PRAME and Historical Immunohistochemical Antibodies Ki-67, P16, and HMB-45 in Ambiguous Melanocytic Tumors.

ABSTRACT: Ambiguous melanocytic lesions/tumors (AMLs) can be simply described as melanocytic neoplasms that cannot be differentiated as either a melanoma or a nevus. Preferentially expressed antigen in melanoma (PRAME) is a novel antibody that can help differentiate between nevi and melanomas. However, its usefulness remains controversial in AMLs. The aim of this study was to demonstrate the importance of PRAME and diagnostic auxiliary antibodies (Ki-67, p16, HMB-45) in the diagnosis of melanocytic lesions, especially in AMLs. This study included 52 ambiguous melanocytic lesions, 40 nevi, and 40 melanomas. All immunohistochemical studies were performed automatically using the Universal Alkaline Phosphatase Red Detection Kit. Different analytic approaches were used for each antibody based on the literature. Statistically, the multinomial forward stepwise elimination logistic regression analysis was used to create a statistical model to predict the diagnosis of melanocytic lesions based on clinical, morphological, and immunohistochemical data. PRAME positivity was very strong and diffuse in the melanoma group and statistically significantly higher than that of the AML and nevus groups. There was no statistically significant difference between the nevus and AML groups. The Ki-67 proliferation index and HMB-45 staining pattern provided valuable indications for distinguishing between these 3 groups. The P16 antibody was limited in supporting the differential diagnosis. Our statistical model showed that a high mitosis count, central pagetoid spread, and PRAME positivity increased the probability of melanoma against an AML diagnosis. This study showed the advantages of evaluating the PRAME antibody together with morphological features and other immunohistochemical markers (Ki-67 and HMB-45) in the differential diagnosis of melanocytic lesions.

Breast cancer metastasis into thyroid papillary carcinoma: A case report.

Both metastatic tumors and breast cancer metastases in the thyroid gland are rare. Tumor metastasis into a primary thyroid cancer is rarer. We present a case with breast cancer metastasis into a metachronous thyroid papillary carcinoma which is the only case in literature.

Kindlin-3 and RASSF6 are probable biomarkers for predicting metastasis in cutaneous melanoma.

It is well known that metastasis is the most crucial factor in determining the fate of the patient. The prognosis of melanoma is very poor at the stage of metastasis. Recently, several genes and proteins, including kindlin3, dioxin receptor (AhR), RASSF6, and claudin-11, which were shown as possible prognostic biomarkers for human tumours, were described. In this study, we focused on these proteins in melanoma within a clinical setting. Forty-three primary melanomas (PMs), 17 metastatic melanomas (MMs), 15 melanocytic nevi (MN), and two melanoma cell lines were included in this retrospective study. All proteins were investigated using immunohistochemistry, and analysis was performed using a semi-quantitative immunoreactive score (IRS). The nevus group showed lower RASSF6 and AhR IRS levels than PMs. RASSF6 and kindlin-3 levels in the PMs with metastasis (MwM) and also in PMs showing lymphovascular invasion were significantly lower. The logistic regression model also proved that kindlin-3 expression was a significant independent predictor of metastasis. The current study supports the role of kindlin-3 and RASSF6 as prognostic biomarkers in melanoma. Besides the prognostic roles of these proteins, they are probably potential candidates for target-oriented therapies for melanoma metastasis blocking.

Are there EWSR1 rearranged cutaneous hidradenomas and mucoepidermoid carcinomas of salivary glands? A FISH study and review of the literature.

MAML2 rearrangements have been previously described for hidradenomas and muco-epidermoid carcinomas (MEC). However, one report showed EWSR1 rearrangement in both tumours. In this study, EWSR1 and MAML2 translocation were investigated in hidradenomas and MECs. Specimens from thirteen MECs of the salivary glands and twenty hidradenomas of the skin were evaluated. Fluorescence in situ hybridisation (FISH) studies with EWSR1 and MAML2 break-apart probes were used. Forty percent of hidradenomas and 84.6% of MECs showed a positive MAML2 break signal. EWSR1 break signal was absent in hidradenomas. Only two MECs showed positive EWSR1 signal and were, thus, reclassified as clear cell carcinoma (CCC). A statistically significant relationship was also observed between clear cells containing hidradenomas and the FISH status. Despite the previous study, EWSR1 translocations could not be established in hidradenomas and MECs. The study further suggests that evaluation of EWSR1 might be obligatory for the correct diagnosis of MAML2-negative MECs to exclude the chance of CCCs. The present study also supports the notion that MAML2 can be used as a marker for hidradenomas and MECs.

