Low serum vitamin D levels are associated with a low percentage of TREM-2+ monocytes in low-grade gliomas and poorer overall survival in patients with high-grade gliomas.

INTRODUCTION: Anti-inflammatory effect of vitamin D (VD) could be beneficial in improving the survival of glioma patients. The aim of our study was to analyse the serum levels of vitamin D in glioma patients and to find an association with the prognosis of glioma patients and other investigated parameters. MATERIAL AND METHODS: The study included 63 patients with gliomas. Percentage of CD14+ monocytes, TREM-1+ and TREM-2+ monocytes were determined by flow cytometry, serum levels of 25(OH)D were evaluated by electrochemiluminescent binding test. RESULTS: Six patients out of 63 had normal levels of VD. A significant difference in the overall survival (OS) in the patients with severe VD deficiency, VD deficiency and insufficiency in grade IV was found. In grade II and III, the levels of vitamin D positively correlated with the percentage of TREM-2+ monocytes, and in grade II also a negative correlation of VD with TREM-1/TREM-2 ratio was observed. CONCLUSION: Levels of VD could influence the prognosis of patients with high-grade gliomas. Serum level of 25(OH)D in low-grade gliomas positively correlated with the percentage of anti-inflammatory acting TREM-2+ monocytes and negatively with TREM-1/TREM-2 ratio. This could be protective against the progression to high-grade glioma, because TREM-2 is associated with protective functions such as: tissue repair, control of local inflammation, or phagocytosis (Tab. 4, Fig. 4, Ref. 79).

Significance of transcriptionally-active high-risk human papillomavirus in sinonasal squamous cell carcinoma: Case series and a meta-analysis.

Sinonasal cancers represent a highly heterogeneous group of head and neck cancers, for which etiological and prognostic significance of high-risk human papillomavirus (HPV) infections has not yet been conclusively established. We investigated the presence of transcriptionally-active high-risk HPV in a series of 34 sinonasal squamous cell cancer (SNSCC) cases and evaluated the effect of transcriptionally-active HPV on the overall survival. In addition, we performed a meta-analysis of previously published studies, including this study, to summarize the prevalence of HPV positivity across histological subtypes of SNSCC. The presence of transcriptionally-active HPV was detected by HPV mRNA using the polymerase chain reaction (PCR) or in situ hybridization (ISH). p16 expression was evaluated as a surrogate marker for transcriptionally-active HPV infection by immunohistochemistry (IHC), the presence of high-risk HPV DNA was tested by PCR and the HPV genotypes were determined by sequencing of PCR amplicons. Transcriptionally-active HPV infections were found in ~25% of the SNSCC cases. The role of HPV infection in keratinizing SNSCC may be higher than previously reported (~32% in our study vs. ~0-6.3% in all other studies). Patients with transcriptionally-active HPV-positive SNSCCs were more likely to be diagnosed at earlier stages (p<0.05) and displayed better mean overall survival, although the difference between HPV-positive and HPV-negative groups was not statistically significant. In contrast to other non-oropharyngeal squamous cell carcinomas (non-OPSCCs) of the head and neck, in SNSCCs, p16/IHC and p16/IHC+HPV DNA displayed high specificity as surrogate markers of transcriptionally-active HPV infections. However, p16/IHC may have significantly lower sensitivity as a surrogate marker of transcriptionally-active HPV in SNSCCs compared to OPSCCs. Furthermore, in our group of SNSCCs, all cases positive for high-risk HPV DNA by PCR were also transcriptionally-active (causative) infections with positive HPV mRNA by ISH. Our results imply a possible different role of HPV-mediated carcinogenesis of squamous cell epithelium in oropharyngeal and sinonasal sites with the latter displaying a lower proportion of causative HPV infections; nevertheless, most cases positive for high-risk HPV DNA, p16/IHC or combination thereof were also found positive for transcriptionally-active HPV. The prognostic significance of HPV status in SNSCCs remains inconclusive and future studies should investigate the presence of transcriptionally-active HPV by direct HPV testing.

TREM-1 and TREM-2 Expression on Blood Monocytes Could Help Predict Survival in High-Grade Glioma Patients.

