Pleomorphic giant cell carcinoma of prostate: Rare tumor with unique clinicopathological, immunohistochemical, and molecular features.

Pleomorphic giant cell carcinoma (PGCC) of the prostate is a rare entity categorized as a variant of prostatic acinar adenocarcinoma in the 2016 World Health Organization (WHO) classification system. PGCC differs from conventional prostatic adenocarcinoma by having bizarre, markedly enlarged, and pleomorphic cells. It differs from high grade urothelial carcinoma by negativity for urothelial differentiation markers, and can be distinguished from sarcomatoid carcinoma by lack of spindle cells. Including two new cases described herein, there have been 51 cases of prostate PGCC reported in the English literature. Clinical features shared by cases of prostate PGCC include poor prognosis, occurrence in older patients, and frequent association with prior therapy. Pathologic features common to cases of prostate PGCC include admixture with a high-grade conventional prostate carcinoma component and absent or reduced expression of prostate differentiation markers. More recent studies have begun to elucidate the molecular characteristics of PGCC, detecting specific mutations and chromosomal translocations, and showing evidence of a high degree of molecular instability in these tumors. We report novel findings in two cases of PGCC including a PIK3CA p.His1047Arg mutation not previously described. One of our cases is the first to clearly demonstrate chronological loss of prostate markers during dedifferentiation from prior conventional prostate carcinoma to PGCC. Herein, we present our two new cases and comprehensively review the literature on all reported cases of PGCC with critical commentary on findings in cases of this rare tumor.

Programmed death ligand-1 expression levels, clinicopathologic features, and survival in surgically resected sarcomatoid lung carcinoma.

AIM: To determine the programmed death ligand-1 (PD-L1) expression rates in sarcomatoid lung carcinomas and to compare clinicopathologic features and survival rates of PD-L1-positive and negative patients. METHODS: PD-L1 expression was evaluated in 65 surgically resected sarcomatoid carcinomas. The clinicopathologic features of cases with PD-L1-positive and negative tumors were compared. Kaplan-Meier survival analysis was performed. Multiple Cox proportional hazard regression analysis was performed to determine independent predictors of overall survival. RESULTS: PD-L1 antibody positivity was found in 72.3% of surgically resected sarcomatoid lung carcinomas. Regarding histopathologic subtypes, PD-L1 expression was positive in 80.4% of pleomorphic carcinomas, 62.5% of spindle- and/or giant-cell carcinomas, and 16.7% of carcinosarcomas. Pleural invasion was observed in 68.1% of PD-L1-positive cases and 27.8% of PD-L1-negative cases (P = 0.008). No difference in survival was found between PD-L1-positive and -negative tumors. The only factor significantly associated with poor survival was the pathological stage of the tumor. CONCLUSIONS: This study reveals a high rate of PD-L1 positivity in a large number of sarcomatoid lung carcinoma cases with pleomorphic carcinoma, spindle- and/or giant-cell carcinoma, and carcinosarcoma subtypes. The only significantly different clinicopathologic feature in PD-L1-positive cases is pleural invasion. PD-L1 positivity is not a significant predictor of survival in sarcomatoid lung carcinomas.

Different p53 genotypes regulating different phosphorylation sites and subcellular location of CDC25C associated with the formation of polyploid giant cancer cells.

