Papillary thyroid carcinoma with fibromatosis-like stroma: a case report and review of the literature.

BACKGROUND: Papillary thyroid carcinoma (PTC) is a common neoplasia with multiple variants. One of these extremely rare and poorly described variants is PTC with fibromatosis-like stroma (PTC-FMS), a peculiar entity distinguished by its predominant mesenchymal component. This paper reviews the literature, discusses the diagnostic challenges, and the clinical and surgical implications of this type of tumor which has fewer than 30 cases reported in the literature. CASE PRESENTATION: We reported a case of PTC-FMS found in a 41-year-old Italian woman, who came to our Institute with a recent growth in the form of a mass on the neck. Further immunohistochemical examination showed ß-catenin aberrant staining both in the nuclei and cytoplasm of the mesenchymal cells. The patient underwent total thyroidectomy and received radioactive iodine (RAI) 2 months after surgery. CONCLUSION: Given the possibility of recurrence of PTC-FMS and the ineffectiveness of RAI therapy, complete surgical resection represents the main treatment for this type of tumor. Despite the fact that the specific nature of these lesions has yet to be determined, guidelines for classical PTC should be followed.

A Potentially Misleading Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) typically presents in patients with a chronic liver disease and rarely develops in healthy liver, especially within an accessory liver lobe. We present a case of a healthy 64-years-old woman who showed a serum alpha-fetoprotein (AFP) value of 226.3 µg/mL during a screening blood test. Past medical history was negative for chronic liver disease or cirrhosis. Intraoperative finding was an ovaloid mass connected with the second hepatic segment by a thin pedicle of hepatic tissue. Lesion was safely resected by laparoscopic approach. Histopathology analysis showed a trabecular hepatocellular carcinoma. After a 6-month follow up, there was no evidence of recurrent disease. This case report showed how serum AFP remains a highly sensitive marker, although the presentation of HCC was unusual. To our knowledge, this is the second case reported in the literature.

Lymphomas in sub-Saharan Africa--what can we learn and how can we help in improving diagnosis, managing patients and fostering translational research?

Approximately 30 000 cases of non-Hodgkin lymphoma (NHL) occur in the equatorial belt of Africa each year. Apart from the fact that Burkitt lymphoma (BL) is very common among children and adolescents in Africa and that an epidemic of human immunodeficiency virus (HIV) infection is currently ongoing in this part of the world, very little is known about lymphomas in Africa. This review provides information regarding the current infrastructure for diagnostics in sub-Saharan Africa. The results on the diagnostic accuracy and on the distribution of different lymphoma subsets in sub-Saharan Africa were based on a review undertaken by a team of lymphoma experts on 159 fine needle aspirate samples and 467 histological samples during their visit to selected sub-Saharan African centres is presented. Among children (<18 years of age), BL accounted for 82% of all NHL, and among adults, diffuse large B-cell lymphoma accounted for 55% of all NHLs. Among adults, various lymphomas other than BL, including T-cell lymphomas, were encountered. The review also discusses the current strategies of the International Network of Cancer Treatment and Research on improving the diagnostic standards and management of lymphoma patients and in acquiring reliable clinical and pathology data in sub-Saharan Africa for fostering high-quality translational research.

S100A13 is a new angiogenic marker in human melanoma.

Angiogenesis is critical in melanoma progression and metastasis and relies on the synthesis and release of proangiogenic molecules such as vascular endothelial growth factor (VEGF)-A and fibroblast growth factors (FGFs). S100A13 is a small calcium-binding protein that facilitates the release of FGF-1, the prototype of the FGF family. S100A13 is upregulated in astrocytic gliomas, in which it correlates with VEGF-A expression, microvessel density and tumor grading, and promotes a more aggressive, invasive phenotype in lung cancer-derived cell lines. To investigate the involvement of S100A13 in human cutaneous melanoma, we analyzed a series of 87 cutaneous melanocytic lesions: 14 common acquired melanocytic nevi, 14 atypical, so-called 'dysplastic' nevi, 45 melanomas (17 radial growth phase and 28 vertical growth phase) and 14 melanoma metastases. Main clinical and pathological features, including histotype, Breslow thickness, Clark's level and outcome were recorded. Microvessel density was determined with CD105/endoglin staining. Semiquantitative determination of S100A13, FGF-1 and VEGF-A protein expression was obtained by immunostaining. Quantification of S100A13 mRNA was achieved by real-time PCR. We found that S100A13 was expressed in melanocytic lesions; compared with benign nevi, S100A13 protein expression was significantly upregulated in melanomas (P=0.024), in which it correlated positively with the intensity of VEGF-A staining (P=0.041) and microvessel density (P=0.007). The level of expression of S100A13 mRNA also significantly increased with progression of disease, from radial growth phase (0.7+/-0.7) to vertical growth phase (3.6+/-3.1) to metastases (7.0+/-7.0) (P<0.001). Furthermore, S100A13 mRNA correlated positively with VEGF-A (P=0.023), TNM stage (P=0.05), risk of relapse (P=0.014) and status at follow-up (P=0.024). In conclusion, S100A13 is expressed in melanocytic lesions when the angiogenic switch occurs and it may cooperate with VEGF-A in supporting the formation of new blood vessels, favoring the shift from radial to vertical tumor growth. Therefore, S100A13 may represent a new angiogenic and prognostic marker in melanoma.