OBJECTIVE: In recent years, the role of the modern inflammatory markers TREM-1 (triggering receptors expressed on myeloid cells) and HMGB1 (high mobility group box 1 protein) in tumorigenesis has begun to be studied. Their role in gliomas is not clear. The aim of our study was to find the role of inflammation in gliomas. Patients and Methods. In 63 adult patients with gliomas and 31 healthy controls, the expressions of TREM-1 and TREM-2 on CD14+ blood cells (method: flow cytometry) and the levels of soluble sTREM-1, HMGB1, IL-6, and IL-10 (Elisa tests) were analyzed. RESULTS: Cox proportional hazard analysis showed that a TREM-1/TREM-2 ratio was associated with reduced overall survival (HR = 1.001, P = 0.023). Patients with a TREM-1/TREM-2 ratio above 125 survived significantly shorter than patients with a TREM-1/TREM-2 ratio below 125. The percentage of CD14+ TREM-1+ cells was strongly associated with a plasma IL-6/IL-10 ratio (positively) and with IL-10 (negatively). Conversely, we found a higher percentage of CD14+ TREM-2+ monocytes in better surviving patients; these cells could downregulate the exaggerated inflammation and potentiate the phagocytosis in the tumor. The serum levels of HMGB1 negatively correlated with the percentage of CD14+ TREM-1+ cells and with the TREM-1/TREM-2 ratio. The positive correlation between the serum levels of a late proinflammatory cytokine HMGB1 with the percentage of TREM2+ CD14+ monocytes can be explained as an effort for suppression of systemic inflammation by anti-inflammatory acting CD14+ TREM-2+ cells. CONCLUSION: We showed that the TREM-1/TREM-2 ratio (expression on the surface of blood monocytes) could help predict prognosis in patients with gliomas, especially in high-grade gliomas, and that systemic inflammation has an impact on the patient's overall survival. This is the first study that showed that TREM expression on monocytes in peripheral blood could help predict prognosis in patients with gliomas.

[Lynch Syndrome -  the Pathologist's Diagnosis]. / Diagnóza Lynchova syndromu od patologa.

Lynch syndrome (formerly known as hereditary non-polyposis colorectal cancer) is the most com-mon hereditary colorectal cancer syndrome. The syndrome is caused by a germline mutation of one of the mismatch repair (MMR) genes responsible for DNA replication error repair. Impaired function of the proteins encoded by these genes leads to microsatellite instability (MSI), which is associated with increased incidence of neoplasms: mainly colorectal cancer. According to recent estimates, up to 5% of all colorectal cancers are associated with Lynch syndrome. Due to this relatively high frequency, familial occurence, absence of premorbid phenotype, and development of malignant tumors at a reproductive age, a correct diagnosis is important not only from an ethical but also from an economical point of view. Unfortunately, clinical means of diagnosis, namely, the revised Bethesda guidelines designed to detect patients suitable for genetic testing for Lynch syndrome, lack sufficient sensitivity. The methods associated with modern pathology are more sensitive than the clinical criteria used to detect patients suspected of having Lynch syndrome. Pathological diagnostics are based on direct or indirect detection of MSI. Indirect methods include analysis of morphological signs associated with MSI in histological samples from colorectal carcinoma patients and immunohistochemical investigation of MMR protein expression. To rule out sporadic cases caused by epigenetic inactivation of an MMR gene, molecular genetic investigation of the BRAF gene and methylation analysis of the MLH1 promoter are performed during diagnostic workup. A suspicion of Lynch syndrome based on the results of the methods mentioned above should be proven by detection of a germline mutation in an MMR gene in peripheral blood leukocytes.

Human papillomavirus and Epstein-Barr virus in nasopharyngeal carcinoma in a non-endemic eastern european population.