BACKGROUND: Our previous studies have confirmed that cobalt chloride (CoCl2) can induce the formation of polyploid giant cancer cells (PGCCs), which is the key to the heterogeneity of solid tumors. PGCC formation is closely related to the abnormal expression of cell cycle-related proteins and cell fusion. In this study, we investigated the molecular mechanism of PGCCs formation by detecting the expression of cell cycle-related proteins in mutant and wild-type p53 cancer cell lines. METHODS: HEY, BT-549, SKOv3 and MDA-MB-231 cells were treated with CoCl2 and the cell cycle was detected by flow cytometry. The expression and subcellular localization of cell cycle-related proteins, kinases, and P53 were compared before and after CoCl2 treatment. Immunoprecipitation was used to analyze the interacting proteins of pCDC25C-Ser216 and pCDC25C-Ser198. The clinicopathologic significances of these cell cycle-related proteins and protein kinases expression were studied. RESULTS: CoCl2 induced the formation of PGCCs and G2/M arrest. CDC25C, cyclin B1, and CDK1 expressions after CoCl2 treatment were lower than that in control cells. Cytoplasmic CDC25C was degraded by ubiquitin-dependent proteasome. The expression of P53 and phosphokinases including CHK1, CHK2, PLK1, and Aurora A increased after CoCl2 treatment. The expression of pCDC25C-Ser216 and pCDC25C-Ser198 depended upon the genotype of p53. The expressions of cell cycle-related proteins and kinases gradually increased with the development of ovarian cancer and breast cancer. CONCLUSION: CHK1, CHK2-pCDC25C-Ser216-cyclin B1-CDK1, and Aurora A-PLK1-pCDC25C-Ser198-cyclin B1-CDK1 signaling pathways may participate in the formation of PGCCs and different phosphorylation sites of CDC25C may be associated with the genotype of p53.

The diagnostic utility of zinc E-box 1 (ZEB1) transcription factor for identification of pulmonary sarcomatoid carcinoma in cytologic and surgical specimens.

OBJECTIVE: Although uncommon, pulmonary sarcomatoid carcinoma carries a worse prognosis due to poor chemotherapeutic response. Currently, a histologic spindle and/or giant cell component indicates sarcomatoid differentiation, with zinc E-box binding homeobox 1 (ZEB1) implicated in promoting epithelial-mesenchymal transition. However, diagnostic use of ZEB1 in limited specimens, including cell block (CB) preparations, remains unclear. MATERIALS AND METHODS: Pulmonary sarcomatoid (SARC, n = 15), typical (TC, n = 10) and atypical carcinoid (AC, n = 10), small cell (SCLC, n = 8) and large cell neuroendocrine carcinoma (LCNEC, n = 9), squamous cell carcinoma (SQ, n = 7), and adenocarcinoma (ADC, n = 7) CBs along with 69 SARCs, 20 TCs, 21 ACs, 9 SCLCs, 10 LCNECs, 71 SQs, 402 ADCs, 16 large cell carcinoma (LCC) and 17 other thoracic tumor (OT) surgical specimens between 2007 and 2018 were retrieved. ZEB1 (Sigma Aldrich, St. Louis, Mo and Novus Biological, Centennial, Colo) immunohistochemistry was graded 1+ to 3+, with ≥1+ and >5% staining considered positive. RESULTS: Nuclear ZEB1 was seen in 80% SARC (12/15), 0% TC (0/10), 0% AC (0/10), 12.5% SCLC (1/8) and 11.1% LCNEC (1/9), 0% SQ (0/7), and 0% ADC (0/7) CBs. In surgical specimens, 75.4% SARCs (52/69), 0% TCs (0/20), 0% ACs (0/21), 11.1% SCLCs (1/9), 30% LCNECs (3/10), 0% SQs (0/71), 0.2% ADCs (1/402), 12.5% LCCs (2/16), and 11.8% OTs (2/17) demonstrated ZEB1. ZEB1 sensitivity and specificity in cytology and surgical specimens were 80% and 96.1%, and 75.4% and 98.1%, respectively. CONCLUSIONS: ZEB1 is sensitive and highly specific for pulmonary sarcomatoid carcinoma in limited cytologic and surgical specimens. Diagnostic pitfalls include high-grade neuroendocrine tumors and large cell carcinoma, which are resolvable by morphologic considerations.

Osteoclast-like giant cell-rich carcinomas of the lung: a clinicopathological, immunohistochemical, and molecular study of 3 cases.

