HIF-1α regulates IL-1ß and IL-17 in sarcoidosis.

Sarcoidosis is a complex systemic granulomatous disease of unknown etiology characterized by the presence of activated macrophages and Th1/Th17 effector cells. Data mining of our RNA-Seq analysis of CD14+monocytes showed enrichment for metabolic and hypoxia inducible factor (HIF) pathways in sarcoidosis. Further investigation revealed that sarcoidosis macrophages and monocytes exhibit higher protein levels for HIF-α isoforms, HIF-1ß, and their transcriptional co-activator p300 as well as glucose transporter 1 (Glut1). In situ hybridization of sarcoidosis granulomatous lung tissues showed abundance of HIF-1α in the center of granulomas. The abundance of HIF isoforms was mechanistically linked to elevated IL-1ß and IL-17 since targeted down regulation of HIF-1α via short interfering RNA or a HIF-1α inhibitor decreased their production. Pharmacological intervention using chloroquine, a lysosomal inhibitor, decreased lysosomal associated protein 2 (LAMP2) and HIF-1α levels and modified cytokine production. These data suggest that increased activity of HIF-α isoforms regulate Th1/Th17 mediated inflammation in sarcoidosis.

Myelolipoma of the Pelvis: A Case Report and Review of Literature.

Myelolipomas are uncommon, benign tumors which typically occur in the adrenal glands and consist of mature adipose tissue and benign hematopoietic components. Myelolipomas can occur outside of the adrenal glands, but the presacral region, retroperitoneum, pelvis, and mediastinum are unusual locations for these tumors. It is important to recognize this entity in these locations since they can attain massive sizes leading to pressure symptoms and need to be differentiated from the malignant tumors like liposarcomas. We present a myelolipoma case in the presacral region. Our case illustrates the clinical approach of these tumors in such unusual locations.

Etiologic factors related to unsatisfactory ThinPrep(®) cervical cytology: Evaluation and potential solutions to improve.

BACKGROUND: In cervical cytology, the unsatisfactory rates for ThinPrep (TP) are slightly higher compared to SurePath. We examined various causes and explored potential for resolution of this discrepancy. MATERIALS AND METHODS: Totally, 19,422 cases were reviewed and 1000 unsatisfactory specimens were selected and analyzed. 531 specimens were available for wash protocol. Out of 114 unsatisfactory specimens associated with atrophic cellular changes (ACC), 48 were resubmitted by provider and reevaluated. RESULTS: Lubricant and lubricant-like debris/contamination (LUBE) was the most common cause of unsatisfactory specimens (68%; 681/1000) followed by blood (7.5%); ACC only (without other interfering factors) (2.4%); inflammation (3.0%); and combinations thereof (1.9%). 11.5% showed scant cellularity without an identifiable cause. 3.3% were virtually acellular. Wash protocol improved cellularity in 48% (256/531) of cases. However, only 29% (73/256) of those were satisfactory (with more than 5000 cells). Quantitative reduction in LUBE after wash protocol varied with different morphological subtypes. Interpretation patterns on satisfactory specimens after wash protocol were comparable to the results on selected cohort of specimens during the same study period. Out of 114 ACC, wash protocol was performed on 68 ACC specimens leading to satisfactory TP in 24% (16/68). Totally, 48 cases reported as unsatisfactory with ACC, were resubmitted by the providers between 2 weeks and 2 years. 44 (92%) showed increased cellularity, out of which 52% (23/44) did not show ACC. CONCLUSION: LUBE was the most common cause of unsatisfactory TP in addition to interference by blood and association with atrophic changes. Knowing the morphological spectrum of LUBE would help to identify it as the cause of unsatisfactory TP. Communicating the cause of unsatisfactory TP such as LUBE, ACC, and blood would hint the provider to take appropriate precaution during submission of the repeat specimen, leading to improved patient care.

Dual color multiplex TTF-1 + Napsin A and p63 + CK5 immunostaining for subcategorizing of poorly differentiated pulmonary non-small carcinomas into adenocarcinoma and squamous cell carcinoma in fine needle aspiration specimens.

BACKGROUND: The distinction of lung adenocarcinoma (ADC) from squamous cell carcinoma (SCC) has important therapeutic implications. Napsin A is a recently developed marker, which has shown high specificity for lung tissue in the surgical pathology specimens. In this study, we have evaluated whether the use of a panel of novel multiplex cocktails of TTF-1 + Napsin A and p63 + CK5 for dual color immunostaining will improve the diagnostic accuracy of lung adenocarcinoma and squamous cell carcinoma in fine needle aspiration (FNA) specimens, usually with relatively scant microfragments of diagnostic material. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded, adequately cellular FNA cell blocks with a confirmed diagnosis of either ADC (n = 22), SCC (n = 20) or poorly differentiated carcinoma (PDC; n = 7), from a total of 49 consecutive cases, were studied. All these cases had subsequently confirmed diagnosis in biopsies or resection specimens. The sections were immunostained with two color methods of TTF-1 + Napsin A and p63 + CK5 multiplex cocktails. The presence of one or more unequivocal individual tumor cells with convincing brown nuclear TTF-1 and red cytoplasmic Napsin A staining, and cells with brown nuclear p63 and membranous / cytoplasmic CK5 staining were interpreted as 'positive'. RESULTS: All 20 FNA cell blocks from SCC cases were positive for dual stain p63 + CK5 and negative for dual stain TTF-1 + Napsin A. The sensitivity and specificity of the dual immunoexpressions of p63 + CK5 for SCC of lung FNAs were both 100%. All 22 ADC cases were positive with dual stain of TTF-1 + Napsin A and negative for dual stain of p63 + CK5. On follow-up of the surgical pathology specimens, 22 cases were confirmed as ADC. The sensitivity of the dual immunoexpression of TTF-1 + Napsin A for ADC of lung FNAs was 100% and the specificity was also 100%. Of the seven PDC cases, five cases that were positive for dual stain p63 + CK5 and negative for dual stain TTF-1 + Napsin A could be categorized as SCC. Two of the seven (2 / 7) PDC cases were positive for dual stain TTF-1 + Napsin A and negative for dual stain p63 + CK5, consistent with ADC. CONCLUSIONS: Simultaneous coordinate or individual immunostaining for Napsin A / TTF-1 in ADC and p63 / CK5 in SCC demonstrated high sensitivity and specificity. The panel with multiplex Napsin A / TTF-1 and p63 / CK5 dual color immunostains could specifically subcategorize PDC into ADC and SCC in lung FNA specimens. Multiplex dual color Napsin A / TTF-1 and p63 / CK5 immunostaining is especially recommended for evaluation of FNA specimens with relatively scant cellularity.

