Glomus tumor closely related to a branch of the left sural nerve: a case of a rare lesion occurring at unusual location.

Glomus tumors are rare benign neoplasms arising from the glomus bodies of the skin; they account for 1.6 % of all soft tissue tumors. Since the great majority of these lesions are found on fingers and toes (especially under the nail, on the fingertip, or in the foot), a correct clinical diagnosis may prove difficult if one or more glomus tumors occur on an extra digital location. We report a case of a glomus tumor with prominent vascular component found in the left leg closely related to a branch of the sural nerve and originally believed to be a schwannoma.

Differential expression of HER2, STAT3, SOX2, IFI16 and cell cycle markers during HPV-related head and neck carcinogenesis.

The aim of this study was to analyze protein and gene expression of HER2 in 224 head and neck precancerous and malignant lesions by immunohistochemistry and FISH analysis. In parallel, expression of pStat3, Sox2, IFI16 and p16, Ki67 was evaluated. Immunohistochemical analysis was assessed on formalin-fixed paraffin-embedded (FFPE) tissue specimens. A combined method for HPV detection consisting of p16 immunostaining and two PCR probes was applied. HER2 gene status was evaluated by FISH analysis. HPV DNA was detected in 24% of cases with predominant HPV16 genotype. HPV-positive lesions had higher HER2, pStat3 and within carcinoma group, and higher IFI16 expression compared to the HPV-negative group (Fig. 1A-B-C). A strong positive correlation between Sox2 and proliferative activity was observed, whereas IFI16 expression displayed a negative relationship with Sox2 and Ki67 activity. The most striking result was higher pStat3 expression in HPV-positive lesions and its strong positive correlation with IFI16 expression. The presence of HPV may induce upregulation of HER2/neu, pStat3 and IFI16. High levels and a strong positive correlation between pStat3 and IFI16 suggest their synergistic pro-apoptotic effects in HPV-positive lesions.

PAD-mediated citrullination is a novel candidate diagnostic marker and druggable target for HPV-associated cervical cancer.

Citrullination is an emerging post-translational modification catalyzed by peptidyl-arginine deiminases (PADs) that convert peptidyl-arginine into peptidyl-citrulline. In humans, the PAD family consists of five isozymes (PADs 1-4, 6) involved in multiple diseases, including cancer. Given that high-risk (hr) human papillomaviruses (HPVs) are the etiological agents of cervical cancer, in this study, we sought to determine whether PAD-mediated protein citrullination would play a functional role in the HPV-driven transformation of epithelial cells. Here we show that both total protein citrullination and PAD4 expression levels are significantly associated with cervical cancer progression. Specifically, epithelial immunostaining for PAD4 revealed an increasingly higher histoscore from low-grade (CIN1) to high-grade (CIN2, CIN3) cervical intraepithelial neoplasia, and invasive squamous cell carcinoma (SCC) lesions, raising the attractive possibility that PAD4 may be used as tumor staging markers. Furthermore, taking advantage of the epidermoid cervical cancer cell line CaSki, which harbors multiple copies of the integrated HPV16 genome, we show that the expression of E6 and E7 HPV oncoproteins is impaired by treatment with the pharmacological pan-PAD inhibitor BB-Cl-amidine. Consistently, p53 and p21, two targets of HPV oncoproteins, are upregulated by the PAD inhibitor, which undergoes cell growth arrest and apoptosis. Altogether, these findings highlight a novel mechanism by which hrHPVs alter host regulatory pathways involved in cell cycle and survival to gain viral fitness, raising the possibility that PADs may represent an attractive target for developing novel host-targeting antivirals effective in preventing cervical cancer progression.

Human papillomavirus tumor-infiltrating T-regulatory lymphocytes and P53 codon 72 polymorphisms correlate with clinical staging and prognosis of oropharyngeal cancer.

The association between human papillomavirus (HPV) DNA positivity, p53 codon 72 polymorphisms, and the type of leukocyte infiltration in head and neck squamous cell carcinomas (HNSCC) and their combined impact upon patient survival is poorly investigated. For this reason, leukocyte infiltration profile and p53 codon 72 polymorphisms were assessed in freshly removed HNSCC specimens (N=71 patients). HPV detection was performed by nested-PCR followed by DNA sequencing. Viral loads were determined by quantitative RT-PCR. The choice to investigate fresh instead of archive paraffin-embedded specimens was privileged to avoid possible artifacts due to sample processing. HPV DNA was detected in 14% of cases. Oropharyngeal carcinomas were the most frequently associated with the presence of HPV16 DNA (41%) and were associated with p53 Pro/Pro or Pro/Arg polymorphisms. In HPV16-positive oropharyngeal carcinomas increased infiltrations of CD3+ and FoxP3+ T-cells correlated with higher HPV16 copy numbers. The presence of HPV may trigger a stronger immune response and may be considered a reliable marker for clinical staging and a more favorable prognosis of oropharyngeal carcinoma.

