Role of miRNA-182 and miRNA-187 as potential biomarkers in prostate cancer and its correlation with the staging of prostate cancer

ABSTRACT Purpose The microRNAs expression has emerged as a potential biomarker for the diagnosis and prognosis of prostate cancer. This study investigated the expression of miRNA-182 and miRNA-187 in prostate cancer patients and established a correlation between miRNA expression and staging of prostate cancer. Materials and Methods This prospective observational study involved patients undergoing transrectal ultrasound-guided biopsy for suspicion of prostate cancer. Pre-biopsy urine samples and prostatic core tissue samples of the patients were preserved and the miRNA-182 and miRNA-187 were studied. Results Sixty-three patients were included in this study, thirty-three patients were diagnosed with prostate cancer and thirty patients having benign histopathology were considered as controls. The expression of miRNA-182 was significantly increased (p=0.002) and miRNA-187 significantly decreased (p <0.001) in prostate cancer tissue specimens. However, the expression of these miRNAs did not significantly differ in the urine of prostate cancer patients as compared to controls. Serum Prostatic Specific Antigen (PSA) inversely correlated with the median expression of miR-187 in prostatic tissue (p=0.002). Further, the expression of miRNA-187 in prostate cancer tissue was significantly decreased in metastatic prostate cancer (p=0.037). Using ROC analysis, miRNA-187 expression was able to distinguish the presence or absence of bone metastasis [area under ROC (AUROC) (±SD) was 0.873±0.061, p <0.001]. Conclusion The miRNA-182 and miRNA-187 appear to be promising biomarkers in prostate cancer and miRNA-187 can serve as an important diagnostic marker of metastatic prostate cancer.

Lupus Nephritis in Indian Children: Flares and Refractory Illness

Objective: To evaluate the incidence of flares and treatment resistance in children with lupusnephritis and their association with renal outcomes. Methods: We retrospectively reviewedthe case records of 34 children treated for lupus nephritis (Class II-IV) at a single center.Patients were followed for a minimum of five years to evaluate treatment response, onset offlares, and renal survival. Regression analyses were performed to identify the factorsassociated with treatment refractoriness, incidence of flares and renal survival. Results: Theincidence of flares was 0.16 episodes/person/year. Eight patients (23.5%) were refractory totreatment. The five-year renal survival was 79%. Multiple episodes of flares (P=0.028) andtherapy refractoriness (P=0.003) were associated with poor renal survival. Conclusions:Prevention and aggressive management of renal flares is expected to prevent progression toend stage renal disease in lupus nephritis.

Etiology and Outcome of Crescentic Glomerulonephritis.

Objective: To determine the etiology, course and predictors of outcome in children with crescentic glomerulonephritis (GN). Study design: Retrospective, descriptive study. Setting: Pediatric Nephrology Clinic at a referral center in Northern India. Methods: Clinic records of patients aged <18 year with crescentic GN diagnosed from 2001-2010 and followed at least 12-months were reviewed. Crescentic GN, defined as crescents in ≥50% glomeruli, was classified based on immunofluorescence findings and serology. Risk factors for renal loss (chronic kidney disease stage 4-5) were determined. Results: Of 36 patients, (median age 10 yr) 17 had immune complex GN and 19 had pauci-immune crescentic GN. The etiologies of the former were lupus nephritis (n=4), postinfectious GN (3), and IgA nephropathy, Henoch Schonlein purpura and membranoproliferative GN type II (2 each). Three patients with pauci-immune GN showed antineutrophil cytoplasmic antibodies (ANCA). Rapidly progressive GN was present in 33 patients, and required dialysis in 12. At median 34 (19-72) months, 2 patients with immune complex GN and 8 with pauci-immune GN showed renal loss. Renal survival was 94.1% at 3 yr, and 75.3% at 8 yr in immune complex GN; in pauci-immune GN survival was 63.2% and 54.1%, respectively (P=0.054). Risk factors for renal loss were oliguria at presentation (hazards ratio, HR 10.50; P=0.037) and need for dialysis (HR 6.33; P=0.024); there was inverse association with proportion of normal glomeruli (HR 0.91; P=0.042). Conclusions: Pauci-immune GN constitutes one-half of patients with crescentic GN at this center. Patients with pauci-immune GN, chiefly ANCA negative, show higher risk of disease progression. Renal loss is related to severity of initial presentation and extent of glomerular involvement.

Disease Course in Steroid Sensitive Nephrotic Syndrome.

