Bilateral Adrenal and testicular Tumours; When a Simple Diagnosis Becomes Complicated.

A 78-year-old man with a BMI 28.7, a moon face and a medical history of diabetes mellitus, hypothyroidism, undefined adrenal insufficiency and history of cardiac ablation, had been in urological follow up for both prostate and bladder cancer. PSA remained low after radiation and adjuvant ADT. Cystoscopy revealed no recurrence after transurethral resection of bladder tumour and instillation of BCG. A routine CT scan as indicated by EAU guideline, showed bilateral enlargement of the adrenal glands as the only abnormality de novo. Patient had no other symptoms than already long-existing fatigue. Considering patient's medical history, subsequently a FDG PET scan was performed which showed intense FDG uptake not only bilaterally in the adrenal glands, but also in both testes. An ultrasound of the testes demonstrated hypodense lesions with increased flow. US imaging raised the suspicion of testicular adrenal rest tumours. Differential diagnoses were primary testis tumour, metastatic disease, BCG-itis, lymphoma or rare endocrine disorders. The combination of bilateral adrenal gland hyperplasia and testicular masses reminded us of seeking the rare diagnosis of ectopic adrenal remnant in both testis and a Cushing-like feature. Endocrinological evaluation could not establish an all-encompassing diagnosis to explain all of the clinical findings. Bilateral orchidectomy was performed. Histological examination showed localization of diffuse large B cell lymphoma (DLBCL) in both testes. Patient was referred to the haematologist and started with chemotherapy, R-CHOP. The diagnostic process in this case was challenging and misleading.

Dissecting the gray zone between follicular lymphoma and marginal zone lymphoma using morphological and genetic features.

Nodal marginal zone lymphoma is a poorly defined entity in the World Health Organization classification, based largely on criteria of exclusion and the diagnosis often remains subjective. Follicular lymphoma lacking t(14;18) has similar characteristics which results in a major potential diagnostic overlap which this study aims to dissect. Four subgroups of lymphoma samples (n=56) were analyzed with high-resolution array comparative genome hybridization: nodal marginal zone lymphoma, t(14;18)-negative follicular lymphoma, localized t(14:18)-positive follicular lymphoma and disseminated t(14;18)-positive follicular lymphoma. Gains on chromosomes 7, 8 and 12 were observed in all subgroups. The mean number of aberrations was higher in disseminated t(14;18)-positive follicular lymphoma than in localized t(14:18)-positive follicular lymphoma (P<0.01) and the majority of alterations in localized t(14:18)-positive follicular lymphoma were also found in disseminated t(14;18)-positive follicular lymphoma. Nodal marginal zone lymphoma was marked by 3q gains with amplifications of four genes. A different overall pattern of aberrations was seen in t(14;18)-negative follicular lymphoma compared to t(14;18)-positive follicular lymphoma. t(14;18)-negative follicular lymphoma is characterized by specific (focal) gains on chromosome 3, as observed in nodal marginal zone lymphoma. Our results support the notion that localized t(14:18)-positive follicular lymphoma represents an early phase of disseminated t(14;18)-positive follicular lymphoma. t(14;18)-negative follicular lymphoma bears aberrations that are more like those in nodal marginal zone lymphoma, suggesting a relation between these groups.

The involvement of Galectins in the modulation of the JAK/STAT pathway in myeloproliferative neoplasia.

BACKGROUND: In patients with myeloproliferative neoplasia (MPN) the development of fibrosis and increased vessel density correlate with poor prognosis. The JAK2(V617F) mutation constitutively activates JAK2, which phosphorylates signal transducer activator of transcription (STAT), up-regulating vascular endothelial growth factor (VEGF), which might be responsible for angiogenesis in MPN. Galectins are involved in the development of fibrosis and angiogenesis and might also be involved in activation of the JAK/STAT pathway in MPN. METHODS: 106 MPN patients, 36 essential thrombocythemia (ET), 25 polycythemia vera (PV) and 45 primary myelofibrosis (PMF), were analyzed for the expression pattern of galectin-1, galectin-3, pSTAT3, pSTAT5 and MVD by immunostaining of bone marrow biopsy sections followed by automated image analysis. The JAK2 mutational status was analysed through real time PCR in blood samples. RESULTS: The expression of galectin-1 was significantly higher in all MPN patients compared to normal controls. Galectin-3 was expressed more in PV patients. MVD was significantly higher in all MPN patients and correlated with galectin-1 and pSTAT5 expression. pSTAT5 expression showed a trend of higher expression in patients carrying the JAK2(V617F) mutation as well as in PV patients. PMF patients and all JAK2(V617F) positive patients showed a significantly higher pSTAT3 expression compared to control and ET patients. CONCLUSION: The findings suggest the involvement of galectin-1 in MPN development, regardless of the subtype. Furthermore involvement of galectin-3 in PV development, pSTAT5 in that of PV and JAK2(V617F) positive patients and angiogenesis, as well as pSTAT3 is involved in the pathogenesis of PMF.

Reproducibility of histologic classification in nonfibrotic myeloproliferative neoplasia.

