Neuroendocrine Transdifferentiation in Cutaneous Melanoma: A Case Report and Review of the Literature.

ABSTRACT: Neuroendocrine transdifferentiation refers to the progressive transformation of a nonneuroendocrine tumor to the one showing evidence of neuroendocrine differentiation on morphological and immunohistochemical grounds. Although this phenomenon has been well-documented in certain malignancies, particularly prostatic adenocarcinoma after androgen deprivation, cases of neuroendocrine transdifferentiation in melanomas are exceptionally rare. Herein, we report a case of a conventional superficial spreading melanoma occurring on the skin of the leg in a young male which showed progressive neuroendocrine transdifferentiation as it progressed through 2 in-transit metastases and a nodal metastatic deposit over a 4-year period. The tumor retained the BRAF V600E mutation throughout the disease process, and disease control was achieved through dual BRAF inhibition therapy. The possibility of melanoma masquerading as a high-grade neuroendocrine malignancy when investigating tumors of unknown primary should be kept in the mind of clinicians and histopathologist alike as a potential diagnostic pitfall, thus helping avoid misdiagnosis and guide appropriate treatment strategies.

Metastatic paraganglioma.

A man in his 70s, with a history of a glomus jugulare paraganglioma diagnosed 18 years ago, presented with an unprovoked deep vein thrombosis (DVT). The paraganglioma had been treated by radiotherapy, and yearly scans had not shown any progression since treatment. A sclerotic focus in L4 vertebral body was reported on a CT scan of the neck and trunk which was done to exclude a neoplastic process being the precipitating factor for the DVT. Nuclear imaging showed multiple areas of bony uptake, suggestive of metastases. A bone biopsy of the left femur resulted positive for metastatic paraganglioma. A monthly intramuscular injection of octreotide 30 mg was prescribed.

Palmar Digital Vein Thrombosis: A Case Report and Review of 36 Cases.

Thrombosis of the palmar digital veins is relatively rare, typically reported in women aged 35-65 years and most commonly occurring on the fourth digit. Clinical presentation varies and the lesion can present on the fingers or the palms of the hands. Diagnosis may be suspected clinically and confirmed on histology and radiologically. The condition can be managed conservatively or surgically. A 58-year-old woman presented with a 3-month history of a tender, skin-coloured nodule on her right palm. This was surgically excised, and the histopathological diagnosis was a thrombosed varix. As no underlying medical issues were raised on further testing, it was thought that her thrombosed varix was likely secondary to repeated trivial mechanical trauma, given that she was a housewife. A literature review yielded 36 cases of thrombosed varix, including our case. Most cases (85.3%) occurred in females, and the mean age of patients was 51.67 years, with two-thirds of patients between 35 and 65 years of age. The fourth digit and the proximal interphalangeal joint were the most commonly affected sites, respectively. Although rare, doctors should consider the possibility of a thrombosed varix when presented with tender and raised nodules on the palms or fingers. LEARNING POINTS: Thrombosis of the palmar digital veins is rare but can occur secondary to mechanical trauma and hypercoagulable states.Physicians should consider the possibility of a thrombosed varix when presented with a tender, raised and firm nodule on the hand or fingers, especially since some cases may be associated with hypercoagulable states which can have more serious sequelae.

Suppressive role exerted by microRNA-29b-1-5p in triple negative breast cancer through SPIN1 regulation.

MiR-29 family dysregulation occurs in various cancers including breast cancers. We investigated miR-29b-1 functional role in human triple negative breast cancer (TNBC) the most aggressive breast cancer subtype. We found that miR-29b-1-5p was downregulated in human TNBC tissues and cell lines. To assess whether miR-29b-1-5p correlated with TNBC regenerative potential, we evaluated cancer stem cell enrichment in our TNBC cell lines, and found that only MDA-MB-231 and BT-20 produced primary, secondary and tertiary mammospheres, which were progressively enriched in OCT4, NANOG and SOX2 stemness genes. MiR-29b-1-5p expression inversely correlated with mammosphere stemness potential, and miR-29b-1 ectopic overexpression decreased TNBC cell growth, self-renewal, migration, invasiveness and paclitaxel resistance repressing WNT/ßcatenin and AKT signaling pathways and stemness regulators. We identified SPINDLIN1 (SPIN1) among predicted miR-29b-1-5p targets. Consistently, SPIN1 was overexpressed in most TNBC tissues and cell lines and negatively correlated with miR-29b-1-5p. Target site inhibition showed that SPIN1 seems to be directly controlled by miR-29b-1-5p. Silencing SPIN1 mirrored the effects triggered by miR-29b-1 overexpression, whereas SPIN1 rescue by SPIN1miScript protector, determined the reversal of the molecular effects produced by the mimic-miR-29b-1-5p. Overall, we show that miR-29b-1 deregulation impacts on multiple oncogenic features of TNBC cells and their renewal potential, acting, at least partly, through SPIN1, and suggest that both these factors should be evaluated as new possible therapeutic targets against TNBC.

