Hsa-miR-139-5p is a prognostic thyroid cancer marker involved in HNRNPF-mediated alternative splicing.

It is critical to identify biomarkers and functional networks associated with aggressive thyroid cancer to anticipate disease progression and facilitate personalized patient management. We performed miRNome sequencing of 46 thyroid tumors enriched with advanced disease patients with a median follow-up of 96 months. MiRNome profiles correlated with tumor-specific histopathological and molecular features, such as stromal cell infiltration and tumor driver mutation. Differential expression analysis revealed a consistent hsa-miR-139-5p downexpression in primary carcinomas from patients with recurrent/metastatic disease compared to disease-free patients, sustained in paired local metastases and validated in publicly available thyroid cancer series. Exogenous expression of hsa-miR-139-5p significantly reduced migration and proliferation of anaplastic thyroid cancer cells. Proteomic analysis indicated RICTOR, SMAD2/3 and HNRNPF as putative hsa-miR-139-5p targets in our cell system. Abundance of HNRNPF mRNA, encoding an alternative splicing factor involved in cryptic exon inclusion/exclusion, inversely correlated with hsa-miR-139-5p expression in human tumors. RNA sequencing analysis revealed 174 splicing events differentially regulated upon HNRNPF repression in our cell system, affecting genes involved in RTK/RAS/MAPK and PI3K/AKT/MTOR signaling cascades among others. These results point at the hsa-miR-139-5p/HNRNPF axis as a novel regulatory mechanism associated with the modulation of major thyroid cancer signaling pathways and tumor virulence.

Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene.

Disruption of the Krebs cycle is a hallmark of cancer. IDH1 and IDH2 mutations are found in many neoplasms, and germline alterations in SDH genes and FH predispose to pheochromocytoma/paraganglioma and other cancers. We describe a paraganglioma family carrying a germline mutation in MDH2, which encodes a Krebs cycle enzyme. Whole-exome sequencing was applied to tumor DNA obtained from a man age 55 years diagnosed with multiple malignant paragangliomas. Data were analyzed with the two-sided Student's t and Mann-Whitney U tests with Bonferroni correction for multiple comparisons. Between six- and 14-fold lower levels of MDH2 expression were observed in MDH2-mutated tumors compared with control patients. Knockdown (KD) of MDH2 in HeLa cells by shRNA triggered the accumulation of both malate (mean ± SD: wild-type [WT] = 1±0.18; KD = 2.24±0.17, P = .043) and fumarate (WT = 1±0.06; KD = 2.6±0.25, P = .033), which was reversed by transient introduction of WT MDH2 cDNA. Segregation of the mutation with disease and absence of MDH2 in mutated tumors revealed MDH2 as a novel pheochromocytoma/paraganglioma susceptibility gene.

Fine-needle aspiration cytology diagnosis of metastatic nonhaematological neoplasms of the breast: a series of seven cases.

Metastatic neoplasms of the breast are rare. Mammary metastases as the initial presentation are even more infrequent and can simulate a primary malignancy clinically and radiologically. Recognition of metastatic tumors in the breast is important because it would prevent unnecessary mutilating surgery and would lead to appropriate treatment of the primary tumor. There is a broad variety of cytological appearances reported about primary tumors and few reports about secondary breast malignancies, specially diagnosed by FNAC. This study was carried out to examine the clinical and cytomorphologic features of metastatic breast tumors found in 12 de Octubre University Hospital during a period of 20 years. It confirms the utility of FNAC and describes findings that can help in the differential diagnosis that sometimes can be very difficult. Seven cases of nonhematological metastatic neoplasms of the breast were identified from the files of the Department of Pathology of the 12 de Octubre University Hospital from a total of 64,000 aspirates. We included only metastatic tumors from extramammary nonhematological neoplasms. There were nine cases of hematological metastatic neoplasm that were excluded. They were diagnosed with FNAC and confirmed by histopathology, with at least three years of follow up. The breast lump was the first manifestation of malignancy in one case of synovial sarcoma. The other six cases had been previously diagnosed of cancer. These included one malignant melanoma, one alveolar rhabdomyosarcoma, one mixed müllerian tumor, one medullary carcinoma of thyroid, one colonic adenocarcinoma, and one gastric adenocarcinoma. The period of time between primary tumor and metastases ranged from one month to eight years. An accurate cytologic diagnosis was made in all the cases. Immunocytochemistry was available but diagnosis could be made with cytomorphology alone in the seven cases. Fine-needle aspiration cytology is an excellent first line diagnostic modality that is particularly informative when clinical previous data are known. If metastatic disease is suspected, the material obtained by FNAC may provide a definitive diagnosis and prevent open surgical biopsy or mastectomy. We concur with previous reports that FNAC is a reliable, rapid, secure, and cost-effective approach to the diagnosis of palpable metastatic breast tumors.