The Bethesda System thyroid diagnostic categories in the African-American population in conjunction with surgical pathology follow-up.

BACKGROUND: It has been reported that African-Americans (AA) have a higher prevalence of overall malignancy compared to Caucasians, in the United States, yet the incidence of thyroid malignancy is half. The aim of this study is to assess the rate of malignant versus benign thyroid disease in AA from an urban-based hospital with an academic setting. Our study analyzed the AA population with respect to fine needle aspiration (FNA) of thyroid lesions, in correlation with final surgical pathology. This is the first study of its kind to our knowledge. DESIGN: We retrospectively reviewed thyroid FNA cytology between January 2005 and February 2011. Consecutive FNA specimens with corresponding follow-up surgical pathology were included. The patients were categorized as African- American (AA) and Non-African-American (NAA), which included Caucasians (C), Hispanics (H), and Others (O). The FNA results were classified using the latest edition of The Bethesda System for Reporting Thyroid Cytopathology (TBS-Thy) and the follow-up surgical pathology was used for the final categorization. RESULTS: We studied 258 cases: 144 AA (56%) and 114 NAA [43 C (17%), 3 H (1%), and 68 O (28%)]. The average age for AA was 51 years (range 20 - 88) and for NAA was 53 years (range 25 - 86). There were more females than males in the AA versus the NAA group (85 vs. 75%). The incidence of thyroid lesions in the FNA specimens was similar between these two populations. The distribution of benign versus malignant diagnosis on follow-up surgical pathology was examined across TBS-Thy class. CONCLUSION: Our data suggest that distribution of benign versus malignant lesions in the thyroid FNA of AA versus NAA, with follow-up surgical pathology, is comparable for TBS-Thy classes, non-diagnostic (I), benign (II), suspicious for malignancy (V), and malignant (VI) in AA versus NAA.

Cytologic diagnosis of recurrent medullary thyroid carcinoma with oncocytic change twenty-one years post-thyroidectomy: case report and review of the literature.

A 66-year-old woman presented 21 years prior with diarrhea and elevated serum calcitonin levels. The left lobe of the thyroid was aspirated but specimen was unsatisfactory. Nevertheless, based on the radiological and clinical impressions, the patient underwent total thyroidectomy and the histologic examination established the diagnosis of medullary thyroid carcinoma (MTC). Approximately 5 years later, the patient had a recurrence of the disease and underwent a neck lymph node dissection, which showed metastatic MTC in a lymph node. Sixteen years later, the patient presented with left neck mass detected by ultrasound in the area of thyroid bed. Fine needle aspiration (FNA) of this area was performed and the FNA diagnosis was consistent with oncocytic variant of MTC. This case illustrates a first report of this uncommon variant of MTC diagnosed by FNA cytology of the thyroid bed.

Paraneoplastic polyarthritis in an ovarian teratoma.

A 34-year-old woman presented to the rheumatology clinic with severe low back pain and arthralgia; later she developed bilateral knee pain and swelling, with limitation in ambulation and minimal improvement with nonsteroidal antiinflammatory drugs. Two weeks later she developed pain on the volar aspect of the right wrist and on the hypothenar region of the right hand. Examination showed swelling and tenderness of the right hypothenar region, tenderness and decreased flexion and extension of the right wrist, and bilateral knee effusions. The combination of arthritis and tenosynovitis raised the possibility of an ovarian tumor. A pelvic ultrasound revealed a complex, hyperechoic ovarian mass consistent with a cystic teratoma. Four weeks after removal of the teratoma, the polyarthritis and related symptoms resolved without therapy.

Testicular ischemia due to intravascular large B-cell lymphoma: a novel presentation in an immunosuppressed individual.

A 56-year-old man presented with fever, disorientation, and testicular pain. He was receiving azathioprine immunosuppression for autoimmune hepatitis. Orchiectomy identified occlusion of spermatic cord vessels by intravascular large B-cell lymphoma (IVLBL) and ischemic changes in the testis. Tumor cells were positive for CD 10, CD 20, CD 30, and Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) and early region RNA (EBER). He was treated with the cessation of azathioprine, chemotherapy, anti-CD 20 immunotherapy, and radiotherapy. Twenty months after diagnosis, he is alive with no evidence of lymphoma or hepatitis. This is the first report of IVLBL presenting with testicular ischemia. It highlights the importance of prompt diagnosis and intervention to achieve durable response. That this lymphoma arose in the setting of immunosuppressive therapy introduces additional complexity relating to pathogenesis, clinical behavior, and treatment.