage IV tumors and smokers. Conclusions : EGFR mutations were most frequently seen with the lepidic and papillary subtypes, not associated with the mucinous subtype, more common in women and non-smokers and significantly associated with the cuboidal cell type. DOI: 10.21276/APALM.1372

Update on small cell carcinoma and its differentiation from squamous cell carcinoma and other non-small cell carcinomas

Small cell lung cancer (SCLC) comprises 14% of all lung cancers, and >30 000 new cases are diagnosed per year in the United States. SCLC is one of the most distinctive malignancies in the entire field of oncology with characteristic clinical properties, responsiveness to specific chemotherapy, genetic features and a highly reliable pathological diagnosis. SCLC is defined by light microscopy, and the most important stain is a good-quality hematoxylin and eosin (H&E)-stained section. The vast majority of cases can be diagnosed on H&E alone; however, in problem cases, immunohistochemistry can be very helpful in making the distinction from other tumors. Cytology is also a powerful tool, often being more definitive than small biopsies with scant tumor cells, crush artifact and/or necrosis. As virtually all SCLCs present in advanced stages, most patients are diagnosed based on small biopsy and cytology specimens. Historically, there has been significant evolution in the histological subclassification of SCLC dating from 1962 when Kreyberg proposed the oat cell and polygonal cell types. The current subclassification recognizes only two subtypes: pure SCLC and combined SCLC. Pathologists need to do their best to make a diagnosis of SCLC or other histological types of lung cancer and this can be achieved in most cases. This review will address some of the diagnostic problems that occur in the minority of cases and outline practical ways to address them. Brief reference will be made to other neuroendocrine lung tumors with an overview of the molecular pathogenesis of this spectrum of tumors.

Clinical, ultrasonographic, computed tomography and histopathological manifestations of ovarian steroid cell tumour, not otherwise specified: our experience of a rare case with female virilisation and review of the literature

Introduction. Ovarian steroid cell tumours, not otherwise specified (NOS) are rare sex cord-stromal tumours of the ovary. These tumours should be considered a cause of isosexual precocious puberty in children and virilisation in adults.Case. We report a case of 40-year-old woman with mental handicap who presented with 3 years of amenorrhea and progressive virilisation. Pelvic ultrasonography identified a 6.19 × 6.15 cm well-defined echogenic-multilobular mass arising from the left ovary. Fluid in the cul-de-sac was noted. Colour Doppler examination with endovaginal ultrasonography showed high vascularity of the tumour with low resistance to flow. A computed tomography (CT) scan of the upper and lower abdomen showed a lobular mass with diaphragms in the left adnexal structure and fluid in the cul-de-sac; no adrenal gland enlargement or additional tumour was detected. Laboratory analysis revealed increased levels of serum total testosterone. Total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed. Histological examination showed a benign steroid cell tumour, NOS without evidence of necrosis, haemorrhage or invasion. The immunohistochemical study showed that the tumour cells were positive for inhibin, CD 99, Melan A and vimentin and negative to CK AE1, CK AE3, progesterone and estrogen receptors.Conclusion. Careful medical history, physical examination, laboratory serum values and imaging studies are helpful in making the pre-operative diagnosis. Steroid cell tumours, NOS are usually benign, unilateral and characterised by the composition of two similar-appearing polygonal cell types. They differ from Leydig cell tumours in the lack of crystals of Reinke in their cytoplasm.

The emergence of geometric order in proliferating metazoan epithelia

The predominantly hexagonal cell pattern of simple epithelia was noted in the earliest microscopic analyses of animal tissues, a topology commonly thought to reflect cell sorting into optimally packed honeycomb arrays. Here we use a discrete Markov model validated by time-lapse microscopy and clonal analysis to demonstrate that the distribution of polygonal cell types in epithelia is not a result of cell packing, but rather a direct mathematical consequence of cell proliferation. On the basis of in vivo analysis of mitotic cell junction dynamics in Drosophila imaginal discs, we mathematically predict the convergence of epithelial topology to a fixed equilibrium distribution of cellular polygons. This distribution is empirically confirmed in tissue samples from vertebrate, arthropod and cnidarian organisms, suggesting that a similar proliferation-dependent cell pattern underlies pattern formation and morphogenesis throughout the metazoa.

Elevated serum pro-MMP2 levels in patients with stage IV thymoma.

