Carbonic anhydrase 4 and crystallin α-B immunoreactivity may distinguish benign from malignant thyroid nodules in patients with indeterminate thyroid cytology.

BACKGROUND: Thyroid nodules are present in 19%-67% of the population and carry a 5%-10% risk of malignancy. Unfortunately, fine-needle aspiration biopsies are indeterminate in 20%-30% of patients, often necessitating thyroid surgery for diagnosis. Numerous DNA microarray studies including a recently commercialized molecular classifier have helped to better distinguish benign from malignant thyroid nodules. Unfortunately, these assays often require probes for >100 genes, are expensive, and only available at a few laboratories. We sought to validate these DNA microarray assays at the protein level and determine whether simple and widely available immunohistochemical biomarkers alone could distinguish benign from malignant thyroid nodules. METHODS: A tissue microarray (TMA) composed of 26 follicular thyroid carcinomas (FTCs) and 53 follicular adenomas (FAs) from patients with indeterminate thyroid nodules was stained with 17 immunohistochemical biomarkers selected based on prior DNA microarray studies. Antibodies used included galectin 3, growth and differentiation factor 15, protein convertase 2, cluster of differentiation 44 (CD44), glutamic oxaloacetic transaminase 1 (GOT1), trefoil factor 3 (TFF3), Friedreich Ataxia gene (X123), fibroblast growth factor 13 (FGF13), carbonic anhydrase 4 (CA4), crystallin alpha-B (CRYAB), peptidylprolyl isomerase F (PPIF), asparagine synthase (ASNS), sodium channel, non-voltage gated, 1 alpha subunit (SCNN1A), frizzled homolog 1 (FZD1), tyrosine related protein 1 (TYRP1), E cadherin, type 1 (ECAD), and thyroid hormone receptor associated protein 220 (TRAP220). Of note, two of these biomarkers (GOT1 and CD44) are now used in the Afirma classifier assay. We chose to compare specifically FTC versus FA rather than include all histologic categories to create a more uniform immunohistochemical comparison. In addition, we have found that most papillary thyroid carcinoma could often be reasonably distinguished from benign disease by morphological cytology findings alone. RESULTS: Increased immunoreactivity of CRYAB was associated with thyroid malignancy (c-statistic, 0.644; negative predictive value [NPV], 0.90) and loss of immunoreactivity of CA4 was also associated with malignancy (c-statistic, 0.715; NPV, 0.90) in indeterminate thyroid specimens. The combination of CA4 and CRYAB for discriminating FTC from FA resulted in a better c-statistic of 0.75, sensitivity of 0.76, specificity of 0.59, positive predictive value (PPV) of 0.32, and NPV of 0.91. When comparing widely angioinvasive FTC from FA, the resultant c-statistic improved to 0.84, sensitivity of 0.75, specificity of 0.76, PPV of 0.11, and NPV of 0.99. CONCLUSIONS: Loss of CA4 and increase in CRYAB immunoreactivity distinguish FTC from FA in indeterminate thyroid nodules on a thyroid TMA with an NPV of 91%. Further studies in preoperative patient fine needle aspiration (FNAs) are needed to validate these results.

Four-vessel umbilical cord associated with multiple congenital anomalies: a case report and literature review.

A case is described of a neonate with a four-vessel umbilical cord containing two arteries and two veins. This was due to a rare persistence of the caudal portion of the right umbilical vein. The infant had multiple congenital anomalies including a complete atrioventricular canal, an interrupted inferior vena cava, a double superior vena cava, a left ventricular hypoplasia, dextrocardia, situs ambiguous, and malrotation of the small bowel. The birth of an infant with a four-vessel cord mandates comprehensive work-up for associated anomalies. The literature is reviewed.

Gastrointestinal and hepatic complications of sickle cell disease.

Sickle cell disease (SCD) is an autosomal recessive abnormality of the beta-globin chain of hemoglobin (Hb), resulting in poorly deformable sickled cells that cause microvascular occlusion and hemolytic anemia. The spleen is almost always affected by SCD, with microinfarcts within the first 36 months of life resulting in splenic atrophy. Acute liver disorders causing right-sided abdominal pain include acute vaso-occlusive crisis, liver infarction, and acute hepatic crisis. Chronic liver disease might be due to hemosiderosis and hepatitis and possibly to SCD itself if small, clinically silent microvascular occlusions occur chronically. Black pigment gallstones caused by elevated bilirubin excretion are common. Their small size permits them to travel into the common bile duct but cause only low-grade obstruction, so hyperbilirubinemia rather than bile duct dilatation is typical. Whether cholecystectomy should be done in asymptomatic individuals is controversial. The most common laboratory abnormality is an elevation of unconjugated bilirubin level. Bilirubin and lactate dehydrogenase levels correlate with one another, suggesting that chronic hemolysis and ineffective erythropoiesis, rather than liver disease, are the sources of hyperbilirubinemia. Abdominal pain is very common in SCD and is usually due to sickling, which resolves with supportive care. Computed tomography scans might be ordered for severe or unremitting pain. The liver typically shows sickled erythrocytes and Kupffer cell enlargement acutely and hemosiderosis chronically. The safety of liver biopsies has been questioned, particularly during acute sickling crisis. Treatments include blood transfusions, exchange transfusions, iron-chelating agents, hydroxyurea, and allogeneic stem-cell transplantation.