Nasopharyngeal carcinoma (NPC) is a rare malignancy in the Czech Republic and Slovakia, with the standardized incidence rate of < 1:100000 person-years. Viral status of NPC in these non-endemic Eastern European regions is currently unknown. In a retrospective study, we evaluated the presence of EBV and HPV in 62 NPC cases. EBV status was determined by the use of in situ hybridization (ISH) for EBV encoded small RNA 1 (EBER1). HPV status was examined with p16 immunohistochemistry, DNA ISH and DNA polymerase chain reaction. Sixty-one studied cases showed non-keratinizing morphology and one was keratinizing squamous cell carcinoma. Only one NPC with non-keratinizing morphology was scored as p16-positive (nuclear and cytoplasmic staining ≥ 70% of tumor cells). This case was positive for high-risk HPV by ISH and the DNA PCR confirmed the presence of HPV18 type. At the same time, this case was found negative for EBV. Remaining sixty-one cases that were scored as p16-negative were all found HPV-negative by ISH and the DNA PCR. EBV was detected in 85.5% (53/62) of cases and 9 cases were EBV-negative, including the case of keratinizing NPC. In contrast with previous reports on the prevalence of EBV-positivity in Caucasian patients with NPC, the majority of patients coming from this non-endemic region show EBV-positivity; therefore, they may be candidates for novel EBV-targeting therapies. Conversely, HPV-positive NPC is very rare and HPV does not seem to play a significant role in the etiopathogenesis of NPC in these Eastern European populations.

The recurrent primary retroperitoneal liposarcoma.

AIM: Describe a patient with multiple recurrences of the primary recurrent liposarcoma. CLINICAL CASE: A 60-years-old man complained of weight loss (BMI 18.4) with a palpable huge retroperitoneal tumour, which displaced left kidney, and was confirmed on USG and CT. Laboratory examination showed anaemia and pathological blood tests. Chest X-ray initially showed a negative finding. A complete transperitonealy surgical extirpation of the tumour with left side nephrectomy was performed on June 28, 2007. The tumour mass weight was 1900 g. It was lying on the posterior face of the kidney in diameters 170x120x120 mm, completely capsulated by thin grey-pink capsula with peripheral fat tissue on the section grey-pink, lobulary shaped, in ¾ parts with central necrotic changes. Histopathologically was confirmed the primary dedifferentiated (non-lipogenous) liposarcoma low grade of malignancy. Nephrectomy specimen was confirmed as age related finding. There was no evidence of positives surgical margins. Despite oncological and surgical treatment, followed repeated recurrence with eight transperitoneal surgeries in the retroperitoneum and abdomen with extirpation of the metastases, left side hemicolectomy, splenectomy and repeated extirpation tumour metastases from abdomen and radix mesenterii. Last tumour weighed 2900 grams. Patient died on January 9, 2011, after the eight surgeries on multiorgans failure due to hemorrhagic shock and persistent atrial fibrilaton by cardiopulmonary insufficiency. As a speciality, he was treated without transfusion because as Jehovah´s witness he refused blood derivates. CONCLUSION: Despite complex surgical and oncological treatment, the prognosis in patient with recurrent liposarcoma was fatal (Tab. 1, Fig. 5, Ref. 50).

Analysis of pheochromocytomas / paragangliomas from Eastern Slovakia.

This multi centre observational cohort study gives a view about the occurrence, clinical and laboratory presentation, localization, histological type and genetic background of pheochromocytoma (PHEO) and paraganglioma (PGL) in Eastern Slovakia. It included 28 patients (18 women + 10 men), of which 23 were diagnosed to have PHEO (82,1%) and 7 patients (25%) suffered from PGL with retroperitoneal, inguinal/pelvic and mediastinal distribution. Arterial hypertension was the major symptom present in 86 % with slight dominance of paroxysmal form (58%). In 3 cases (10,7%), the diagnosis was gained after differentiation of adrenal incidentaloma in asymptomatic patients. Five patients (17,8%) were classified to have malignant form of the disease. 9 patients (32,1%) were confirmed to have hereditary form - five of them (17,8%) with familiar medullar thyroid cancer (FMTC) and mutations in RET gene classified as multiple endocrine neoplasia 2A and 4 patients (14,3%) with germline mutations of SDHB gene, respectively. There was found a relatively high occurrence of other co-morbidities: thyroid disease in 20 patients (71,4%), impairment of glucose metabolism in 11 patients (39,3%) and apart from FMTC, 4 patients (14,3%) suffered also from other malignancy. Together with a bigger size of the primary tumor (6,6 cm), higher concentrations of metanephrines and prevalence of extra-adrenal tumors, malignant and hereditary forms, we suppose genetic and environmental factors of Eastern Slovakia may play a role in the etiopathogenesis of the tumors.

Gliosarcoma with alveolar rhabdomyosarcoma-like component: report of a case with a hitherto undescribed sarcomatous component.