There is increasing evidence that matrix metalloproteinases (MMPs) play important roles in tumor invasion and metastasis. Using a one-step sandwich enzyme immunoassay, we investigated whether serum pro-MMP2 levels could be predictors of the development and extension of thymoma. The subjects of this study were 33 patients with thymoma and 26 patients with nonmalignant thoracic disease. Serum pro-MMP2 levels were elevated in patients with stage IV thymoma (938.6+/-80.2ng/ml) compared with those in the controls (P = 0.03). Patients with stage IVb thymoma had significantly higher serum pro-MMP2 levels than patients with other stages, being 1088.7+/-440ng/ml in stage IVb, 686.0+/-74.0ng/ml in stage I (P = 0.01), 685.8+/-48.6ng/ml in stage II (P = 0.01), and 691.7+/-74.0 ng/ml in stage III (P = 0.02). Serum pro-MMP2 levels were elevated in patients with polygonal cell type thymoma compared with those with mixed cell type thymoma, being 823.1+/-55.5ng/ml vs 613.6+/-59.9ng/ml, respectively (P = 0.04). Using the reference limit of 850ng/ml (mean +/- 2SD) set from analyses in the control group, all patients who had pro-MMP2 levels below the cutoff level survived. On the other hand, four of nine patients who had an elevated pro-MMP2 level died from recurrence. Serum pro-MMP2 levels may serve as a marker that could be used as an indicator of distant metastases in thymoma. Elevated pro-MMP2 levels may be correlated with poor survival.

Evaluation of the malignant grade of thymic epithelial tumors according to the epithelial subclassification.

We investigated the clinicopathological correlations among 49 surgically resected thymic epithelial tumors (TET), which were subclassified according to the six subtypes established by the Marino, Kirchner, and Müller-Hermelink system, which were renamed as follows: spindle cell type (medullary thymoma), mixed spindle and polygonal cell type (mixed medullary and cortical thymoma), small polygonal cell type (predominantly cortical thymoma), large polygonal cell type (cortical thymoma), atypical type (well differentiated thymic carcinoma), and cytologically malignant type (high-grade thymic carcinoma). The related categories were grouped for statistical analysis as follows: group 1, spindle cell type and mixed type; group 2, small polygonal cell type and large polygonal cell type; group 3, atypical type; group 4, cytologically malignant type. The association of each group with the presence of myasthenia gravis, tumor stage, and the length of survival was studied. Myasthenia gravis was significantly present in patients with small polygonal type, large polygonal type, and atypical type tumors (groups 2 and 3) (P = 0.003). The tumors in group 1 showed the lowest tumor stage while those of group 4 had the most advanced tumor stage (P = 0.002). The patients in group 4 had the worst prognosis, followed by those in group 3, 2, and 1, in that order. The differences among these groups were statistically significant (P = 0.0003). From our results, we determined that TET can be separated into an extremely low-grade malignancy group (group 1), a low-grade malignancy group (group 2), an intermediate malignancy group (group 3), and a high-grade malignancy group (group 4).

Fine needle aspiration diagnosis of neuroendocrine tumors in the liver

Ten neuroendocrine tumors (NET) in the liver are presented, in which the diagnosis was made on fine needle aspiration cytology and cell blocks from the aspirate. In seven of the patients with liver metastasis, a biopsy-proven extrahepatic primary NET had been previously diagnosed, while in three patients no extrahepatic neoplasm could be identified, suggesting that the NET may have been a primary in the liver. Based on cytomorphological findings the cases were typed as either round cell type, spindle cell type or polygonal cell type. In all cases, immunopositivity for neuroendocrine markers provided reliable evidence of the cell of origin and distinguished them from well-differentiated hepatocellular carcinoma, adenocarcinomas and other neoplasms, which sometimes may present a diagnostic dilemma.

High K-ras mutation rates in goblet-cell-type adenocarcinomas of the lungs.

Adenocarcinomas of the lungs show a variable histology. We have subclassified such lesions into five cell types: hobnail, columnar, polygonal, mixed and goblet cell types, and investigated their relationships with K-ras mutations. Codons 12, 13 and 61 of the K-ras gene in 120 surgically resected pulmonary adenocarcinomas were examined by the mutation-allele-specific amplification method. Point mutations were observed in 10% of the adenocarcinomas limited to K-ras codon 12 and the commonest base substitution (nine cases) was a G to T transversion. Of the five types, goblet cell lesions demonstrated the highest mutation index, which at 100% (6/6) was significantly different from that of all other cell types. No relationship between K-ras mutation and cigarette smoking was observed. From these findings, it appears that development of goblet-cell-type adenocarcinomas of the lung may involve different carcinogenic mechanisms from adenocarcinomas of other subtypes.

A review of 79 thymomas: modification of staging system and reappraisal of conventional division into invasive and non-invasive thymoma.