The prognostic effect of immunoscore in patients with clear cell renal cell carcinoma: preliminary results.

PURPOSE: This study aimed to evaluate the density of CD8+ and CD3+ tumor-infiltrating lymphocytes (TILs) and determine whether the immunoscore has any prognostic effect on the oncological outcomes in patients with clear cell renal cell carcinoma (RCC). MATERIALS AND METHODS: A total of 129 patients diagnosed with clear cell RCC following radical or partial nephrectomy between 2009 and 2014 were retrospectively analyzed. Both tumor core (CT) and the invasive margin of nephrectomy specimens were assessed. The specimens were immunostained for anti-CD8+ and anti-CD3+ TILs. The patients were divided into three groups (favorable, intermediate, and poor risk) according to immunoscore levels. RESULTS: In the multivariate analysis, a favorable immunoscore (I3-4) was associated with prolonged disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) (HR 2.652, 2.848, and 2.933, respectively; all p < 0.001). The lower Fuhrman grade and pathological tumor-node-metastasis (TNM) stage had better DFS, PFS, and OS, whereas prolonged PFS was associated with a higher density of CD8+ CT (HR 1.602, 95% CI 0.934-3.470; p = 0.014). The shorter DFS, PFS, and OS were observed in the group with poor immunoscore (I0-1) at the early TNM stage of RCC (p < 0.001). In the metastatic subgroup analysis, the immunoscore showed better estimation than the International Metastatic RCC Database Consortium model and the Memorial Sloan-Kettering Cancer Center risk model for progression and OS (p < 0.001). CONCLUSION: The additional contributions of immunoscore to TNM stage, Fuhrman grade, and the WHO/ISUP 2016 grade for estimating oncological outcomes were found in ROC analysis. According to our preliminary results, immunoscore can be a promising prediction tool in clear cell RCC for postoperative oncological outcomes following nephrectomy.

Hypoxic Gene Signature of Primary and Metastatic Melanoma Cell Lines: Focusing on HIF-1ß and NDRG-1

Background: Hypoxia is an important microenvironmental factor significantly affecting tumor proliferation and progression. The importance of hypoxia is, however, not well known in oncogenesis of malignant melanoma. Aims: To evaluate the difference of hypoxic gene expression signatures in primary melanoma cell lines and metastatic melanoma cell lines and to find the expression changes of hypoxia-related genes in primary melanoma cell lines at experimental hypoxic conditions. Study Design: Cell study. Methods: The mRNA expression levels of hypoxia-related genes in primary melanoma cell lines and metastatic melanoma cell lines and at experimental hypoxic conditions in primary melanoma cell lines were evaluated by using real-time polymerase chain reaction. Depending on the experimental data, we focused on two genes/proteins, the hypoxia-inducible factor-1 beta and the N-myc downstream regulated gene-1. The expression levels of the two proteins were investigated by immunohistochemistry methods in 16 primary and metastatic melanomas, 10 intradermal nevi, and a commercial tissue array comprised of 208 cores including 192 primary and metastatic malignant melanomas. Results: The real-time polymerase chain reaction study showed that hypoxic gene expression signature was different between metastatic melanoma cell lines and primary melanoma cell lines. Hypoxic experimental conditions significantly affected the hypoxic gene expression signature. In immunohistochemical study, N-myc downstream regulated gene-1 expression was found to be lower in primary cutaneous melanoma compared to in intradermal nevi (p=0.001). In contrast, the cytoplasmic expression of hypoxia-inducible factor-1 beta was higher in primary cutaneous melanoma than in intradermal nevi (p=0.001). We also detected medium/strong significant correlations between the two proteins studied in the study groups. Conclusion: Hypoxic response consists of closely related proteins in more complex pathways. These findings will shed light on hypoxic processes in melanoma and unlock a Pandora's box for development of new therapeutic strategies.

The Effect of Platelet-Rich Plasma on the Temporomandibular Joint After Radiotherapy in Rabbits.