UNLABELLED: Gliosarcoma (GS) is a relatively rare glioblastoma variant characterized by biphasic glial and mesenchymal differentiation patterns. The sarcomatous part most commonly resembles fibrosarcoma or so-called malignant fibrous histiocytoma. Rarely, GS shows heterologous lines of differentiation in the form of osteosarcoma, chondrosarcoma, liposarcoma, leiomyosarcoma, squamous or glandular malignant epithelial differentiation, or primitive neuroectodermal tumor (PNET)-like foci. When rhabdomyoblastic differentiation occurs, it is in the form of malignant spindle cells, with cross-striated strap cells or rounded rhabdomyoblasts reminiscent of the embryonal type of rhabdomyosarcoma. We are reporting a case of GS with an alveolar rhabdomyosarcoma-like component. The tumor consisted of poorly differentiated primitive small round cells growing in a solid and alveolar pattern, with minimal cytoplasm, markedly elevated mitotic activity and numerous apoptotic nuclei. Rhabdomyosarcomatous differentiation was confirmed by desmin and myogenin immunopositivity. To the best of our knowledge, this histologic pattern has not been previously reported in GS. Differential diagnostic considerations are discussed. KEYWORDS: gliosarcoma - alveolar rhabdomyosarcoma - myogenin - desmin.

Recurring multifocal leiomyosarcoma of the urinary bladder 22 years after therapy for bilateral (hereditary) retinoblastoma: a case report and review of the literature.

We report on a case of urinary bladder leiomyosarcoma in a 23-year-old woman, 22 years after therapy for bilateral retinoblastoma. The tumor presented with dysuria and macroscopic haematuria. Cystoscopy revealed a tumor localized in the trigonum covered by an ulcerated urothelium. The patient underwent a transvesical tumor resection. Eight months later, a second leiomyosarcoma developed in the vertex, at a site different from the previous one. A cystoscopic trans-urethral tumor resection was performed, followed by combined chemotherapy. One year later another recurrence occurred at the site of the primary resection. Open laparotomic resection of the involved bladder wall was performed. The patient remains both recurrence and metastases free after twenty months of follow-up. Molecular analysis of the peripheral blood showed rare germline point mutation in the intron 24 of the RB1 gene. FISH analysis of the tumor tissue revealed polyploid cells with relative loss of normal RB1 gene locus, indicating deletion and second hit loss of the second RB1 allele function. Along with the ten previously reported cases, this report suggests a non-random association between the hereditary retinoblastoma and urinary bladder leiomyosarcoma. Therapy with cyclophosphamide seems to be an important risk factor. Life-long surveillance for second malignancies, including bladder leiomyosarcoma is therefore mandatory in these patients.

[Targeted therapy of melanoma: fact or fiction?]. / Cielená liecba melanómu: fakt alebo fikcia?

Advanced malignant melanoma is incurable by the current means of therapy. Traditional morphological classification (nodular melanoma, lentigo maligna melanoma, nevoid melanoma etc.) does not have any significant prognostic or predictive impact. Recent advances in molecular pathogenesis and the availability of targeted therapies have produced several positive results. In the near future, the main challenge for pathologists, geneticists and oncologists will be the identification of accurate therapeutic targets, as well as mechanisms of resistance, in melanoma in the particular patient in care.

[Arteriovenous malformation in small intestine as atypical etiology of lower gastro-intestinal bleeding--a case report]. / Cievna malformácia v tenkom creve ako netypický zdroj krvácania z dolnej casti tráviaceho traktu--kazuistika.

Lower gastrointestinal tract bleeding (LGIB) is the acute abdomen, defined as gastrointestinal tract bleeding under the ligament of Treitz. We present the case report of patient iteratively hospitalized because of repeated LGIB. There were performed gastrofibroscopy, colonoscopy and capsule endoscopy, without the bleeding localization. Scintigraphy and computer tomography showed the origin of bleeding in terminal small intestine; the computer tomography diagnosed the arteriovenous malformation in this area. During laparotomy the resection of 120 cm of terminal small intestine was performed with end-to-end anastomosis. The recurrence of bleeding was not diagnosed. LGIB takes about 0.5% of acute hospitalization at surgery departments. After the stabilization of vital functions, the exclusion of the upper gastrointestinal tract bleeding and fast gastrointestinal tract preparation, the urgent colonoscopy is recommended. In case of non-successful colonoscopy, the most of authors recommend angiography, capsule endoscopy and double-balloon endoscopy. The conservative management is adequate in more than 2/3 of patients; in part of them the intervention during colonoscopy is possible. Surgical intervention with gastrointestinal tract resection is performed in less than 17% of patients. The urgent surgery is needed in 4.7% of patients. All the diagnostic and curative interventions have greater success and should be performed during the acute bleeding.