A clinicopathological study of surgically resected thymomas was performed using Masaoka's staging and modified Masaoka's staging systems, and the utility of these two staging systems was compared. The modification enabled adjustment for the disproportion in the number of cases between Stage I and Stage II. Analysis of survival rates, according to the tumor stage, indicated that the old classification should be reappraised, that is, division into non-invasive and invasive thymomas, although staging may contribute to the indication for postoperative radiotherapy, especially for Stage II disease. Analysis of the cases showed a wide spectrum of aggressiveness, varying from cases showing slow progression with a relatively favorable prognosis, such as the spindle cell type, to cases with rapid progression leading to tumor death in a relatively short time, such as the epithelial cell predominant and polygonal cell type. The pathological stage at the time of first surgical resection would reflect the degree of aggressiveness of thymoma in many instances. Therefore, not only staging the tumor extent but also grading of its aggressiveness are needed in order to predict the prognosis of patients with thymoma. For the latter, histology and cytopathology are helpful.

Characteristics of in vitro passaged cells derived from a rat transplantable malignant fibrous histiocytoma.

Morphologic and functional characteristics were investigated on in vitro passaged cells (MT-P) derived from a rat transplantable malignant fibrous histiocytoma (MFH-MT). There were spindle, polygonal, and giant cell types in MT-P. Ultrastructurally, the polygonal and giant cells had the abundant cytoplasm with many lysosomes and processes, whereas the spindle cells possessed smooth cell surface and a small number of lysosomes in their cytoplasm. Immunorosette formation for Fc- and C3-surface receptors and phagocytic activity were demonstrated in 10-20% of MT-P. MT-P were positive for acid phosphatase, nonspecific esterase and alkaline phosphatase. Chromosomes counted in 100 MT-P ranged from 32 to 100 with two peaks of 64 and 76. Tumors induced in syngeneic rats by inoculating MT-P showed variable histologic patterns. They were composed partly of histiocytic cells arranged in a compact sheet. Fibroblastic cells often arranged in a storiform pattern or were supported by myxoid matrix. Osteosarcoma-like structures were occasionally found in the tumors. These results suggest that MFH-MT is heterogeneous, although some cells constituting the tumors have histiocytic markers.

The characteristics of thymoma with myasthenia gravis: a 28-year experience.

Of 134 patients with thymoma, 79 (59%) also had myasthenia gravis (MG). The thymoma with MG differed from that in the absence of MG in the following aspects: The ratio of lymphocytes to epithelial cells in the tumor was larger, the polygonal cell type was more prominent (i.e., in 83% of the MG patients this cell type predominated), and the differentiation of epithelial cells in the tumor was more advanced in the group with MG than in the group without MG. Furthermore, the clinical stage of thymoma was earlier, the recurrence rate was lower, and the survival curve was better in the group with MG than in the group without MG. These findings suggest that the thymoma with MG is less malignant than that without MG.

Relationship between cellular morphology and immunocytological findings of spontaneous pituitary tumours in the aged rat

A total of 339 spontaneous pituitary tumours from 284 aged rats were studied by light microscopy. Based on the cellular morphology in preparations stained by haematoxylin and eosin, tumour cells were classified into 4 types: (1) granular; (2) agranular small; (3) agranular large polygonal; and (4) agranular large slender cells. Eight tumours consisted of mixed neoplastic masses of 2 types of cells. A total of 85 cases representative for each tumour type was used for special staining and immunocytochemistry. All tumours of the granular cell type and some tumours of the agranular large polygonal cell type had granules which stained red by azocarmine and were positive for prolactin. All agranular small cell type tumours were also positive for prolactin and agranular slender cell type tumours were positive for adrenocorticotropic hormone. Only tumours of the agranular large polygonal cell type gave an indefinite or negative reaction for all the various pituitary hormones. These results indicate a relatively good correlation between the cellular morphology and the immunocytochemistry of spontaneous pituitary tumours in aged rats.

Collagen types synthesized by isolated calvarium cells

Three populations of cells were isolated from embryonic chick calvaria by three sequential incubations with a collagenase-trypsin solution. Population 1 contained presumptive ‘osteoprogenitor cells’ of fibroblast-like cell shape. A compact, polygonal cell type, called ‘osteoblast-like’ cells, was predominant in the populations 2 and 3. Incorporation of 45Ca 2+ into acid-soluble material was measured for additional characterization of the cells. All calvarium cells synthesized type I collagen and a small amount of type V (A,B) collagen. Type II collagen was not detected in any culture. Type III collagen was synthesized by a few cells of the first population but not by cells of subsequent harvests. The overall level of collagen synthesis was higher in calvarium cells, particularly in the populations 2 and 3, as compared with tendon fibroblasts. The qualitative pattern of collagen synthesis remained virtually unchanged during 6–8 weeks in primary cultures and was not influenced by subculturing either.