Laryngeal lymphoma: the high and low grades of rare lymphoma involvement sites.

The larynx is an extremely rare site of involvement by lymphomatous disease. We present two cases of isolated laryngeal high-grade and another low-grade lymphoma, together with a literature review of laryngeal lymphoma management.

Clinical outcome of pediatric collagenous gastritis: case series and review of literature.

Collagenous gastritis (CG) is characterized by patchy subepithelial collagen bands. Effective treatment and the clinical and histological outcome of CG in children are poorly defined. The aim of this study is to summarize the published literature on the clinical outcome and response to therapy of pediatric CG including two new cases. We performed a search in Pubmed, OVID for related terms; articles including management and clinical and/or endo-histologic follow up information were included and abstracted. Reported findings were pooled in a dedicated database including the corresponding data extracted from chart review in our patients with CG. Twenty-four patients were included (17 females) with a mean age of 11.7 years. The clinical presentation included iron deficiency anemia and dyspepsia. The reported duration of follow up (in 18 patients) ranged between 0.2-14 years. Despite most subjects presenting with anemia including one requiring blood transfusion, oral iron therapy was only documented in 12 patients. Other treatment modalities were antisecretory measures in 13 patients; proton pump inhibitors (12), or histamine-2 blockers (3), sucralfate (5), prednisolone (6), oral budesonide in 3 patients where one received it in fish oil and triple therapy (3). Three (13%) patients showed no clinical improvement despite therapy; conversely 19 out of 22 were reported with improved symptoms including 8 with complete symptom resolution. Spontaneous clinical resolution without antisecretory, anti-inflammatory or gastroprotective agents was noted in 5 patients (4 received only supplemental iron). Follow up endo-histopathologic data (17 patients) included persistent collagen band and stable Mononuclear cell infiltrate in 12 patients with histopathologic improvement in 5 patients. Neither collagen band thickness nor mononuclear cell infiltrate correlated with clinical course. Intestinal metaplasia and endocrine cell hyperplasia were reported (1) raising the concern of long term malignant transformation. In summary, CG in children is a chronic disease, typically with a variable clinical response and an indolent course that is distinct from the adult phenotype. Long term therapy usually included iron supplementation but cannot be standardized, given the chronicity of the disease, variability of response and potential for adverse events.

An unusual site for calciphylaxis: a case report.

BACKGROUND: Calciphylaxis is a rare condition characterized by calcification of the tunica media of small arteries with or without endovascular fibrosis, extravascular calcification and vascular thrombosis, leading to tissue ischemia and hence necrosis of tissues supplied by respective vessel. CASE REPORT: An 83-year-old lady presented with a 2-week history of rapidly progressing painful necrotic vulval lesion. This patient was being treated medically with bisphosphonates for mild hypercalcaemia secondary to a parathyroid adenoma. The diagnosis of calciphylaxis was made by biopsy of lesion, revealing extensive necrotic areas and multiple abscesses with numerous thrombosed and calcified blood vessels. CONCLUSIONS: This case shows an unusual presentation of calciphylaxis, in a patient with primary hyperparathyroidism, in the absence of end stage renal failure. The pathogenesis of the condition is still relatively unknown. Particularly of note in this case is the presentation of the lesion 9 months after the start of treatment with bisphosphonate after the relative decrease of serum parathyroid levels and serum calcium levels. This leads to the question of initiation of the pathology - did the bisphosphonate treatment have an input in initiation of the lesion? The case under review adds a new differential diagnosis to necrotic vulval lesions, other than malignancy.

Lymphoma of the cervix.