Primary sclerosing liposarcoma of the ovary: Case report and a review of the literature.

INTRODUCTION: Primary soft tissue sarcoma of the ovary is uncommon, with most literature reports being in the format of a single case report or small case series. PRESENTATION OF CASE: We report a case of a primary sclerosing liposarcoma of the ovary in a 67-year-old lady. She presented with a rapidly growing ovarian mass, which was surgically excised. Histologically, the lesion appeared nodular with alternating hypercellular and low-cellularity areas, with areas of necrosis. It comprised atypical spindled, oval and stellate cells set in abundant myxoid and fibrous hyalinised stroma. Immunohistochemistry showed expression of p16, CDK4, CD34, S-100 and MDM2. The case was sent to a referral centre where MDM2 gene amplification was detected by interphase fluorescent in-situ hybridisation (FISH) analysis, rendering a diagnosis of well-differentiated sclerosing liposarcoma with focal low-grade dedifferentiation. DISCUSSION: To the best of our knowledge, this is the first reported example of a sclerosing variant of liposarcoma in the ovary. Differential diagnosis includes microcystic stromal tumour (MST), sclerosing stromal tumour (SST), atypical spindle cell lipoma, myxoid liposarcoma, myxofibosarcoma, solitary fibrous tumour and low grade fibromyxoid sarcoma. CONCLUSION: Ovarian sarcomas are characterised by a rapid and aggressive clinical course, requiring multidisciplinary team input for ongoing management. Complete surgical resection with clear margins is the mainstay of treatment.

Different clinocopathological presentations of steroid cell tumour - Report of three rare cases.

INTRODUCTION AND IMPORTANCE: We present three cases of steroid cell tumour due to their rarity, their differing clinical presentations and the distinct pathology. CASE PRESENTATION: Case 1: A 50-year-old female presented with heavy menstrual bleeding. Adenomyosis and multiple leiomyomata were found along with an incidental 2.5mm, paratubal steroid cell tumour. Given the size of the tumour and the histopathological features this was considered benign. Case 2: A 69-year-old female patient presented with virilization, found to have a left ovarian steroid cell tumour. Since there was capsular infiltration, close follow up was advised. Case 3: A 35-year-old female patient presenting with an acute abdomen due to torsion of a 15 cm right ovarian mass. The mass showed immunomorphological features of a steroid cell tumour. Since this tumour was large and had features of necrosis, high mitotic activity and nuclear pleomorphism, it was regarded as malignant. CLINICAL DISCUSSION: Steroid cell tumours of the ovary are rare (<0.1 % of all ovarian neoplasms) with uncertain malignant behaviour and are difficult to diagnose especially if classical virilising symptoms are absent. CONCLUSION: Thorough histopathological analysis and immunohistochemistry are essential in arriving at a definite diagnosis when the classical presentation is absent.

Unusual Aspects of Small Cell Carcinoma of the Ovary of Hypercalcaemic Type: Retained SMARCA4 Immunohistochemical Staining and Positive Staining With TLE1.

Small cell carcinoma of the ovary of hypercalcaemic type (SCCOHT) is a rare and aggressive ovarian neoplasm that is most common in the second and third decades. Molecular studies have established inactivating SMARCA4 alterations as the driver of SCCOHT, these being present in over 95% of these neoplasms. SMARCA4 alterations almost always result in loss of immunoreactivity with SMARCA4 (BRG1) antibody, and this is an extremely useful adjunct in the diagnosis of SCCOHT. Herein, we report 7 cases of SCCOHT (2 from the same patient) with retention of nuclear immunoreactivity with SMARCA4, but with SMARCA4 alterations identified on molecular testing. All cases exhibited loss of SMARCA2 (BRM) immunoreactivity. In addition, following the identification of diffuse TLE1 immunoreactivity in one of these cases (which did not exhibit an SS18 gene rearrangement characteristic of synovial sarcoma), we stained a total of 63 cases of SCCOHT (14 on whole tissue sections: 49 on tissue microarray) with this marker and 7 of 14 (50%) and 22 of 49 (45%) were positive on whole sections and tissue microarray, respectively. Most cases were focally positive but occasional cases exhibited diffuse immunoreactivity. Our observations highlight the importance of SMARCA2 immunohistochemical staining and molecular testing in suspected cases of SCCOHT that exhibit retained SMARCA4 immunoreactivity. Th common expression of TLE1 in these neoplasms represents a potential diagnostic pitfall since synovial sarcoma may be considered in the differential, especially in cases with retained SMARCA4 immunohistochemistry.