[Post-radiation dedifferentiation of meningioma into chondroblastic osteosarcoma]. / Postradiacná dediferenciácia meningeómu do chondroblastického osteosarkómu.

We report a case of post-radiation dedifferentiation of meningothelial meningioma into chondroblastic osteosarcoma. The tumor developed in a 61-year-old man, seven years after adjuvant stereotactical radiotherapy of recurring meningioma. Histologically, there was a continuous transition from atypical meningioma into chondroblastic osteosarcoma. The patient died three weeks after the surgery, without additional oncological treatment. To our knowledge, this case represents only the second reported case of post-radiation dedifferentiation of meningioma into osteosarcoma.

[Perivascular epithelioid cell tumor (PEComa) of the liver: a case report and review of the literature]. / Perivascular epithelioid cell tumor (PEComa) pecene: popis prípadu a prehl'ad literatúry.

Perivascular epithelioid cell tumor (PEComa) is rare entity and has been described only recently. By immunohistochemistry and genetics it belongs to the family of tumours which comprises angiomyolipoma, clear cell "sugar" tumor of lung, lymphangioleiomyomatosis and clear cell myomelanotic tumor of ligamentum falciforme/teres hepatis. We describe an unusual case of hepatic PEComa arising in a 55-year-old woman with previous history of glioblastoma. Histologically the tumor grew in expansive way, and was composed of clear and eosinophilic epithelioid cels, without vascular or lipomatous component characteristic of angiomyolipoma. There was mild nuclear pleomorphism, sporadic mitotic activity and haemorrhage without necrosis. On immunohistochemistry, the tumor was HMB-45+50, Melan-A and smooth muscle actin positive. Tyrosinase, S-100 protein, cytokeratin coctail, EMA, vimentin, muscle specific actin, CD10, TTF-1, hepatocyte, desmin and cyclin D1 were negative. Sporadic nuclear p53 positivity was seen. The main differential diagnosis of hepatic PEComa includes clear cell variant of liver cell adenoma and hepatocellular carcinoma, metastases of various clear cell carcinomas and metastasis of malignant melanoma. In respect of uncertain biologic potential of PEComa, long term follow up is indicated.

Paraganglioma of the mesenterium: a case report.

Extra-adrenal paragangliomas constitute 10 % or less of phaeochromocytomas/paragangliomas. Even rarer is the occurrence of paragangliomas outside the usual distribution of paraganglionic tissue. We report a case of extra-adrenal paraganglioma occurring in the small intestine mesentery in a 65-year-old man. To our knowledge, there are only seven case reports of paraganglioma occurring in this non-typical site. Computed tomography showed a solid expansive non-homogenously enhancing mesenteric mass, measuring 10 x 8 cm with peripheral cystic component. Histologically, the tumour had a typical organoid "zellballen" pattern, showed immunohistochemical positivity for synaptophysin, neuron specific enolase, CD-56, chromogranin, and focally vimentin, and was cytokeratin and EMA negative. S-100 protein stained few sustentacular cells. The patient was free from recurrence or metastasis three months after tumour resection. Although rare, paraganglioma should be included in the preoperative differential diagnosis of solid mesenteric tumours, to prevent any potential life-threatening event peroperatively in the case of a catecholamines-producing tumour.

[Epithelioid hemangioma of the foot]. / Epiteloidný hemangióm nohy.

Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia, EH/ALHE) is a rare benign angioproliferative lesion which typically occurs in the region of the head and neck. In the literature, occurence on the extremity is only rarely described. A case of multiple occurence of EH/ALHE in the skin of the toes and metatarsal bone with osteolysis is reported. Occurence on the extremity, superficial and deep affection and some "atypical" microscopic features may cause diagnostic dilemma. The key diagnostic features of EH/ALHE are vascular channels lined with epithelioid endothelial cells, surrounding layer of myopericytes, absence of atypia and mitotic activity and characteristic inflammation. Immunohistochemistry may be helpful in settling the diagnosis.