Primary non-Hodgkins lymphoma of the uterine cervix is a very rare diagnosis. A 54-year-old woman presented with a 3-month history of postmenopausal bleeding per vaginum. On examination, a friable, fungating lesion was seen on the cervix. Histology revealed a CD 20 positive high-grade non-Hodgkin's diffuse large B cell lymphoma from cervical biopsies and endometrial curettage. She was diagnosed as stage IE after workup and subsequently treated with six cycles of R-CHOP chemotherapy followed by radiotherapy of the involved field.

Evaluation of a method allowing preservation of fresh lymph nodes for flow cytometric immunophenotyping.

BACKGROUND: Flow cytometric immunophenotyping (FCI) of lymph nodes (LN) requires fresh unfixed tissue, with analysis being carried out within few hours post surgery. This study evaluated a novel method for fresh LN preservation, in order to allow histomorphology-based FCI. METHODS: This study was carried out prospectively on 30 LN with suspected involvement by haematolymphoid neoplasms (HLN). FCI was performed on each fresh and post cryopreserved LN cell suspension. Percentage positivities (PP) and mean fluorescent intensities (MFI) were calculated on both preparations for a combination of T and B-lymphoid antigens together with viability. RESULTS: The cryopreservation method applied in this study did not affect significantly PP and had minor impact on MFI of the tested antigens. Overall, there was minimal decrease in PP and MFI on the cryopreserved cells when compared with fresh cells, for most antigens with only a mild increase in apoptotic cells. However, these changes were not diagnostically significant, since both reactive processes and HLN present within analyzed LN could be identified and differentiated. Viability was more than 75% for all cryopreserved LN composed of haematolymphoid cells. CONCLUSION: The method presented in this study confers the possibility of storing fresh LN biopsies for later FCI, thus allowing a morphology-based immunophenotypic approach. This would allow a more sensitive, specific, and cost-effective management of LN specimens, whilst maintaining the important benefits provided by FCI.

Expression and clinical significance of Wnt players and survivin in pituitary tumours.

Deregulation of the Wnt pathway has been implicated in oncogenesis of numerous tissues including the pituitary gland. Immunohistochemical localization and quantification of ß-catenin, Cyclin D1, c-MYC and Survivin expression in 47 pituitary adenomas (35 non-functioning, seven GH-secreting, three prolactinomas, two ACTH-secreting tumour) and six normal controls was undertaken in this study and correlation of protein expression to patient and tumour characteristics analysed. ß-catenin was strictly membrane-bound with no difference observed between normal and tumour tissue. In contrast, Cyclin D1 and c-MYC localization was nuclear and significantly higher in tumour versus normal tissue (p < 0.05). c-MYC expression correlated negatively with age at diagnosis (p = 0.006, R = -0.395) while Cyclin D1 expression correlated positively with age (p = 0.036, R = 0.306) and was higher in males than in females (p = 0.036). c-MYC expression was significantly lower in patients with functional tumours requiring octreotide treatment and in patients with non-functioning tumours suffering from hypopituitarism. Survivin expression was extremely low in tumours and absent in normal controls. Involvement of the canonical Wnt pathway appears to be minimal, given the segregation of ß-catenin to the membrane. Our data suggest that c-MYC may have an important role in early pituitary tumorigenesis while Cyclin D1 is likely to promote tumour growth at a later stage. We also report a novel gender difference in Cyclin D1 expression, the biological significance of which merits further analysis. The reported reduction of c-MYC in functional tumours subsequently treated with octreotide further supports a role of c-MYC in early tumorigenesis and not in recurrence. The decrease in c-MYC in patients with hypopituitarism provides the first in vivo evidence for hormonal regulation of c-MYC expression.

A difficult case of Crohn's disease?

A young lady with a long history of recurrent infections was referred to the gastroenterology department by an infectious disease consultant because of a long history of profuse diarrhoea. A nitroblue tetrazolium (NBT) test performed in her mid-teens had shown zero reduction of the dye. The clinical, biochemical, radiological and endoscopic findings were suggestive of possible underlying Crohn's disease. However, the NBT test was more suggestive of a granulomatous colitis which frequently mimics Crohn's disease in patients with Chronic granulomatous disease. Management with immunosuppressants is proving to be very difficult in this patient in view of recurrent sepsis on introducing these drugs.