Early phases of polycythemia vera, essential thrombocythemia, and primary myelofibrosis (PMF) can be difficult to distinguish by morphologic studies alone because they share many morphologic characteristics. Histologic criteria according to the 2008 World Health Organization (WHO) classification are part of the myeloproliferative neoplasia (MPN) diagnosis. Our aim was to assess the reproducibility of morphologic characteristics and determine their relative importance for histologic diagnoses on selected trephine biopsy sections. For the study, 56 prefibrotic MPN trephine specimens were blindly reviewed by 4 hematopathologists using a scoring list of 16 histologic characteristics mentioned in the WHO classification. Consensus was defined as agreement by 3 of 4 hematopathologists. High degrees of consensus were reached for individual major morphologic features used in the WHO classification, especially for the nuclear features of megakaryocytes (83%). Some of the features correlated positively or negatively with the histologic diagnosis of PMF. Consensus for the histologic classification of MPN was reached in 39 (70%) of 56 cases without knowledge of clinical data. This finding indicates a difference in the relative importance assigned to individual histologic characteristics by different hematopathologists.

Interobserver variability of laryngeal mucosal premalignant lesions: a histopathological evaluation.

The objective of this study is to measure interobserver variability in the classification of laryngeal mucosal premalignant lesions by reassessing the histopathology of previously diagnosed cases and to determine the possible therapeutic consequences of disagreement among observers. Histopathological assessment of 110 laryngeal mucosal premalignant lesions was done by three pathologists. Each slide had to be classified according to the World Health Organization, Squamous Intraepithelial Neoplasia, and the Ljubljana Squamous Intraepithelial Lesions systems. After the independent assessment, a joint meeting took place. To assess the relation between histopathological grading and subsequent clinical management, we created a two- and a three-grade system besides one comprising all options. For all analyses, the SAS/STAT statistical software was used. The highest unweighted κ-values concerning the all-options system are observed for the Squamous Intraepithelial Neoplasia classification (0.28, 95% confidence interval 0.23-0.33), followed by the World Health Organization and Ljubljana classifications. For the two-grade system the Ljubljana classification shows the highest unweighted κ-values (0.50, 95%, 0.39-0.61), followed by the World Health Organization and Squamous Intraepithelial Neoplasia classifications. For the three-grade system, the unweighted κ-values are similar. The implementation of weighted κ-values led to higher scores within all three classification systems, although these did not exceed 0.55 (moderate agreement). Given the high level of consensus, simultaneous pathological assessment may be said to provide added value in comparison with independent assessment. In the current study, no clear tendency is observed in favor of any one classification system. The proposed three-grade system could be an improved histopathological tool because it is easier to correlate with clinical decision making and because it yields better unweighted κ-values and proportions of concordance than the all-options system. Furthermore, clinical management could benefit from assessment by more than one pathologist in suspected cases of dysplasia or carcinoma.

Expression of aberrantly glycosylated Mucin-1 in ovarian cancer.

AIMS: Mucin 1 (MUC1) is an important tumour-associated antigen (TAA), both overexpressed and aberrantly glycosylated in adenocarcinomas. The aim of this study was to examine the MUC1-glycosylation status of primary ovarian adenocarcinomas and metastatic lesions. METHODS AND RESULTS: Paraffin-embedded tissue sections of 37 primary ovarian adenocarcinomas representing all histotypes (22 serous, five mucinous, two clear-cell, eight endometrioid), four serous borderline tumours with intraepithelial carcinoma, seven sections of ovarian endometriosis and 13 metastatic lesions were analysed by immunohistochemistry. Non-neoplastic ovarian surface epithelium and serous cystadenomas were used as controls. All epithelia expressed MUC1 protein. Of primary tumours, 76% expressed the differentiation-dependent glycoform and 84% the cancer-associated glycoform (Tn/Sialyl-Tn-epitopes). In metastatic lesions this was 77% and 85%, respectively. Notably, in 57% of ovarian endometriosis and 75% of intraepithelial lesions, the cancer-associated MUC1 epitopes were expressed, whereas normal ovarian surface epithelium and serous cystadenomas did not express these epitopes. CONCLUSIONS: The underglycosylated MUC1 epitopes are expressed by all histotypes of primary ovarian adenocarcinomas, by the vast majority of metastatic lesions and by possible ovarian cancer precursor lesions, but not by normal ovarian tissue. These results indicate that MUC1-associated Tn/STn-epitopes are important targets for immunotherapy and diagnostic imaging in ovarian cancer patients.

Cytologic diagnosis of rhabdomyosarcoma in a child with a pleural effusion. A case report.

BACKGROUND: A pleural effusion in children is usually caused by infectious diseases; malignant effusion is very uncommon. In a case of a malignant effusion in a child, a pleura-based metastasis of a neoplasm with a typically high prevalence in childhood has to be considered. Examples are neuroblastoma, nephroblastoma, Wilms' tumor, hepatoblastoma, malignant germ cell tumor and rhabdomyosarcoma. CASE: A 4-year old boy presented with a unilateral pleural effusion. Cytologic examination of the effusion revealed malignant small round cells admixed with very large cells with atypical nuclei. In formalin-fixed cell blocks prepared for immunocytochemistry the cells expressed desmin and myf-4. The cytologic diagnosis was consistent with metastatic rhabdomyosarcoma. Subsequent computed tomography revealed a mass above the diaphragm, which was biopsied. Histologic examination of a needle biopsy specimen confirmed the diagnosis of rhabdomyosarcoma. Molecular examination revealed a PAX3-FKHR fusion transcript specific to the alveolar type of rhabdomyosarcoma. CONCLUSION: This case illustrates the usefulness of immunocytochemistry on cell block preparations in diagnosing difficult cases of effusion cytology.