Possible implication of local immune response in Darier's disease: an immunohistochemical characterization of lesional inflammatory infiltrate.

Cell-mediated immunity is considered to be normal in Darier's Disease (DD), an inherited skin disorder complicated by skin infections. To date, there are no investigations on the local inflammatory infiltrate in DD skin lesions. In this immunohistochemical study we characterized and quantified it, making comparisons with two other inflammatory skin disorders, that is, pemphigus vulgaris (PV) and lichen ruber planus (LRP), and with the normal skin (NSk). We found a significant (P < .05) decrease of CD1a+ Langerhans cells (LCs) in DD, compared to PV, LRP, and NSk, and of CD123+ plasmacytoid dendritic cells (pDCs), compared to PV and LRP. We hypothesize that the genetic damage of keratinocytes might result in a loss of some subsets of dendritic cells and, consequently, in an impaired local immune response, which might worsen the infections that inevitably occur in this disease.

Inducible nitric oxide synthase expression in melanoma: implications in lymphangiogenesis.

Cutaneous melanoma preferentially metastasizes via the lymphatic route. However, the mechanisms of lymphatic invasion and metastasis to regional lymph nodes are poorly understood. Nitric oxide is a free radical molecule synthesized from L-arginine by nitric oxide synthases that plays a critical role in various physiological and pathological processes, including tumor growth and angiogenesis. We have tested whether inducible nitric oxide synthase expression correlates with lymphatic vessel density identified with D2-40 antibody and/or blood microvessel density identified with CD105/endoglin in a series of melanocytic nevi (n=28) and cutaneous melanomas (n=38), representative of various pT. Inducible nitric oxide synthase expression was significantly lower in melanocytic nevi in comparison with primary and metastatic melanomas (P<0.001). Mean microvessel density was significantly higher in primary and metastatic melanomas in comparison with melanocytic nevi (P<0.001 for intratumoral and P=0.001 for peritumoral vessels). Vertical growth phase melanomas showed a higher intratumoral microvessel density in comparison with radial growth phase melanomas (P=0.02). The number of peritumoral lymphatics was significantly lower in nevi as compared with primary and metastatic melanomas (P=0.01). No correlation between microvessel or lymphatic vessel and clinical outcome was found in melanomas. A significant direct correlation was observed between inducible nitric oxide synthase immunostaining in melanocytic tumor cells and the density of lymphatic vessels (peritumoral: P=0.001; intratumoral: P=0.08), and the density of peritumoral blood microvessel (P=0.02). Our findings support the hypothesis that inducible nitric oxide synthase is implicated not only in blood, but also in lymphatic vascular neoformation in melanoma. Mechanistic studies are needed to address the possibility that inducible nitric oxide synthase controls lymphangiogenesis, dissemination and lymphatic borne metastases.

Nucleolin protein expression in cutaneous melanocytic lesions.