Objective: To review the disease course in patients with steroid sensitive nephrotic syndrome (SSNS) and the factors that determine outcome Design: Retrospective, analytical Setting: Pediatric Nephrology Clinic at referral center in North India Participants/patients: All patients with SSNS evaluated between 1990 and 2005 Intervention: None Main outcome measures: Disease course, in patients with at least 1-yr follow up, was categorized as none or infrequent relapses (IFR), frequent relapses or steroid dependence (FR), and late resistance. Details on complications and therapy with alternative agents were recorded. Results: Records of 2603 patients (74.8% boys) were reviewed. The mean age at onset of illness and at evaluation was 49.7±34.6 R E S E A R C H P A P E R INDIAN PEDIATRICS 881 VOLUME 49__NOVEMBER 16, 2012 and 67.5±37.9 months respectively. The disease course at 1-yr (n=1071) was categorized as IFR in 37.4%, FR in 56.8% and late resistance in 5.9%. During follow up, 224 patients had 249 episodes of serious infections. Alternative medications for frequent relapses (n=501; 46.8%) were chiefly cyclophosphamide and levamisole. Compared to IFR, patients with FR were younger (54.9±36.0 vs. 43.3±31.4 months), fewer had received adequate (≥8 weeks) initial treatment (86.8% vs. 81.7%) and had shorter initial remission (7.5±8.6 vs. 3.1±4.8 months) (all P<0.001). At follow up of 56.0±42.6 months, 77.3% patients were in remission or had IFR, and 17.3% had FR. Conclusions: A high proportion of patients with SSNS show frequent relapses, risk factors for which were an early age at onset, inadequate initial therapy and an early relapse.

An aetiological & clinicopathological study on cutaneous vasculitis.

Background & objectives: Cutaneous vasculitis has protean clinical manifestations. It may be idiopathic or associated with a spectrum of conditions such as infections, drugs, etc. Skin is involved in both small vessel vasculitis (SVV) and medium vessel vasculitis (MVV). Overlapping features are seen between SVV and MVV. The histopathological features may not always relate with the clinical lesions. The aim of the present study was to evaluate the aetiological factors and clinicopathological association in patients with cutaneous vasculitis. Methods: In this cross-sectional study, detailed history and clinical examination were done on patients with biopsy proven cutaneous vasculitis. Two skin biopsies were taken from each patient for routine histopathology and direct immunofluorescence. Results: Of the 61 patients studied, hypersensitivity vasculitis (HSV) [23 (37.7%)] and Henoch Schonlein purpura (HSP) [16 (26.2%)] were the two most common forms. Systemic involvement was seen in 32 (52.45%) patients. Drugs were implicated in 12 (19.7%) cases, infections in 7 (11.4%) and connective tissue disorders in 4 (6.5%) cases. Histologically SVV was the most common pattern, seen in all the clinically diagnosed patients with SVV (47), and in 12 of the 14 clinically diagnosed patients with MVV. Direct immunofluorescence showed positivity for at least one immunoreactant in 62 per cent of the patients and the most common deposit was C3 followed by IgG, IgA and IgM. Interpretation & conclusions: Majority of our patients with cutaneous vasculitis were idiopathic. Histologically, SVV was seen in most of our patients. No association was seen between history of drug intake and tissue eosinophilia and also between histologically severe vasculitis and clinical severity. The presence of immunoreactant IgA was not specific for HSP.

Crescentic glomerulonephritis: A clinical and histomorphological analysis of 46 cases.

Background: Crescentic glomerulonephritis (CrGN), defined as crescents involving more than 50% of the glomeruli, includes pauci-immune, immune complex-mediated and anti-glomerular basement membrane disease. Objectives: The present study was aimed at evaluating the various clinical, biochemical and histological parameters in CrGN with respect to these categories and clinical outcome. Materials and Methods: Renal biopsies diagnosed as CrGN between Jan 2008 and Feb 2010 were included. Clinical and laboratory parameters were retrieved along with the therapeutic approach and clinical outcome, wherever available. Renal biopsy slides were evaluated for various glomerular, tubulo-interstitial and arteriolar features. Appropriate statistical tests were applied for significance. Results: A total of 46 cases of CrGN were included; majority (71.7%) of cases were pauci-immune (PI) while 28.3% were immune complex-mediated (IC). Among clinical features, gender ratio was significantly different between PI and IC groups (P = 0.006). The various histological parameters, including proportion of cellular crescents, tuft necrosis and Bowman's capsule rupture, were similar in both the groups. Four unusual associations, including idiopathic membranoproliferative glomerulonephritis (MPGN), multibacillary leprosy, acute lymphoblastic leukemia and C1q nephropathy were detected. Adequate follow-up information was available in 21 (46%) of the patients. Of these, 11 (52.4%) were dialysis-dependent at the last follow-up. Adult patients required renal replacement therapy more frequently than pediatric cases (P = 0.05). Presence of arteriolar fibrinoid necrosis also showed association with poor clinical outcome (P = 0.05). Conclusions: Crescentic glomerulonephritis remains one of the main causes of acute renal failure with histological diagnosis. Immunohistologic examination is essential for accurate classification into one of the three categories. This condition should be considered in rare causal associations like leprosy or MPGN with renal failure, to allow for timely performed renal biopsy and appropriate aggressive therapy.