Three cases of primary carcinomas of the lung each with an extensive osteoclast-like giant cell component are presented. The patients are 3 men between the ages of 58 and 67 years (average, 62.5 years) who presented with nonspecific symptoms. A history of malignancy, infectious, or granulomatous disease was negative in all the patients. Diagnostic imaging disclosed the presence of a large intrapulmonary mass; in 1 case in the right upper lobe and in 2 cases in the right lower lobe. Surgical resection via lobectomy was performed in the 3 patients. Grossly, the tumors were described as soft, friable intrapulmonary masses, reddish in color, and measuring from 6 to 13 cm in largest diameter. Histologically, the tumors were each characterized by the extensive presence of a multinucleated osteoclast-like giant cell component, which represented approximately 80% of the tumor mass. The osteoclast-like giant cell component was admixed with a sarcomatoid carcinoma in 2 cases and an adenocarcinoma in 1 case. Immunohistochemistry showed that the osteoclast-like giant cells were positive for CD-68, cathepsin K, and histone H3, whereas the carcinoma component was positive for keratin, thyroid transcription factor-1, and histone H3 (patchy). Molecular studies were performed in 2 patients with negative results. Clinical follow-up was obtained in 2 patients; 1 died 14 months after initial diagnosis, whereas 1 remains alive 6 months after initial diagnosis. One patient was lost to follow-up. The current neoplasms represent an unusual type of lung carcinoma that needs highlighting as a separate type from conventional giant cell carcinoma.

c-MET Overexpression as a Poor Predictor of MET Amplifications or Exon 14 Mutations in Lung Sarcomatoid Carcinomas.

INTRODUCTION: MNNG HOS transforming gene (MET) abnormalities such as amplification and exon 14 mutations may be responsive to targeted therapies. They are prevalent in lung sarcomatoid carcinomas (LSCs) and must be diagnosed as efficiently as possible. Hypothetically, c-MET overexpression by immunohistochemistry (IHC) may prove effective as a screening test for MET abnormalities. METHODS: Tissue samples were obtained from consecutive patients with a resected LSC in four oncologic centers. IHC was performed using the SP44 antibody (Ventana, Tucson, Arizona) and evaluated using the MetMab score and H-score. Fluorescence in situ hybridization was applied with the dual color probe set from Zytovision (Clinisciences, Nanterre, France). True MET amplification was diagnosed when MET gene copy number was 5 or greater and the ratio between MET gene copy number and chromosome 7 number was greater than 2. All MET exon 14 alterations including those affecting splice sites occurring within splice donor and acceptor sites were detected in the routine molecular testing on genetic platforms. RESULTS: A total of 81 LSCs were included. Fourteen (17%) exhibited positive IHC using the MetMab score and 15 (18.5%) using the H-score. MET amplification was detected in six tumors (8.5%) and MET exon 14 mutation in five (6%). A weak positive correlation between IHC and fluorescence in situ hybridization was found (r = 0.27, p = 0.0001). IHC sensitivity for MET amplification was 50%, with a specificity of 83%, positive predictive value of 21.4%, and negative predictive value of 94.7%. IHC sensitivity for MET exon 14 mutations was 20%, with a specificity of 83%, positive predictive value of 7%, and negative predictive value of 94%. CONCLUSION: IHC is not a relevant screening tool for MET abnormalities in LSC.

PD-L1 expression in pleomorphic, spindle cell and giant cell carcinoma of the lung is related to TTF-1, p40 expression and might indicate a worse prognosis.

Lung sarcomatoid carcinoma of the lung is a rare tumor with a poor prognosis. More than 90% of them are pleomorphic, spindle cell and giant cell carcinoma (PSCGCC). This rare subtype of lung cancer is thought to be more resistant to chemotherapy, and a small subset of them seems to exhibit targetable mutations. Immunotherapy against PD1/PDL-1 is a new emerging treatment, and might be of interest in PSGSCC because they frequently express PD-L1. The aim of our work is to evaluate PD1 and PDL-1 expression in a surgical series of lung PSCGCC and their relationship with morphological and immunohistochemical parameters and prognosis. Thirty-six patients who underwent surgical resection of a PSGSCC were included. PD-L1 (E1L3N) expression on tumor cells and PD1 (NAT105) expression by tumor infiltrating lymphocytes (TILs) were performed by immunohistochemistry. Results were compared to immunohistochemistry tests of TTF1, Napsin A, p40 and to molecular study of EGFR, KRAS, BRAF and HER2. Seventy-five % of PSCGCC were considered as positive for PD-L1.PD-L1 expression in PSGSCC is associated with TTF-1 and/or Napsin A expression (47.2%, p = 0.039). Few p40 positive PSCGCC expressed PD-L1 (8.3%, p = 0.013). PD1 expression was not related to TTF-1 and/or Napsin A expression (p = 0.47), p40 expression (p = 0.68) or survival (p = 0.14). PD-L1 or PD1 expression were not related to the age, gender, pT, pN, stage, visceral pleura invasion, histopathological subtype, the presence of giant cell component, the predominance of sarcomatoid component, and the presence of EGFR or BRAF or HER2 or PIK3CA mutation (p>0.05). PD-L1 expression was correlated with a worse overall survival in PSCGCC (p = 0.045). PD-L1 expression is frequent in PSCGCC and might be associated with the expression of adenocarcinoma markers (TTF-1, Napsin A) or the lack of expression of squamous cell carcinoma marker (p40).