Differential diagnosis of adipocytic differentiation in androgen-secreting mature ovarian teratoma with Leydig cell hyperplasia.

Mature cystic teratomas (dermoid cysts) of the ovary are very rarely associated with androgen production. The source of androgens in these cysts may be tumours such as Sertoli-Leydig cell tumour or Leydig cell hyperplasia. In this study, we present a case of virilisation in a postmenopausal female patient, where Leydig cell hyperplasia in a mature cystic teratoma was found to be responsible for the production of testosterone. In addition, extensive areas of lipomatous differentiation were identified. These areas showed significant alterations in adipocytic morphology, and differential diagnoses such as spindle cell lipoma (SCL) and atypical lipomatous tumour (ALT) were excluded after additional workup. Adipose tissue is traditionally described as an energy reservoir, but recently it has become clear that adipose tissue is a complex endocrine organ with additional metabolic roles in whole body homeostasis. Exuberant proliferation of lipomatous tissue in this teratoma raises the possibility of a synergistic role of Leydig cells and adipocytes in the development of hyperandrogenism.

Interaction between inflammation and angiogenesis during different stages of cervical carcinogenesis.

OBJECTIVE: The primary aim of this study was to investigate the role of angiogenesis and inflammatory cell response in cervical carcinogenesis. METHODS: Formalin-fixed tissue specimens from 58 uterine cervical specimens (8 CIN1, 14 CIN2, 28 CIN3, and 8 SCC), representing the different stages of cervical carcinogenesis, were immunohistochemically analyzed. Normal cervical tissue specimens were also included as controls. The present study assessed the expression of CD31 and CD105 to evaluate microvessel density (MVD), the macrophage marker CD68 and the panleukocyte marker CD45. In addition, expression of iNOS (inducible Nitric Oxide Synthase) was also evaluated. RESULTS: MVD, measured by either CD31 or CD105, increased along the continuum from normal epithelium to squamous cell carcinoma, and a significant correlation between the CD105-MVD and the CD31-MVD was observed (r=0.8735; p<0.0001). Furthermore, the number of infiltrating macrophages was significantly associated with progression to malignancy. Interestingly, there was a close positive correlation between macrophage counts and CD105-MVD (r=0.7525; p<0.0001). In striking contrast to the other angiogenic and inflammatory markers tested, iNOS expression was significantly reduced as cervical lesion grade progressed from low to high. CONCLUSIONS: Our findings demonstrated a positive correlation between neovascularity and macrophage counts, whereas iNOS expression displayed an inverse relationship with macrophage density and tumor progression. Low iNOS expression may modify the function of tumor-infiltrating macrophages toward a malignant phenotype that promotes tumor progression rather than an anti-tumor response.

Thymic stromal lymphopoietin in human pancreatic ductal adenocarcinoma: expression and prognostic significance.

Thymic stromal lymphopoietin (TSLP) has emerged as an important, but contradictory, player conditioning tumor growth. In certain contexts, by driving T helper (h) 2 responses via tumor-associated OX40 Ligand (OX40L)+ dendritic cells (DCs), TSLP may play a pro-tumorigenic role. The study elucidates the importance of TSPL in pancreatic ductal adenocarcinoma (PDAC), by analyzing: i) TSLP levels in PDAC cell-line supernatants and plasma from patients with locally-advanced/metastatic PDAC, pre- and post-treatment with different chemotherapeutic protocols, in comparison with healthy donors; ii) TSLP and OX40L expression in PDAC and normal pancreatic tissues, by immunohistochemistry; iii) OX40L expression on ex vivo-generated normal DCs in the presence of tumor-derived TSLP, by flow cytometry; iv) clinical relevance in terms of diagnostic and prognostic value and influence on treatment modality and response. Some PDAC cell lines, such as BxPC-3, expressed both TSLP mRNA and protein. Normal DCs, generated ex vivo in the presence of TSLP-rich-cell supernatants, displayed increased expression of OX40L, reduced by the addition of a neutralizing anti-TSLP polyclonal antibody. OX40L+ cells were detected in pancreatic tumor inflammatory infiltrates. Abnormally elevated TSLP levels were detected in situ in tumor cells and, systemically, in locally-advanced/metastatic PDAC patients. Of the chemotherapeutic protocols applied, gemcitabine plus oxaliplatin (GEMOX) significantly increased circulating TSLP levels. Elevated plasma TSLP concentration was associated with shorter overall survival and increased risk of poor outcome. Plasma TSLP measurement successfully discriminated PDAC patients from healthy controls. These data show that TSLP secreted by pancreatic cancer cells may directly impact PDAC biology and patient outcome.