Hepatocellular carcinoma. Polygonal cell type with fibrous stroma--an atypical variant with a favorable prognosis.

Hepatocellular carcinoma, even when treated with operative resection, is generally regarded as uniformly fatal. Isolated reports of an unusual histologic variant characterized by polyglonal cells with a fibrous stroma (PCFS) suggest a more favorable outcome. Twelve cases of PCFS, representing the largest reported group, are presented. The mean age of the patients at the time of onset was 23.1 years and the male to female ratio was 1:2. Successful operative resection of the primary neoplasm and metastatic foci has resulted in a significant percentage of long-term survivors with a mean survival time of 68 months and two- and five-year survival rates of 82% and 63%, respectively. The variant shows cytologic similarity to differentiated hepatocellular carcinoma with a unique stromal appearance suggesting a pattern of fibrosis associated with focal nodular hyperplasia. Focal nodular hyperplasia is noted occasionally in the liver adjacent to PCFS. The possibility that PCFS represents an intermediate stage between focal nodular hyperplasia and the more malignant variants of hepatocellular carcinoma is discussed.

Brushing Cytology as a Diagnostic Toll for Subtypes of the Small Cell Lung Cancer

Small cell carcinoma is most malignant in lung cancer. Its prognosis varies according to the histologic subtypes. So, it is important to make the early diagnosis of histologic subtypes for the establishment of suitable treatment. We found that the cytological examination of the bronchial brushing specimens was useful for the early diagnosis of histologic subtypes.We made histological and cytological examination in twenty-three cases with small cell lung cancer. In the examination, it was revealed that cell arrangement, sizes and shapes of nuclei on the cytological specimens were important to make an accurate diagnosis for the histologic subtypes.The following cytological features are manifested for each subtype:(1) for oat cell type, round or ovoid nuclei are very small in size and naked, (2) for intermediate fusiform cell type, naked and spindle nuclei are arranged with a ribbon or a pallisade-like pattern, (3) for intermediate polygonal cell type, large and pleomorphic nuclei are arranged irregularly or with a ribbon-like pattern.

Peritoneoscopy in the staging of 190 patients with small-cell anaplastic carcinoma of the lung with special reference to subtyping

Peritoneoscopy with liver biopsy was routinely done as a pretreatment staging procedure in 190 patients with small-cell anaplastic carcinoma of the lung. Subtyping of the patients according to the WHO classification included 28.3% with fusiform cell type (WHO II,1), 28.9% with polygonal cell type (WHO II,2), 41.5% with lymphocytelike cell type (WHO II,3) and 1.3% with mixed types (WHO II, 4). Liver metastases were found in 21% of the patients with adequate liver biopsy. In addition macroscopic signs of liver metastases were observed in 9%. No significant differences were observed among the histological subtypes. Liver function tests, such as alkaline phosphatase, LDH and GOT, were of little value in excluding liver metastases. On the other hand, 2 of 3 abnormal liver function tests were highly indicative of liver metastases. In patients with positive liver biopsy, 41% had liver metastases alone and 76% had no other evidence of distant metastatic disease if bone-marrow involvement identified with bone marrow examination is excluded as a staging procedure.

Long-term cell culture of adult rat liver epithelial cells

The livers of adult rats were dissociated after collagenase-hyaluronidase perfusion. A high yield of viable cells was obtained and these regularly gave rise to continuous lines of polygonal epithelial cell types.

Classification of fibroma and the coma of the ovary. An ultrastructural study.

The fine structure of 6 ovarian neoplasms, 5 fibromas, and 1 thecoma, as diagnosed by the light microscope, was studied. Based on such features as cellular shape, organelle composition, and nuclear patterns, the cells apparently formed a morphological continuum, comparable to that observed in the normal ovarian cortical stroma. The cells varied from a spindly fibroblast-like type with a thin elongated nucleus and scanty cytoplasm to a polygonal theca interna type with a large round nucleus, a prominent nucleolus, and abundant cytoplasm containing abundant endoplasmic reticulum, well-developed Golgi apparati, numerous mitochondria, and a variable number of lipid droplets. Intermediate-type cells increasing in plumpness and structural complexity bridged the gap between the two extreme varieties. The proportions of the spindly, intermediate, and polygonal cell types in the different neoplasms varied according to their degree of cellularity and collagen content: the first type was most frequently seen in the heavily collagenized and the second in the less heavily collagenized neoplasms. The finding in this study support the view that the ovarian fibroma and thecoma are not two different neoplasms, but are variants of a single neoplasm with a common origin from the ovarian stroma.