Primary papillary serous carcinoma of the peritoneum: report of a case with diagnosis by fine needle aspiration and immunocytochemistry.

BACKGROUND: Primary papillary serous carcinoma (PPSC) of the peritoneum is a rare neoplasm, histologically indistinguishable from papillary serous carcinoma of the ovary, which diffusely involves the peritoneum but spares or minimally invades the ovaries. To the best of our knowledge, the preoperative and the fine needle aspiration diagnosis of this disorder have not been reported before. CASE: A woman developed an extensive peritoneal neoplasm 4 years after hysterectomy and bilateral salpingo-oophorectomy for benign disease. Fine needle aspiration of the tumor was performed, and the cytologic and immunocytochemical findings were consistent with papillary serous carcinoma. A diagnosis of PPSC of the peritoneum was rendered because review of all slides from previous surgical specimens showed no evidence of carcinoma and no other primary tumors were found elsewhere. CONCLUSION: Fine needle aspiration cytology coupled with immunocytochemical and clinical data allows an unequivocal preoperative diagnosis of papillary serous carcinoma (primary peritoneal or with an ovarian origin). The sole limitation to establish a primary peritoneal origin before surgery is the requirement to histologically study the ovaries. Based on this fact, the preoperative fine needle aspiration cytology diagnosis of PSCP should be restricted to oophorectomized patients.

Cutaneous metastasis of occult hepatocellular carcinoma: a case report.

BACKGROUND: Skin metastases from hepatocellular carcinoma (HCC) represented only 0.8% of all known cutaneous metastases in a recent large series. The most frequent site appears to be the head, but this fact has received little attention. An accurate cytologic diagnosis is extremely difficult in patients with unknown liver dysfunction. We report the cytologic features of a face metastasis from occult HCC. CASE: A 65-year-old woman presented with a mass in the right preauricular region of 2 months' duration. Her past medical history was noncontributory. Fine needle aspiration cytology was performed. Following the cytologic diagnosis, computed tomography revealed a 6-cm mass in the right lobe of the liver, portal vein thrombosis and involvement of the superior vena cava. The smears were very cellular. The most frequent pattern was trabecular with transmural endothelization. The cells had an epithelial appearance and polyhedral shape, exhibiting distinct borders. The nuclei were centrally placed, with a prominent nucleolus. The cytoplasm was granular. There were numerous atypical bare nuclei. Subsequent staining with antihepatocyte showed positivity in most tumor cells. The final diagnosis was metastatic HCC. CONCLUSION: HCCs should be considered in the differential diagnosis of carcinomas metastatic to the face, even in the absence of liver symptoms.

Fine needle aspiration of chromophobe renal cell carcinoma.

OBJECTIVE: To describe the cytomorphologic findings of chromophobe renal cell carcinoma (CRCC) in order to preoperatively distinguish this rare neoplasm from other primary or secondary tumors arising from the kidney or presenting as retroperitoneal masses. STUDY DESIGN: Clinical data, fine needle aspiration (FNA) and follow-up surgical specimens from 4 patients with CRCC (3 primaries and 1 metastatic to the liver) were reviewed. Electron microscopy was available for 2 histologic specimens. RESULTS: Two tumors (1 primary and 1 metastatic case) were readily identified as CRCC on FNA. The 2 remaining cases were diagnosed as renal cell carcinoma (RCC) consistent with CRCC. All tumors showed aspirates with moderate to high cellularity, with the cells arranged in small clusters and single cells. Neoplastic cells had abundant heterogeneous cytoplasm, a thickened cell membrane, nuclear hyperchromasia, nuclear outline irregularity, significant nuclear size variation, intranuclear inclusions and frequent binucleation. Histology of the 4 renal tumors was characteristic of CRCC, with positivity for Hale's colloidal iron in all cases. Ultrastructurally, characteristic cytoplasmic microvesicles were observed in the 2 cases that we studied. CONCLUSION: In the adequate clinicoradiologic setting, CRCC has distinctive cytologic features that may allow an accurate preoperative FNA diagnosis.