A Singular Case of Neurosyphilis Manifesting Through a Meningovascular Chronic Inflammatory Process in Association with the Occurrence of Two Aneurysms Involving the Distal A2 Segment of Both Anterior Cerebral Arteries: A Case Report and Review of the Literature.

BACKGROUND: Although syphilis has become a rare disease in the Western world since the Second World War, it is believed to have infected 12 million people in 1999, with greater than 90% of cases occurring in the developing world. Moreover, since the year 2000, the rates of syphilis have been increasing in the United States, the United Kingdom, Australia, and Europe. Because of the mimic nature of the disease and the overall low rate of occurrence of its manifestations in advanced stages, a proper diagnosis may prove difficult. CASE REPORT: We report the case of a 41-year-old African man affected by neurosyphilis that manifested itself through a meningovascular chronic inflammatory process, with the peculiar feature of a bilateral aneurysm of probable mycotic origin involving the distal tract of A2 segment of both anterior cerebral arteries. CONCLUSIONS: Because of the mostly nonspecific nature of clinical manifestations of syphilis (particularly advanced syphilis) and its consequent tendency to masquerade as many other diseases, even a skilled physician may find its diagnosis quite challenging; thus, thorough clinical and radiologic investigations should be supported by serologic testing for syphilis in all cases of cognitive impairment. Mycotic intracranial aneurysms in association with neurosyphilis rarely are reported; however, they require early diagnosis and meticulous, individualized treatment. Because syphilis appears to be on the raise, further studies on the topic are warranted.

Plexiform schwannoma of the posterior pharyngeal wall in a patient with neurofibromatosis 2.

We report a case of plexiform schwannoma of the posterior pharyngeal wall that occurred in a 37-year-old man who had been previously diagnosed with neurofibromatosis type 2 (NF2). Plexiform schwannoma has been rarely reported in association with NF2. Moreover, as far as we know, only 6 cases of posterior pharyngeal wall schwannoma have been previously reported in the literature, none of which was associated with NF2 and none of which was histopathologically differentiated in schwannoma or plexiform schwannoma. The patient was treated with laser excision of the tumor via a transoral route, and at 6 and 12 months of follow-up, he exhibited no signs of recurrence. To the best of our knowledge, our patient represents the first reported case of a posterior pharyngeal wall schwannoma that occurred in association with NF2 and the first case in which the schwannoma was removed via transoral laser excision. This case illustrates that plexiform schwannoma is a possible finding in NF2 and that transoral laser excision is a safe surgical procedure in such a case.

Eosinophilic inflammation of chronic rhinosinusitis with nasal polyps is related to OX40 ligand expression.

The aims of this study were to investigate OX40 ligand expression in sinus tissue from patients with nasal polyposis compared with patients with chronic rhinosinusitis without nasal polyps (NPs), and to determine if OX40 ligand expression is related to eosinophilic sinus infiltration. Twenty patients with chronic rhinosinusitis (11 with and nine without NPs) and seven controls were enrolled in the study. The mRNA expression of OX40 ligand and thymic stromal lymphopoietin and its receptor were analyzed. The immunoreactivity score for OX40 ligand and the eosinophil count were obtained. The mRNA expression and immunoreactivity score of OX40 ligand were higher in patients with nasal polyposis than in patients without NPs, as well as healthy controls. The mRNA expression of thymic stromal lymphopoietin and its receptor was significantly higher in nasal polyposis than in the control, but not significantly higher than in chronic rhinosinusitis without NPs. A correlation between the number of OX40 ligand-positive cells and the number of eosinophils in sinus biopsies was found only in patients with nasal polyposis. In conclusion, the thymic stromal lymphopoietin/OX40 ligand axis is up-regulated in nasal polyposis and is related to the intensity of eosinophilic inflammation.

In vivo growth inhibition of head and neck squamous cell carcinoma by the Interferon-inducible gene IFI16.