Missing in metastasis B, regulated by DNMT1, functions as a putative cancer suppressor in human lung giant-cell carcinoma.

Missing in metastasis B (MIM-B) has been widely reported to inhibit cancer cell invasion and proliferation in a variety of human cancers. However, the functions of MIM-B in lung cancers are still controversial. In addition, the mechanisms and regulation of MIM-B are poorly understood. In the present study, we found that the invasion level of 95C human lung giant-cell carcinoma cells was elevated when MIM-B was knocked down, while the invasion of 95D was suppressed when MIM-B was overexpressed, proving that MIM-B suppresses human lung giant-cell carcinoma cell invasion, which is similar to its function in most cancers. Furthermore, we reported that an increase in DNA methylation density in the promoter of MIM-B by DNA methyltransferase 1 (DNMT1) is correlated with the silencing of MIM-B expression and the high metastasis of 95D human lung giant-cell carcinoma cell line. Taken together, MIM-B, which is regulated by DNMT1 through DNA methylation, is a putative cancer suppressor in human lung giant-cell carcinoma.

Value of uroplakin III in distinguishing variants of primary bladder urothelial carcinoma from malignancy metastatic to the urinary bladder.

BACKGROUND: Urothelial carcinoma (UC) variants can be difficult to differentiate from carcinoma metastatic to the bladder. MATERIALS AND METHODS: We examined immunostaining for uroplakin III in 43 cases of primary bladder UC variants including micropapillary UC (n=19), nested variant of UC (n=2), pleomorphic giant-cell carcinoma (n=8), plasmacytoid UC (n=4), lymphoepithelioma-like carcinoma (n=2), large cell undifferentiated carcinoma (n=2), UC with abundant myxoid stroma (n=3) and lipid cell variant (n=3) and in 11 tumors from other organs metastatic to the bladder. These tumors included invasive ductal carcinoma of the breast (n=2), colorectal adenocarcinoma (n=4), endometrioid adenocarcinoma (n=1) and serous papillary carcinoma of the uterus (n=1) melanoma (n=1), embryonal carcinoma of the testis (n=1), and renal clear cell carcinoma (n=1). RESULTS: Out of the 43 UC variants, 35 (81%) were positive for uroplakin III, including micropapillary, lipid cell variant and UC with abundant myxoid stroma. Pleomorphic giant cell carcinoma, plasmacytoid UC and nested variant of UC were less commonly positive. Of the 11 metastatic tumors, six were found to be positive for uropIakin III: metastatic colorectal adenocarcinoma, clear cell carcinoma of the kidney and embryonal carcinoma of testis. CONCLUSION: UP III Positivity for uroplakin III is not found only in primary bladder UC variants, but in some tumors that have metastatized to the bladder. Staining for uroplakin III alone should not be taken as evidence of UC.

Polyploid giant cancer cells with budding and the expression of cyclin E, S-phase kinase-associated protein 2, stathmin associated with the grading and metastasis in serous ovarian tumor.