Testicular mass in an elderly patient: a rare presentation of Hodgkin's lymphoma.

A testicular mass in an elderly man has a high probability of being a lymphoma. However, when the pathologist is faced with a neoplastic lymphoid infiltrate in the testes, one rarely considers Hodgkin's lymphoma as a possibility, as a vast majority turn out to be diffuse large B cell lymphomas. The authors discuss the second case of Hodgkin's lymphoma, nodular sclerosis subtype, presenting as a painless enlarged testicle and associated symptoms similar to irreducible hernia in a 73-year-old gentleman. The patient was later found to have subdiaphragmatic lymph node disease. Hodgkin's lymphoma should therefore be given due consideration in the differential diagnosis of a testicular tumour with a predominantly lymphoid infiltrate.

Distinction of isolated tumour cells and micrometastasis in lymph nodes of breast cancer patients according to the new Tumour Node Metastasis (TNM) definitions.

Isolated tumour cells and micrometastases represent two different staging categories and are often dealt with differently when identified in sentinel lymph nodes of breast cancer patients. The reproducibility of these categories was found to be suboptimal in several studies. The new edition of the TNM (Tumour Node Metastasis) is expected to improve the reproducibility of these categories. Fifty cases of possible low-volume nodal involvement were represented by one to four digital images and were analysed by members of the European Working Group for Breast Screening Pathology (EWGBSP). The kappa value for interobserver agreement of the pN (TNM) staging categories and of the isolated tumour cells category were 0.55 and 0.56 reflecting moderate reproducibility, and the kappa of the micrometastatic category (0.62) reflected substantial reproducibility. This is an improvement over the results gained on the basis of the previous edition of the TNM. Maximal adherence to the category definitions supplemented by explanatory texts in the staging manual should result in more homogeneous nodal staging of breast cancer.

Incidence of inflammatory bowel disease in Malta between 1993 and 2005: a retrospective study.

BACKGROUND: The primary aim of the study was to estimate the incidence of Crohn's disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel disease (IBD), in Malta in a well-defined population during a 13-year study period. METHODS: Diagnostic criteria for CD and UC were defined. A diagnosis of IBD was obtained from the histopathology reports at St. Luke's Hospital, Malta, between January 1993 and December 2005. The date of diagnosis was defined as the date of the first histopathology report revealing signs of IBD. RESULTS: Incidence rates were standardized using the direct method on the European Standard Population. The mean incidence of UC in males was 8.16 per 100,000 per year and for females was 7.59 per 100,000 per year, while that for CD in males was 0.96 per 100,000 per year and for females 1.622 per 100,000 per year. Using linear regression, in UC there is an almost significant (P = 0.069) increasing trend with time but no difference by gender (P = 0.591). On the other hand, in CD there is no significant trend with time (P = 0.555) but almost a significant difference by gender (P = 0.078). CONCLUSIONS: This is the first Maltese study in which the incidence of IBD has been recorded. In Malta the incidence of UC is similar to the overall incidence of other European countries while the incidence of CD is lower. In fact, the incidence rates of CD are among the lowest in Europe, similar to other southern European countries.

Cutaneous melanoma in the Maltese Islands: 2000-2004.

This study aimed to, prospectively, over the 5-year period 2000-2004, accurately determine features of cutaneous melanoma in the Maltese Islands. Data from clinicians were supplemented by histology reports, and where necessary, histology slides were reviewed. Information collected included demographic details including age and gender, anatomical site, Clark's level, Breslow thickness and clinico-pathological melanoma type. During the study period the age-standardised (European Standard Population) rates for invasive melanoma were 8.81 per 100,000 (males) and 7.29 per 100,000 (females) and increased with age. By the end of the study, information on 166 cases of primary invasive cutaneous malignant melanoma were collected. The commonest site affected in males was the trunk (54%) and in females the lower limbs (41%). Overall, 33.8% of invasive melanomas had a Breslow thickness >1.5mm. The initial melanoma excision was performed by a dermatologist in 68.2% and plastic surgeon in 20.8%. More cases presented in late spring and summer, particularly in females. Melanoma incidence in Malta is lower than that in high-incidence countries and northern Europe and is similar to that in southern Europe. However, incidence appears to be increasing and a relatively high proportion of patients present with thick lesions emphasising the importance of continued efforts to diagnose cases earlier.