BACKGROUND: Nucleolin is a major nucleolar argyrophilic protein involved in carcinogenesis. There are only few studies on its tissue expression in human cancer and none in melanoma. We aimed at exploring this protein and its prognostic impact in cutaneous melanocytic lesions. METHODS: We studied 193 cases including benign, dysplastic and malignant melanocytic lesions. Nuclear positivity was evaluated by immunohistochemistry and quantified by automated image analysis. RESULTS: Most dysplastic and malignant lesions showed high percentages of cells with abnormal patterns of nuclear positivity (Abn+N) consisting in multiple, irregular, positive dots (ID+) and a coarse, irregularly positive nucleoplasm (CNpl+) or both (ID+CNpl+). The patterns CNpl+ and/or ID+CNpl+ were never observed in benign lesions, in which ID+ were also virtually absent. Abn+N% was significantly lower in dysplastic nevi than in primary melanomas and metastases and in primary melanomas than in metastases (p < 0.05). Furthermore, Abn+N was the second powerful prognostic discriminator, after melanoma thickness, and a significantly lower survival was observed in vertical growth phase melanoma patients showing Abn+N in more than 50% of melanoma cells. CONCLUSION: An altered nuclear nucleolin expression seems to accompany melanoma progression. Further investigation on nucleolin functionality and subcellular trafficking could add information on its altered role in melanoma.

Utility of tumour-infiltrating CD25+FOXP3+ regulatory T cell evaluation in predicting local recurrence in vertical growth phase cutaneous melanoma.

Tumour-infiltrating lymphocytes (TILs) represent the local immune response to cancer, however, their correlation with tumour behaviour is not unanimously considered in the literature. Most studies have not characterized TILs, that are known to comprise distinct subsets, bearing different roles in the complex tumour microenvironment. Characterization of patient lymphocytes has been mainly performed in peripheral blood, that is not always representative of the local immune status. Only few investigations have been performed at the tissue level in cancer, including melanoma. TILs encompass different populations of effector and regulatory T cells (Tregs), and the relevance of the latter in tumour progression is widely accepted. The transcription factor gene product FOXP3 is considered the most reliable marker of Tregs. However, it has not been extensively evaluated in primary cutaneous melanoma. We analyzed 66 vertical growth phase primary cutaneous melanomas, aiming at finding differences in TIL subsets between two groups of cases, that behaved differently in terms of local recurrence. In our study, the percentage of Tregs, as characterized by CD25 and FOXP3 expression, both among tumour cells, inside tumour parenchyma and at its periphery, and among TILs, at the tumour-stroma boundary, was significantly higher in cases that recurred than in those that did not (p=0.00065; p=0.00014; p<0.00001, respectively). TIL characterization by immunohistochemistry in melanoma diagnostic reports, could add further information. The analysis of a larger series of patients and correlation with other clinical parameters, such as distant metastases and/or patient survival, are mandatory for validating its use as a prognostic indicator.

A look into the evolution of Epstein-Barr virus-induced lymphoproliferative disorders: a case study.

OBJECTIVES: Epstein-Barr virus (EBV)-induced lymphoproliferative disorders (LPDs) are lymphoid proliferations arising as a result of the loss of an effective EBV-specific cytotoxic T-cell response. LPDs may occur for primary or acquired impairment of the immune system, as well as in some persons without documented immunodeficiency. METHODS: In this article, we describe the case of a human immunodeficiency virus-positive patient affected by an EBV-LPD of the stomach who developed a nodal diffuse large B-cell lymphoma with complex morphologic and molecular features. RESULTS: GeneScan analysis of the gastric specimen identified two different heavy-chain immunoglobulin gene (IGH) rearrangements characterized by a dominant peak of 285 base pairs (bp) in length and a smaller peak of 266 bp in length. In the lymph node sample, IGH evaluation also demonstrated two different peaks; however, the main peak corresponded to the minor peak detected in the EBV-LPD specimen at the diagnosis. In addition, a monoclonal immunoglobulin light chain gene (IGL) rearrangement was also found. We also demonstrated that the major peak in the stomach corresponded to the EBV-positive population observed in the histologic sections. CONCLUSIONS: This case may provide additional insights to better understanding the "hit-and-run" role for EBV in lymphomagenesis. However, we could not exclude that our findings represent the co-occurrence of two unrelated B-cell neoplasms rather than a progression from an EBV-positive neoplasm to an EBV-negative one.

Benign glomus tumor of the urinary bladder.