BACKGROUND: We previously reported that polyploid giant cancer cells (PGCCs) exhibit cancer stem cell properties and express cell cycle-related proteins. HEY PGCCs induced by cobalt chloride generated daughter cells and the daughter cells had a strong migratory and invasive ability. This study is to compare the expression of cyclin E, S-phase kinase-associated protein 2 (SKP2), and stathmin between PGCCs with budding and control HEY cells, and determine the clinicopathological significance of cell cycle-related protein expression in ovarian tumors. METHODS: We used western blot and immunocytochemical staining to compare the expression levels of cyclin E, SKP2 and stathmin between PGCC with budding daughter cells and control HEY cells. In addition, immunohistochemical staining for cyclin E, SKP2 and stathmin was performed on a total of 80 paraffin-embedded serous ovarian tumor tissue samples. The samples included 21 cases of primary high-grade carcinoma (group I) and their metastatic tumors (group II), 26 cases of primary low-grade carcinoma without metastasis (group III), and 12 cases of serous borderline cystadenoma (group IV). RESULTS: Single PGCC with budding in the stroma showed high correlation with the metastasis of ovarian carcinoma. Group I had a significantly higher number of single PGCCs with budding in the stroma than group III (85.71% [18/21] vs. 23.08% [6/26] cases; χ2 = 18.240, P = 0.000). The expression of cyclin E, SKP2, and stathmin was compared among the four groups. The expression levels of cyclin E, SKP2, and stathmin increased with the malignant grade of ovarian tumors and group II had the highest expression levels. The expression of cyclin E (χ2 = 17.985, P = 0.000), SKP2 (χ2 = 12.384, P = 0.000), and stathmin (χ2 = 20.226, P = 0.000) was significantly different among the 4 groups. CONCLUSIONS: These data suggest that the cell cycle-related proteins cyclin E, SKP2, and stathmin may be valuable biomarkers to evaluate the metastasis in patients with ovarian serous carcinoma.

[Clinical characteristics and prognosis of three rare and poor-prognostic subtypes of primary liver carcinoma].

OBJECTIVE: To explore the clinicopathological features and prognostic factors of three rare and poor-prognostic pathological subtypes of primary liver carcinoma, and improve the clinical diagnosis and surgical treatment. METHODS: A retrospective analysis of clinicopathological data of 69 patients with rare pathological subtypes of primary liver carcinoma, diagnosed by postoperative pathology in our hospital from October 1998 to June 2013 was carried out. The data of 80 cases of common poorly differentiated hepatocellular carcinoma treated in the same period were collected as control group. Kaplan-Meier method was used to analyze the survival rate, and Cox proportional hazards model was used for prognostic analysis in the patients. RESULTS: Thirty-four cases were combined hepatocellular carcinoma and cholangiocarcinoma (CCC, 28 males, 6 females), with a median age of 52 years (range, 33 to 73). Ninteen cases were giant cell carcinoma (GCC, 16 males and 3 females), with a median age of 59 years (range, 38 to 66). Sixteen cases were sarcomatoid carcinoma (SC, 14 males and 2 females), with a median age of 57 years (range, 46 to 70). The survival analysis revealed that median survival time and the 1-, 3-, 5-year survival rates for these 3 groups were 20 months, 61.8%, 29.4%, and 20.6% in the CCC patients, 13 months, 52.6%, 31.6%, and 0% in the GCC patients, and 8 months, 31.3%, 0%, 0% in the SC patients, respectively. The median survival time and survival rate of the SC group were significantly lower than those of the other three groups (P < 0.05). However, in the SC group, the incidences of hilar lymph nodes metastasis, vascular tumor emboli and invasion of adjacent organs were significantly higher than those in the other three groups (P < 0.05). There were no statistically significant differences among the other three groups (P > 0.05). The levels of carcino-embryonic antigen were higher in the three rare subtype groups than that of the control group. The incidences of multiple tumors of the three rare subtype groups were higher than that of the control group (P < 0.05). Positive surgical margin was an independent unfavorable prognostic factor. CONCLUSIONS: The combined hepatocellular carcinoma and cholangiocarcinoma, giant cell carcinoma and sarcomatoid carcinoma have a poor prognosis. Among them sarcomatoid carcinoma is the most malignant and poor prognostic one. Radical resection is recommended.

Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1).

Programmed death-1 (PD-1) is a coinhibitory inducible receptor present on T-cells and macrophages. Tumor cells with increased programmed death ligand-1 (PD-L1) are believed to escape immunity through activation of PD-1/PD-L1 pathway and suppression of effector-immune responses. Recent strategies targeting the PD-1/PD-L1 axis have shown promising results in patients with several tumors types, including lung carcinomas. Preliminary data suggest that PD-L1 protein expression might have predictive response to such therapies. Sarcomatoid carcinomas (SCs) of the lung include rare subtypes of poorly differentiated non-small-cell lung carcinomas of high grade and aggressive behavior. The biology of these neoplasms is poorly understood and they frequently show increased local inflammatory and lymphocytic infiltration. Here, we report the expression of PD-L1 in 13 SCs from two large retrospective lung cancer cohorts. Using automated quantitative immunofluoresence and a mouse monoclonal antibody directed against the extracellular domain of PD-L1, we show that 9 of 13 patients (69.2%) with SCs are positive for PD-L1 and their levels are higher than in conventional non-small-cell lung carcinoma. These results provide rationale for the potential use of targeted immunotherapy in lung SCs.

The value of biomarkers in patients with sarcomatoid carcinoma of the lung: molecular analysis of 33 cases.

UNLABELLED: To better understand the prognosis of sarcomatoid carcinoma of the lung, the correlation between several biomarkers (ERCC1 [excision repair cross-complementation group 1] and EGFR [epidermal growth factor receptor] expression, EGFR and KRAS mutations, and EGFR copy number) and clinical outcomes in 33 patients with lung sarcomatoid carcinoma was evaluated. Survival analysis identified several significant factors that predicted overall survival. BACKGROUND: Sarcomatoid carcinoma (SC) of the lung is a rare histologic group of lung cancers with a poor prognosis. To better understand the prognosis of lung SC, in this study, we evaluated the correlation between several biomarkers and clinical outcomes in patients with lung SC. PATIENTS AND METHODS: A cohort of 33 patients with lung SC was studied. Protein expressions of excision repair cross-complementation group 1 (ERCC1) and epidermal growth factor receptor (EGFR) were examined by immunohistochemistry. Somatic EGFR and KRAS mutations were identified by direct sequencing. EGFR gene copy number was evaluated by fluorescence in situ hybridization. ERCC1 messenger RNA expression in paraffin-embedded tumor specimens was detected by branched DNA assay. RESULTS: Our analyses identified 9 patients (9/32) with EGFR mutations and only 1 patient (1/32) with a KRAS mutation. No exon 19 deletion of EGFR gene was detected. Lower messenger RNA levels of ERCC1 were detected in patients with EGFR mutations and/or fluorescence in situ hybridization amplified status. Survival analysis identified several significant factors, including performance status and clinical staging, that predicted for overall survival. CONCLUSION: SC exhibits diverse genotypic variations. Results of our study suggest that chemotherapy could still be an optimal solution for untreated advanced SC, whereas EGFR tyrosine kinase domain inhibitors alone may not be an effective approach.

Suppression of lung cancer cell invasion and metastasis by connexin43 involves the secretion of follistatin-like 1 mediated via histone acetylation.

Although connexin has been recognized as a tumor suppressor in many types of cancer, the underlying mechanisms are poorly understood. We have previously shown that transfection of connexin43 (Cx43) cDNA retarded the growth of a highly metastatic human pulmonary giant cell carcinoma cell line, PG, both in vitro and in vivo. Here, we further demonstrate that the metastasis and invasion, but not the migration, of PG cells are also inhibited following Cx43 transfection. The diminishment of metastasis and invasion is associated with down-regulation of genes including MMP-2, S100A, LAMA4, and HDAC10, as well as up-regulation of genes such as MTSS1 and FSTL1 as revealed by gene chip analysis. Interestingly, the suppression effects of Cx43 are related to secreted factor(s), which are blocked by FSTL1 antibody treatment in a dose-dependent manner. Furthermore, the FSTL1 promoter was shown to be associated with acetylated histones H3 and H4 upon Cx43 transfection. These data suggest that Cx43 inhibits the invasion and metastasis of PG cells by modulating the secretion of FSTL1, which is regulated by histone acetylation. Cx43 may act as a "histone deacetylase inhibitor" to modulate gene expression and subsequent cellular functions in PG cells.