OBJECTIVES: Platelet-rich plasma (PRP) was administered into the temporomandibular joint (TMJ) space, which had been exposed to radiotherapy (RT), in an attempt to prevent and/or treat the late-term complications associated with RT when used for the treatment of head and neck cancers (nasopharyngeal cancer in particular) on the musculoskeletal system. METHODS: A total of 13 adult male New Zealand ( Oryctolagus cuniculus) rabbits were used in the study. The animals were classified into 3 groups: 6 in the RT group, 6 in the RT+PRP group, and 1 in the control group (exposed to neither). The TMJ space of each rabbit was exposed to 2240 cGy external RT in total, and PRP was administered into the TMJ space 1 month later. The joints were surgically removed 1 month later and examined histopathologically. RESULTS: In the group given RT+PRP, the level of inflammation, amount of muscle fibrosis, vascular wall fibrosis, synovial membrane and condyle cartilage thickness, temporal extrabone fibrous cell layer count, and intramuscular changes were similar to those recorded in the control group, although the positive effects of PRP were not found to be statistically significant. CONCLUSIONS: The findings of the present study demonstrate that injections of PRP may increase joint inflammation and therefore enhance blood supply, resulting in the onset of regeneration. These favorable effects of PRP may be helpful in the fight against late-term musculoskeletal complications of RT and may minimize such side effects as sore jaw, malnutrition, and weight loss.

Lip cancer: Reconsidering the at-risk patients with pathological assessment.

OBJECTIVES: This study was aimed to overview the treatment protocols of lip cancer and find out a cutoff point of tumor diameter and depth of invasion (DOI) for the survival parameters. MATERIALS AND METHODS: One hundred and ninety-one patients with lip SCC were studied. RESULTS: The average age of the patients was 62 years. Among 191 patients, 82.7% of the patients were men, 96.4% of them had lower lip cancer, and 84% were staged as early (pT1, pT2 ). Primary tumor excision with neck dissection was applied to 62.3% of the patients. Lymph node metastases rate was found to be 11%, and recurrence rate was 6.3%. There was statistically significant difference in between the tumor diameters and DOI values of patients with and without metastasis, and recurrence (p < 0.01, p < 0.05, respectively). Regarding to the lymph node metastasis, the optimal cutoff point was found to be 7.5 mm for DOI and 21.5 mm for tumor diameter. Regarding to the recurrence, the optimal cutoff point was found to be 7.5 mm for DOI and 24.5 mm for tumor diameter. CONCLUSION: T2 lip cancer patients also seem to be in at-risk group for metastasis and recurrence. As a conclusion, elective neck dissection and frequent follow-up are recommended for these early-stage lip cancer patients.

Transducing-Like Enhancer of Split 1: A Potential Immunohistochemical Marker for Glomus Tumor.

Glomus tumors (GTs) are rare, perivascular soft tissue tumors. Although GTs are usually found in the subcutaneous tissue, they may be detected in extracutaneous sites and mucosal areas. Transducing-like enhancer of split 1 (TLE1) is a highly useful immunohistochemical marker, which basically helps in differential diagnosis of synovial sarcoma. Based on a coincidental detection of TLE1 in one GT case, we studied 26 additional GT cases to establish the importance and distribution of TLE1 in GTs. Of 24 subcutaneous GTs, 22 (91.6%) were positive for TLE1 antibody and the remaining 2 mucosal GTs were negative. Of the 22 positive cases, 10 showed strong nuclear positivity. There was no difference between the subtypes of the GTs. Although TLE1 expression is significantly correlated to SS18 (SYT) rearrangements in synovial sarcomas, the fluorescence in situ hybridization analyses of the GTs showed no evidence of translocation involving this locus. TLE1 is a potential immunohistochemical marker for GTs, but further studies are required to confirm this finding.

Two Different Cell Populations Is an Important Clue for Diagnosis of Primary Cutaneous Adenoid Cystic Carcinoma: Immunohistochemical Study.

Primary cutaneous adenoid cystic carcinoma (PCACC) is a very rare malignancy. The differential diagnosis of PCACCs in pathology practice can be difficult and a group of primary and metastatic lesions, including adenoid basal cell carcinoma of the skin, should be considered in the differential diagnosis. Besides histomorphological clues, immunohistochemistry studies are very helpful in the differential diagnosis of PCACC. We report herein a case of PCACC with extensive immunohistochemical studies and review the literature from an immunohistochemistry perspective.

Extradigital Glomus Tumor of Thigh.