Calcineurin inhibitor toxicity in renal allografts: Morphologic clues from protocol biopsies.

Background: Calcineurin inhibitors (cyclosporine and tacrolimus) are important constituents of post renal transplant immunosuppression. However, renal toxicity limits their utility. Histological features of calcineurin inhibitor toxicity (CNIT) have been the subject of few studies using protocol biopsy samples, and consensus on diagnostic criteria is still evolving. Aims: To analyze the spectrum of histological changes in protocol renal allograft biopsies with evidence of CNIT and identify additional features that are likely to help the pathologist in arriving at a diagnosis. Materials and Methods: One hundred and forty protocol allograft biopsies performed at 1, 6 and 12 months post renal transplant were studied. The defining features of CNIT included: isometric vacuolization of proximal tubular cells, arteriolar hyalinosis with medial/peripheral nodules and striped pattern of tubular atrophy/interstitial fibrosis. Other features such as global glomerulosclerosis, vacuolization of smooth muscle cells of arterioles, tubular microcalcinosis, ischemic shrinkage of glomeruli and hyperplasia of juxtaglomerular apparatus (JGA) were also analyzed and graded semiquantitatively. Results: CNIT was seen in 17/140 protocol biopsies (12.1%). In addition to the diagnostic criteria, arteriolar hyalinosis, smooth muscle cell vacuolization of arterioles and hyperplasia of JGA were found to be useful indicators of CNIT. Conclusions: There is a relatively high incidence of CNIT in protocol allograft biopsies. A critical analysis of renal biopsy in adequate number of serial step sections to identify these features is mandatory, as many of these features are subtle and are likely to be missed if not specifically sought.

Primary neuroendocrine carcinoma of thymus: A rare cause of Cushing's syndrome.

Thymomas constitute majority of the thymic neoplasms. In contrast, neuroendocrine tumors (carcinoid and neuroendocrine carcinoma) of thymus are extremely rare. Thymic carcinoids may present rarely with Cushing's syndrome due to the ectopic production of adrenocorticotropic hormone (ACTH). Recognition of this association is imperative for appropriate management of patients. We describe three cases of rare atypical carcinoid tumor (neuroendocrine carcinoma) of the thymus. Case 1, of a 26-year-old man presenting with Cushing's syndrome, case 2 - a 23-year-old female with Cushingoid features, and Case 3 - a 39-year-old man complaining of progressively worsening dyspnea. Computed tomography (CT) scans of chest in all three patients revealed anterior mediastinal mass. Excision of tumors and histological examination of the three tumors showed a carcinoid tumor with nuclear pleomorphism, increased mitotic activity and focal necrosis. The features suggested a diagnosis of atypical carcinoid tumor in all the three cases. The tumor cells in Cases 1 and 2 showed focal immunohistochemical staining for ACTH. Atypical carcinoid (neuroendocrine carcinoma, well-differentiated and moderately-differentiated) of the thymus is a rare thymic tumor which carries a worse prognosis compared to thymoma and requires aggressive therapy. Hence, an accurate diagnosis is essential.

Invasive papillary carcinoma of male breast.

Breast carcinoma is uncommon in males and constitutes less than one per cent of all cancers in men. Invasive papillary carcinoma is a rare morphological type of breast cancer. Since papillary carcinoma has a favorable prognosis as compared to other histopathological subtypes, an accurate diagnosis is essential. We report two cases of this rare histological type of male breast cancer. A 62-year-old man presented with a lump in the central quadrant of right breast and underwent simple mastectomy. Histological examination showed features of invasive papillary carcinoma. The other case was of an 81-year-old male patient with a subareolar mass in the right breast. Wide local excision of the lump showed features of an intracystic invasive papillary carcinoma. The patient subsequently underwent simple mastectomy, however, no residual tumor was found in the resection specimen. Both the patients were free of disease at one year of follow-up. Invasive papillary carcinoma is an uncommon morphological type of breast cancer in males. The intracystic variant of papillary carcinoma is extremely unusual and may be missed on cytological examination. A thorough sampling is essential for an accurate diagnosis of invasion in these cases.