Abnormal nuclear structures (micronuclei, nuclear blebs, strings, and pockets) in a case of anaplastic giant cell carcinoma of the thyroid: an immunohistochemical and ultrastructural study.

The authors report a case of a 70-year-old woman with an anaplastic giant cell thyroid carcinoma, along with immunohistochemical and electron microscopic findings. Histologically, the tumor is characterized by mononucleated and multinucleated giant cells, lack of architectural cohesion, atypical mitoses, and extensive areas of coagulative necrosis. Tumor cells showed AE1/AE3 positivity as well as nuclear overexpression of p53 and ki-67. Semithin sections revealed multiple nuclei with heterogeneous size ranging from micronuclei to large-size (giant) nuclei. Micronuclei were confirmed by electron microscopy that disclosed also the presence of nuclear blebs, strings, and pockets. Morphological findings of these abnormal nuclear structures in conjunction with p53 and Ki-67 nuclear overexpression suggested a faulty mitotic checkpoint/mitotic catastrophe in the progression of anaplastic giant cell thyroid carcinoma.

[PAR-1 regulation of intracellular Ca²(+) mobilization in pulmonary giant cell carcinoma cell line PLA801D/PLA801C].

OBJECTIVES: To investigate molecular mechanisms of PAR-1 regulation on intracellular Ca²(+) mobilization in lung giant cell carcinoma cells in vitro and its involvement in tumor metastasis. METHODS: Free intracellular Ca²(+) ([Ca²(+)]i) was measured in lung giant cell carcinoma PLA801C and PLA801D cells by confocal microscopy. Sense and anti-sense PAR-1 expression vectors were transfected into PLA801C (C+)and PLA801D(D-) cells, respectively. The effects of PAR-1 expression were investigated by thrombin and TRAP-induced mobilization of [Ca²(+)]i in the C+ and D-cells. RESULTS: There were significant differences of the mean values of [Ca²(+)]i between PLA801D (59.55) and PLA801C cells (35.46, P < 0.01). The mean [Ca²(+)]i of C+ cells (45.77) was significantly higher than that of its control CV cells (35.46, P < 0.05), and the mean [Ca²(+)]i of D-cells (48.42) was significantly lower than that of its control DV cells (59.55, P < 0.05). The peaks of [Ca²(+)]i of C+ and CV cells were 48.19 ± 9.84 and 45.64 ± 9.87 (P < 0.05) respectively at 80 s and 100 s after thrombin treatment, but were 111.31 ± 25.00 and 52.93 ± 11.21 (P < 0.05) respectively at 60 s after TRAP treatment. The peaks of [Ca²(+)]i of D- and DV cells were 40.71 ± 5.89 and 61.07 ± 21.36 (P < 0.05) respectively at 60 s after thrombin treatment, but were 84.98 ± 11.23 and 102.58 ± 21.48 (P < 0.05) respectively at 40 s after TRAP treatment. CONCLUSIONS: The high metastatic potential of PLA801D and PLA801C may be related to [Ca²(+)]i of the tumor cells. PAR-1 may play an important role in the metastasis of lung giant cell carcinoma cells by up-regulating the intracellular Ca²(+).

Interleukin-34 is expressed by giant cell tumours of bone and plays a key role in RANKL-induced osteoclastogenesis.