Glomus tumors are benign neoplasms that arise from neuromyoarterial glomus bodies. They represent around 1-5% of all soft-tissue tumors. High temperature, sensitivity, and pain and localized tenderness are the classical triad of symptoms. Most glomus tumors represent in the subungual area of digits. Extradigital glomus tumors are a very rare entity. There are rare cases of these tumors reported to be in shoulder, elbow, knee, wrist, even stomach, colon, and larynx. We are reporting a case of a glomus tumor on thigh and discuss the histological and immunohistochemical features.

The Effect of Helicobacter pylori on Gastric Cancer Treated with Adjuvant Chemotherapy After Curative Resection.

Helicobacter pylori has been associated with diverse pathologies of varying severity. We investigated the H. pylori infection status and its association with the pathologic features and clinical outcomes in stage III gastric cancer patients treated with adjuvant therapy after curative resection. Between 2004 and 2009, the records of 76 consecutive patients were retrospectively reviewed. H. pylori infection was confirmed by examination of pathological specimen. The relationship between H. pylori and the clinicopathological features was analyzed by Fisher exact test, Student's t test, and Kaplan-Meier method. Of the 76 patients, 16 patients (21.1 %) were confirmed for H. pylori infection. The median age was 59 years. Twenty-three patients received chemotherapy and remainder received chemoradiotherapy. H. pylori status did not correlate with the clinicopathologic features. It was greater in non-neoplastic tissue than the tumor tissue (21.1 vs 7.9 %). Median follow-up was 21 months. During this period, 88.2 % patients had experienced tumor recurrence, and 85.5 % patients had died. Recurrence was observed in 87.5 % patients and in 88.3 % patients in H. pylori-positive and H. pylori-negative patients, respectively (P = 0.92). Disease-free survival was 28.4 ± 7.9 months and overall survival was 31.5 ± 7.4 months in H. pylori-positive patients compared with 28.3 ± 3.7 and 33.2 ± 3.4 months, respectively, in H. pylori-negative patients. H. pylori infection status did not have effect on the overall or disease-free survival (p = 0.85 and P = 0.86), respectively. H. pylori status might not be useful as a prognostic and predictive factor for clinical outcomes.

Clinical experience in appendiceal neuroendocrine neoplasms.

AIM OF THE STUDY: To analyse the incidence of appendiceal neuroendocrine neoplasms in appendectomy specimens and establish the epidemiological and histopathological features, treatment, and clinical course. MATERIAL AND METHODS: Between 2004 and 2013, 975 patients who underwent appendectomy in Ankara Oncology Education and Research Hospital were retrospectively analysed. RESULTS: Neuroendocrine neoplasm was detected in the nine of 975 (0.9%) patients. Neuroendocrine neoplasms were diagnosed in eight patients by appendectomy, which was performed because of the prediagnosis of acute appendicitis, and in one patient by the suspicious mass detection during surgical procedures that were done in the appendix for a different reason. Eight of the patients' tumours were in the tip of the appendix, and one of the patients' tumours was at the base of appendix. Tumour size in 77.8% of patients was equal or less than 1 cm, in 22.2% patients it was 1-2 cm. There was tumour invasion in the muscularis propria layer in four patients, in the serosa layer in three patients, and in the deep mesoappendix in two patients. Patients were followed for a median of 78 months. In the follow-up of patients who were operated because of colon cancer, metachronous colon tumour evolved. This patient died due to progressive disease. Other patients are still disease-free. CONCLUSIONS: The diagnosis of neuroendocrine neoplasm is often incidentally done after appendectomy. Tumour size is important in determining the extent of disease and in the selection of the surgical method during operation.

Scrotal skin metastasis from rectum adenocarcinoma.

Cutaneous metastases of rectal adenocarcinoma is a rare phenomenon. We present a 65 year-old man with a painless nodule on the scrotal skin. Excisional biopsy of the nodules revealed a metastasis from rectum adenocarcinoma. Afterwards, the left scrotum was treated with a radiation therapy and the patient also received a salvage chemotherapy. The patient is still alive without any distant metastasis after the therapy, which was initiated 12 months ago.

Surgical management of recurrent malignant schwannoma of the scalp.