Lymphoepithelioid cell lymphoma (Lennert's lymphoma). Report of a case with fine needle aspiration cytology.

BACKGROUND: Lymphoepithelioid cell lymphoma (LCL) is a rare morphologic variant of peripheral T-cell lymphoma. Although their histopathologic and immunohistochemical findings are well known, the cytopathologic features have not been well documented. This report describes the fine needle aspiration cytology (FNAC) findings of a case of LCL. CASE: A 75-year-old woman presented with cervical, supraclavicular, axillary and mediastinal lymphadenopathy. FNAC of a cervical lymph node was performed. The smears contained a polymorphous infiltrate formed by abundant histiocytes disposed singly or in clusters, small and medium-sized to large atypical lymphoid cells and reactive cells, including eosinophils and plasma cells. Isolated capillary-sized vessels also were observed. Histopathologic and immunohistochemical examination confirmed the diagnosis of Lennert's lymphoma. CONCLUSION: Although histopathologic and immunohistochemical studies were required for a definitive diagnosis, the findings of FNAC in this case appeared distinctive and suggested the possibility of LCL.

Fine needle aspiration cytology of neurothekeoma. A case report.

BACKGROUND: Neurothekeoma (NT) is a rare, benign neoplasm of soft parts with a distinctive histologic appearance. To our knowledge, the cytologic findings have not been described before. We present a case of NT with the cytologic features on fine needle aspiration cytology (FNAC). CASE: A 54-year-old female presented with a circumscribed nodule in the left breast. The lesion was evaluated by FNAC. The smears showed an abundant, metachromatic, myxoid matrix with fusiform and epithelioid cells, some binucleated or multinucleated, loose or in groups and sometimes forming concentric whorls. The lesion was removed, and the diagnosis of NT was made after histopathologic study. CONCLUSION: NT is an extremely rare neoplasm in the mammary region. Fusiform and epithelioid cells arranged in concentric whorls in a myxoid tumor of soft tissue are a distinctive characteristic of this neoplasm and can suggest the diagnosis.

Fine-needle aspiration biopsy of the retroperitoneum: a series of 111 cases not including specific organs.

We report on our experience in fine-needle aspiration (FNA) biopsy of the retroperitoneum: 111 FNA biopsies performed on 99 patients. Cytologic diagnoses were divided into four groups: nondiagnostic (unsatisfactory samples because of a low cellularity and/or improperly prepared smears) aspirates (20%), benign (16%), suspicious for malignancy (13%), and malignant (50%). There were no known false-positive samples. We had two false-negative diagnoses due to sampling errors. Among diagnostic smears, the procedure showed a sensitivity of 97% and a specificity of 100%. The predictive value of a positive result was 100% and the predictive value of a negative result was 90%. The overall accuracy was 98%. Metastatic carcinomas accounted for the largest number of lesions in the group of malignant tumors. A primary tumor site was known for the majority of the cases before the aspiration was performed. In the remaining cases we were unable to suggest an origin. It is therefore important to emphasize the role of ancillary studies in patients that are at the first assessment of the disease or when a second intercurrent malignancy is suspected. In our limited experience, a suggestion of the correct subtype of retroperitoneal sarcoma was not possible. As in the rest of cytopathology, a multidisciplinary approach is mandatory in this setting to improve patient management.

Usefulness of light microscopy in lymph node fine needle aspiration biopsy.

OBJECTIVE: To evaluate light microscopic examination of lymph node fine needle aspiration biopsy (FNAB) in order to determine the indications for ancillary procedures and biopsy. STUDY DESIGN: Reports and smears from 693 consecutive lymph node FNABs were reviewed. Fifty-five cases were excluded because of inadequacy of the material, and another 26 were excluded because follow-up information was not available. RESULTS: Cytologically, 220 cases were diagnosed as positive for malignancy and 392 as negative. Global sensitivity was 94.1% and specificity 96.9%. Sensitivity was higher for nonlymphoid neoplasms (98.2%) than for lymphoproliferative disorders (82.8%). CONCLUSION: Lymph node FNAB is a cost-effective procedure, and with adequate cytologic examination and follow-up, a large number of biopsies and time-consuming ancillary techniques can be avoided.