Glomus tumors are rare, mesenchymal neoplasms of adulthood, which occur in both the sexes with equal frequency. Most of these tumors are benign, but some cases with atypical/malignant behavior have been reported. They most often occur in the extremities, typically in the subungual region of the fingers, and rarely involve the internal organs. We report the case of a 63-year-old man who presented with hematuria. The cystoscopy showed a polypoid lesion of the anterior wall of the bladder, which was diagnosed on biopsy as a benign glomus tumor. To the best of our knowledge, this is the first case of benign glomus tumor of the bladder described in the literature. This report widens the spectrum of the differential diagnoses of bladder neoplasms.

Lymphoepithelioma-like carcinoma of the ovary.

Only one case of lymphoepithelioma-like carcinoma of the ovary has been reported so far. A new case is herein illustrated in a 69-year-old woman: an ovarian mass adherent to urinary bladder dome with peritoneal carcinomatosis. Histologically, undifferentiated carcinomatous areas were intermingled with abundant lymphoid tissue. Epstein-Barr virus has not been detected either in neoplastic or in lymphoid cells.

Beclin 1 and LC3 autophagic gene expression in cutaneous melanocytic lesions.

Beclin 1 and LC3 autophagic genes are altered in several human cancer types. This study was designed to assess the expression of Beclin 1 and LC3 in cutaneous melanocytic lesions, in which they have not yet been investigated. In melanoma, we correlated their expression with conventional histopathologic prognostic factors. In 149 lesions, including benign nevi, dysplastic nevi, radial growth phase melanomas, vertical growth phase melanomas, and melanoma metastases, proteins were evaluated by immunohistochemistry, and, in representative cases of benign nevi, vertical growth phase melanomas and melanoma metastases were evaluated by Western blotting. In most lesions, messenger RNA level was also assessed by real-time reverse transcriptase polymerase chain reaction. Both genes were expressed in all the investigated conditions. Beclin 1 cytoplasmic protein and messenger RNA, as well as LC3 messenger RNA, significantly decreased with tumor progression (P < .05). The percentage of cases with high cytoplasmic expression of beclin 1 from 100% in benign nevi declined to 86.4% in dysplastic nevi, 54.5% in radial growth phase melanomas, 54.3% in vertical growth phase melanomas, and 26.7% in melanoma metastases. The lowest expression of LC3 II protein was observed in melanoma metastases (53.3% of cases) (P < .05); LC3 II protein overexpression was, however, found in several nonbenign lesions, with the highest percentage (45.5%) in radial growth phase melanomas. LC3 II protein expression was inversely correlated to thickness, ulceration, and mitotic rate. In a multivariate analysis, messenger RNAs for both genes discriminated between nonmalignant (benign and dysplastic nevi) and malignant (radial, vertical growth phase melanomas, and melanoma metastases) lesions. Our results, therefore, indicate that beclin 1 and LC3 II autophagic gene expression is altered also in melanocytic neoplasms.

The prognostic role of Beclin 1 protein expression in high-grade gliomas.

High-grade gliomas (HGG) have a poor outcome, however, prognostic subgroups of patients may be individuated by some clinico-biological parameters. It was recently demonstrated that the main response of HGG to therapy is autophagic death. Autophagy is involved in tumor suppression, and is defective in HGG, in which we previously found an underexpression of beclin 1 autophagic gene protein product. Underexpression of Beclin 1 protein has been correlated to poor patient outcome in other tumor types. In this paper, the prognostic role of Beclin 1 expression in HGG patients was investigated. We first evaluated the tumor cell cytoplasmic expression of Beclin 1 protein (BPCE), in a sample of 76 HGG by immunohistochemistry, and compared it with cell proliferation and apoptosis. We found high BPCE score positively correlated with apoptosis, and negatively with cell proliferation (p < 0.05). We then correlated BPCE score with survival and other prognostic parameters (histological grading, MGMT gene methylation status, age, patient performance status according to the Karnofski classification (KPS), extent of surgery, radiation therapy (RT) modality, temozolomide chemotherapy (TMZ CHT), and optimal/suboptimal post-surgical treatment). Forty-seven (61.8%) and twenty-nine (38.2%) patients showed high and low BPCE scores, respectively. BPCE showed statistically significant correlations with survival both at the univariate (p = 0.03) and multivariate analysis (p = 0.037). High BPCE was also positively correlated with high KPS values (p = 0.023), and with the accomplishment of an optimal postoperative therapy (p = 0.037). Furthermore, among patients showing a MGMT methylated gene, survival was significantly higher in cases with a higher BPCE score. BPCE score might be added to pathological evaluation of HGG for prognostic purposes.