Localization of malignant schwannoma in the head and neck region is rare. Malignant schwannoma is a highly aggressive, slowly growing, encapsulated tumor of nerve sheath origin. The most common presentation of this tumor is a subcutaneous progressively enlarging mass with or without neurologic symptoms. These tumors arise from neurofibromas with or without von Recklinghausen disease, and most of the remains develop from peripheral nerve trunks. We report a case with recurrent malignant schwannoma of the scalp that is an uncommon presentation and discuss the clinicopathologic properties of this tumor.

Hemangiopericytoma of the pineal region.

We report a unique case of a 37-year-old female suffering from hemangiopericytoma of the pineal region, successfully excised by surgery. Hemangiopericytomas are rare malignant vascular tumors arising from mesenchymal cells with pericytic differentiation. These tumors usually develop in the limbs, pelvis, head, neck, and mostly in the muscle tissue. They are aggressive lesions that tend to occur at an earlier age than other meningeal tumors, recur with high frequency, and metastasize extracranially. Hemangiopericytomas represent less than 1% of all CNS tumors. Surgery remains the mainstay treatment. Radiotherapy and/or chemotherapy are the other treatment options.

A child with myelodysplastic syndrome with hypocellular fibrosis.

A 9-year-old girl with intractable anemia, rare mucocutaneous bleeding, and pallor was presented. Hemoglobin was 49 g/L; reticulocyte 0.79%, mean corpuscular volume 81 fL, platelet 37×109/L; white blood cell count 3.2×109/L with dysmorphic cells in peripheric blood. Further evaluation revealed 10% cellularity with grade IV reticulin fibrosis, immature, and/or dysplastic hematopoietic cells without sideroblasts, or blast increase in biopsy, Monosomy 8 was found in bone marrow aspiration material using FISH. Vitamin B12, folic acid, hemoglobin electrophoresis, immunoglobulin levels, CD55, CD59, complement 3, 4, abdominal ultrasonography, chest x-ray were normal; diepoxybutane, acid ham, sucrose lysis tests, viral serologies, antinuclear antibody, anti DNA were negative. On diagnosis of "Myelodysplastic Syndrome-refractory cytopenia with hypocellular fibrosis," she received a successful allogeneic BM transplantation from her full matched sibling.

FAS, FAS ligand, tumor infiltrating lymphocytes, and macrophages in malignant melanoma: an immunohistochemical study.

BACKGROUND: FAS and its ligand, FASL, have important roles in the neoplasia-immunity relationship. In melanoma, the importance of FAS and FASL remains controversial, despite a group of studies. In this study, we aimed to demonstrate the distribution of FAS/FASL in melanotic lesions and to investigate the correlation between tumor infiltrating lymphocytes and macrophages. METHODS: Ten intra-dermal nevi, 12 primary malignant melanoma, and eight skin and 15 lymph node metastases were included in this study. FAS and FASL were studied in all of the groups using classical labeled streptavidin-biotin immunohistochemical method. Tumor infiltrating lymphocyte status and macrophage number demonstrated by CD68 immunostain were also evaluated in primary melanoma and skin metastases. RESULTS: FAS positivity was detected in all of the cases. FASL expressions were seen in 60% of the intra-dermal nevus and in all of the other groups. There were significant differences in FASL between nevus and primary melanoma, nevus and skin metastasis, and nevus and lymph node metastasis. There were strong positive correlations between FAS expression and intra-neoplastic macrophage score and between FASL and density of lymphocyte infiltration in skin metastases. CONCLUSION: Although FAS and FASL expression is a constant feature of melanotic lesions, its diagnostic importance is very limited because of the different results obtained in the past studies. The correlation between FAS status and macrophage number and between FASL status and lymphocyte number in skin metastasis but not in primary lesions might point to diverse FAS/FASL interaction between neoplastic cells and macrophages in the different microenvironments.

Lung cancer associated with a single simultaneous solitary metastatic lesion in stomach: a case report with the review of literature.

Metastatic tumors of the stomach are rare. Although neoplasms from almost every tissue have been reported to metastasize to the stomach, lung cancer is a rare cause. We report the case of 46-years-old man presented with superior Vena Cava syndrome. Histopathological diagnosis was non-small cell lung cancer with computed tomography-guided needle biopsy of lung. Since gastric symptoms occurred during follow up of patient, upper gastrointestinal endoscopy performed. Upper gastrointestinal endoscopy and biopsy showed metastasis of stomach secondary to primary squamous cell lung cancer and additionally lack of another distant site metastasis indicated that gastric region was the single site of tumor spread.