The Interferon-inducible gene, IFI16 has been implicated in the control of cell growth, apoptosis, angiogenesis and immunomodulation. In a previous study we demonstrated that restoring levels of IFI16 in a head and neck squamous cell carcinoma (HNSCC)-derived cell line, HNO136, reduced its growth in vitro accompanied by a marked increase in doxorubicin-induced apoptosis. To evaluate the ability of IFI16 to inhibit in vivo tumorigenesis of HNO136 cells and to characterize the molecular mechanisms responsible for its anti-tumor activity, IFI16 expression on cell growth was evaluated by an in vivo tumorigenicity assay. After excision, tumors were subjected to morphometric and immunohistochemical analyses with markers of apoptosis, angiogenesis, and inflammation. Restoring IFI16 expression significantly reduced the in vivo tumorigenesis of HNO136, decreased tumor vascularization and increased areas of tumor necrosis. Further analysis revealed that IFI16 expression triggered apoptosis of tumor cells, as evaluated using TUNEL assay. Finally, restoring IFI16 protein to HNO136 cells increased CD45+ inflammatory cell infiltration of the tumor burden, predominantly consisting of CD68/CD14 positive macrophages. In accordance with our previous in vitro experiments, this study demonstrates for the first time that IFI16 exerts in vivo anti-tumoral activity by promoting apoptosis of tumor cells, by inhibiting neo-vascularisation, and by increasing the recruitment of macrophages through the release of chemotactic factors.

Cell cycle and viral and immunologic profiles of head and neck squamous cell carcinoma as predictable variables of tumor progression.

BACKGROUND: The aim of this study was to determine whether the aberrant expression of cell-cycle or immune-response markers together with human papillomavirus (HPV) positivity impacts patient survival in different head and neck squamous cell carcinoma (HNSCC) subsets. METHODS: A total of 59 HNSCC specimens were analyzed for expression of cell cycle and proliferation markers, and macrophage infiltration. HPV was evaluated by polymerase chain reaction and DNA sequencing. RESULTS: The HPV presence in oropharynx carcinoma was associated with survival advantage. Low Ki67 expression was associated with favorable outcome in oropharynx and oral cavity carcinoma. A more favorable outcome was associated with low cyclin E expression in larynx carcinoma and with low p53 expression in squamous cell carcinoma (SCC) of the oral cavity. A direct correlation between macrophage infiltration and tumor proliferation index was observed irrespective of the tumor subset. CONCLUSIONS: The assessment of proliferation, viral, and immunologic profiles may be crucial to finding beneficial treatments for the different HNSCC subsets.

[Fatal outcome after postexposure rabies vaccination in a patient with Parkinson's disease]. / Smrtni slucaj tokom postekspozicione vakcinacije protiv besnila obolelog od Parkinsonove bolesti.

INTRODUCTION: In Serbia and Montenegro postexposure rabies vaccination is performed using five doses of rabies vaccine with a potency of 2.5 I.U. It is given on 0, 3rd, 7th, 14th and 28th day, combined with human rabies immunoglobulin with the first dose. Modern rabies vaccines produced in cell cultures rarely cause neurologic complications, among which Guillain-Barre syndrome and parkinsonism. CASE REPORT: The authors report a case of a 78-year-old woman with a documented five-year history of Parkinson's disease, who was bitten by a rabid cat. Twelve hours later, when the rabies infection of the cat was confirmed by an immunofluorescence test, the patient received the first dose of rabies vaccine Verorab (Aventis), a cell culture vaccine, together with the human rabies immunoglobulin produced in Belgrade. After the third dose of rabies vaccine, the symptoms of Parkinson's disease progressed and vaccination was interrupted. However, one month later, the patient died with predominantly neurological symptoms. As the patient died at the time when incubation of rabies might have been expected, autopsy and rabies diagnostics were performed. AUTOPSY AND PATHOHISTOLOGIC FINDINGS: The autopsy and pathohistologic findings from the specimens treated with routine hematoxylin and eosin staining, together with immunofluorescence test, excluded rabies as a cause of death and revealed neurodegenerative changes typical for Parkinson's disease. Using two different fluorescent rabies antibodies, we performed a direct immunofluorescence antibody tests, but no rabies antigens were detected. However, in histologic slides of the brain stem, large intracytoplasmic inclusions were found in some neurons, identified as Lewy bodies characteristic for Parkinson's disease. CONCLUSION: Parkinson's disease, with its complications, was the cause of death of the patient bitten by a rabid cat. Furthermore, the coincidence of the progression of Parkinson's disease symptoms, at the time of postexposure rabies vaccination, points to the vaccine as a possible contributing factor to aggravation of the disease and lethal outcome.