Diffuse lipomatosis of the thyroid gland: a pathologic curiosity.

We report the case of a 45-year-old man who presented with a 4-year history of midline neck swelling associated with recent onset respiratory distress. Local examination showed a lobulated diffuse thyroid enlargement. A subtotal thyroidectomy was performed. The right lobe weighed 225 g and the left lobe weighed 130 g. Multiple sections from both the lobes revealed diffuse infiltration of the stroma by mature adipose tissue. There was no evidence of amyloid deposits or papillary carcinoma. A final diagnosis of diffuse lipomatosis of the thyroid gland was rendered. Lipomatosis or adenolipomatosis of the thyroid gland is an extremely rare entity. The various differential diagnoses of fat in the thyroid include benign entities like amyloid goiter, adenolipoma, lymphocytic thyroiditis, intrathyroid thymic or parathyroid lipoma and malignant tumors like liposarcoma and encapsulated papillary carcinoma. Adequate clinical details and a thorough histopathological examination are mandatory for diagnosis.

Hepatic tuberculosis mimicking Klatskin tumor: a diagnostic dilemma.

Tubercular involvement of liver is rare and usually occurs in association with pulmonary or miliary tuberculosis, as diffuse involvement without recognizable pulmonary tuberculosis or rarely in a localized form, which presents as a tuberculoma or tubercular abscess. We report the case of a 22-year-old boy presenting with features of obstructive jaundice and a clinico-radiological picture highly suggestive of a perihilar cholangiocarcinoma (Klatskin tumor), but found to have tubercular involvement of porta hepatis. We review the literature on this unusual presentation, highlight the considerable diagnostic challenge such cases can pose, and also emphasize the need to consider tuberculosis in differential diagnosis of lesions involving the porta hepatis, particularly in areas endemic for the disease.

Ganglioneuroma of the adrenal gland: a rare case.

Ganglioneuromas, which are benign tumors of sympathetic nervous system, are rare to arise in adrenal gland. They are usually clinically silent and detected during work-up for other unrelated conditions. Currently, histopathology is the only tool to diagnose ganglioneuroma and to differentiate it from ganglioneuroblastoma and neuroblastoma. We discuss the case of a 40-year-old female found to have a right adrenal mass during investigation of dull ache in right upper abdomen. Clinico-radiological assessment was non-confirmatory on the nature of the mass, and excision was done. Histological examination showed the mass to be a ganglioneuroma arising in the adrenal gland. In conclusion, ganglioneuroma occurs rarely in adrenal gland and pre-operative diagnosis is difficult since the symptoms are usually non-specific. Histological examination is the mainstay of diagnosis and should be thorough to exclude neuroblastomatous foci, portending a worse outcome.

Renal tubular dysgenesis.

A neonate with acute renal failure due to renal tubular dysgenesis is described. The diagnosis was confirmed on renal histology, characterized by short and poorly developed proximal renal tubules.

Multiple myeloma presenting as collapsing glomerulopathy.

A 54 year old male patient was admitted with advanced renal failure of recent onset. Serology was noncontributory. Renal biopsy showed collapsing glomerulopathy with interstitial fibrosis. Bone marrow examination confirmed the diagnosis of multiple myeloma. With chemotherapy multiple myeloma went into remission. However he continued to remain dialysis dependent and a repeat kidney biopsy showed progression to endstage renal disease.

Morphometric study of lymphoid cells in mycosis fungoides and its simulators.

The distinction of early stages of mycosis fungoides from benign lymphoid disorders of skin is difficult by conventional histological techniques. We studied 10 cases of mycosis fungoides, 10 cases of large plaque parapsoriasis, 10 cases of other benign lymphoid disorders of skin and 5 cases of lymph nodes. Nuclear area, perimeter of the nucleus, nuclear contour index, cytoplasmic area, form factor and nuclear cytoplasmic ratio as well as DNA-ploidy were determined by image analysis. There were statistically significant difference (P value < 0.05) between all parameters except nuclear cytoplasmic ratio of the lymphoid cells of Mycosis Fungoides and benign lymphoid disorders of skin. Aneuploidy was found in 50% cases of Mycosis Fungoides. Histopathological parameters like epidermotropism pautrier micro-abscess and atypical lymphocytic infiltrate in both epidermis and dermis were more marked in aneuploid than diploid cases. So, the determination of nuclear contour index and DNA-ploidy is of importance to differentiate between Mycosis Fungoides and benign lymphoid disorders of skin.