Interleukin-34 (IL-34) is a newly discovered regulator of myeloid lineage differentiation, proliferation, and survival, acting via the macrophage-colony stimulating factor receptor (M-CSF receptor, c-fms). M-CSF, the main ligand for c-fms, is required for osteoclastogenesis and has been already identified as a critical contributor of the pathogenesis of giant cell tumours of bone (GCTs), tumours rich in osteoclasts. According to the key role of M-CSF in osteoclastogenesis and GCTs, the expression of IL-34 in human GCTs was first assessed. Quantitative analysis of IL-34 mRNA expression in 14 human GCTs revealed expression of this cytokine in GCTs as well as M-CSF and c-fms. Immunohistochemistry demonstrated that osteoclast-like cells exhibited a huge immunostaining for IL-34 and that mononuclear stromal cells were slightly positive for this protein. In contrast to osteoblasts, bone-resorbing osteoclasts showed very strong staining for IL-34, suggesting its potential role in the pathogenesis of GCTs by facilitating osteoclast formation. The role of IL-34 in osteoclastogenesis was then studied in murine and human models. IL-34 was able to support RANKL-induced osteoclastogenesis in the absence of M-CSF in all models. Multinucleated cells generated in the presence of IL-34 and RANKL expressed specific osteoclastic markers and resorbed dentine. IL-34 induced phosphorylation of ERK 1/2 and Akt through the activation of c-fms, as revealed by the inhibition of signalling by a specific c-fms tyrosine kinase inhibitor. Furthermore, IL-34 stimulated RANKL-induced osteoclastogenesis by promoting the adhesion and proliferation of osteoclast progenitors, and had no effect on osteoclast survival. Overall, these data reveal that IL-34 can be entirely substituted for M-CSF in RANKL-induced osteoclastogenesis, thus identifying a new biological activity for this cytokine and a contribution to the pathogenesis of GCTs.

[Maldiagnosis of giant-cell tumor of the bone in a patient with hyperparathyroid osteodystrophy].

The paper describes a case of maldiagnosis of giant-cell tumor in a patient with parathyroid osteodystrophy, in this connection elbow joint resection and replacement were made. Parathyroid adenoma with the symptoms of primary hyperparathyroidism was diagnosed only two years after surgery. Progression of diseases was accompanied by severe bone changes and the development of urolithiasis complicated by chronic renal failure. Thus, the interpretation of bone tissue changes without considering clinical and laboratory data led to the unwarranted surgical intervention and the late diagnosis of primary hyperparathyroidism. Differential diagnosis of a giant-cell tumor should be made, by obligatorily considering clinical and laboratory data, including the parameters of calcium metabolism.

Pleomorphic giant cell carcinoma of the urinary bladder.

In this report, we present the clinicopathologic features of 8 cases of the pleomorphic giant cell variant of urothelial carcinoma. This is a rare variant of bladder cancer recognized by the current World Health Organization classification of urologic tumors. The pleomorphic giant cell component varied from 20% to 100% of the tumor specimen; in 2 cases, the pleomorphic giant cell component composed greater than 50% of the tumor with 1 case showing pure pleomorphic giant cell carcinoma. The architectural pattern of the tumor varied from infiltrating pleomorphic tumor with bizarre giant cells to solid expansile nests with discohesive growth pattern; a hypocellular desmoplastic stromal response was present in 2 cases (25%) with single cells in sclerotic stroma. At histology, giant, bizarre, anaplastic cells with frequent typical or atypical mitotic figures were present in all cases. Seven mixed cases had concurrent conventional high-grade urothelial carcinoma; 2 cases presented features of micropapillary or lymphoepithelioma-like urothelial carcinoma. Variable size intracytoplasmic vacuoles were present in 2 cases. All patients had advanced-stage cancer (>/=pT3), and 6 (75%) had lymph node metastases. Immunohistochemical staining demonstrated that both pleomorphic giant cell and associated conventional urothelial carcinoma were positive for cytokeratins 7, CAM 5.2 and AE1/AE3, and epithelial membrane antigen; P63, thrombomodulin, and uroplakin III were positive in 6, 3, and 2 cases, respectively. Follow-up information was available in all cases (range, 6-74 months; mean, 20 months). Five of the patients died of disease from 6 to 17 months, and 2 patients were alive with metastases at 11 and 19 months. One patient had no evidence of disease at 74 months. In summary, pleomorphic giant cell is an aggressive variant of urothelial carcinoma associated with poor prognosis that presents at an advanced clinical stage. In limited samples, it may be misdiagnosed as secondary carcinoma or sarcoma, a pitfall of paramount importance for its clinical management.