Gastrointestinal involvement in polyarteritis nodosa.

Polyarteritis nodosa (PAN) is a necrotizing, focal segmental vasculitis that affects predominantly medium-sized arteries in many different organ systems. It is associated with hepatitis B virus (HBV) in about 7% of cases, a decline from about 30% before the mandatory testing of blood products and the widespread vaccination programs. HBV PAN is an early postinfectious process. The hepatitis is silent in most cases, with mild transaminase level increases in 50% of patients. Gastrointestinal involvement occurs in 14% to 65% of patients with PAN. Postprandial abdominal pain from ischemia is the most common symptom. When transmural ischemia develops, there may be necrosis of the bowel wall with perforation, associated with a poor prognosis. Liver involvement occurs in 16% to 56% of patients, although clinical manifestations related to liver disease are quite rare. Acalculous gangrenous cholecystitis may develop owing to arteritis involving the wall of the gallbladder. Microaneurysms on arteriography or computed tomography angiography are characteristic of PAN, but are seen in other conditions. Tissue biopsy may confirm the diagnosis, although involvement is segmental. Corticosteroids are used for non-HBV PAN with cyclophosphamide added for severe disease. For PAN related to HBV, a 2-week course of corticosteroids is begun, with plasma exchanges and an antiviral agent. Corticosteroids and cyclophosphamide have improved patient outcome so that the 1-year survival rate is now about 85%.

Endophytic lesions: a predictor of failure in laparoscopic renal cryoablation.

BACKGROUND AND PURPOSE: Laparoscopic renal cryoablation is an emerging minimally invasive management option for T(1) renal lesions. In an analysis of patients treated with laparoscopic cryoablation for renal lesions, our objective was to compare the treatment outcomes in patients with exophytic/partially exophytic and endophytic (peripheral but completely intrarenal) lesions. PATIENTS AND METHODS: We retrospectively reviewed medical records of 32 consecutive patients with anterior renal lesions who were treated with laparoscopic renal cryoablation between 2003 and 2005. Biopsy samples were obtained from the majority of lesions intraoperatively. The lesions were managed with 17 gauge needles and two freeze/thaw cycles. Follow-up was performed with CT scans at 3, 6, and 12 months, and then yearly. Treatment failures were defined as continued enhancement on CT or growth of the lesion. Statistical analysis was performed using t-test, correlative, and multiple regression analysis. RESULTS: A total of 35 lesions in 32 patients were identified. Median lesion size was 1.9 cm. Median age was 67 years, with most patients having significant comorbidities. The median preoperative and postoperative creatinine level was 1.3 and 1.5 mg/dL (P = 0.38). Of the biopsy samples from 27 of 35 lesions, 18 showed renal cell carcinoma, 5 were found to be benign, and findings from 4 were inconclusive. Three lesions were completely endophytic. The median follow-up was 18 months, with treatment failures noted in 2 of 35 lesions (6%), both of which were endophytic (P < 0.0001). Multivariate analysis revealed that only the endophytic status of a lesion was a predictor of failure (P < 0.05). These were lesions that relied entirely on intraoperative ultrasonography for targeting, which suggests that failure was a technical error. CONCLUSIONS: Experience with renal cryoablation is still evolving. Our series further defines the role of laparoscopic renal cryoablation and its limitations in managing peripheral endophytic tumors. Completely endophytic lesions have a significantly higher risk of treatment failure. Reliance solely on intraoperative ultrasonography with no visual cues is a risk factor for treatment failure.

Utility of PTEN and ERG immunostaining for distinguishing high-grade PIN from intraductal carcinoma of the prostate on needle biopsy.

Intraductal carcinoma of the prostate and high-grade prostatic intraepithelial neoplasia (PIN) have markedly different implications for patient care but can be difficult to distinguish in needle biopsies. In radical prostatectomies, we demonstrated that PTEN and ERG immunostaining may be helpful to resolve this differential diagnosis. Here, we tested whether these markers are diagnostically useful in the needle biopsy setting. Separate or combined immunostains were applied to biopsies containing morphologically identified intraductal carcinoma, PIN, or borderline intraductal proliferations more concerning than PIN but falling short of morphologic criteria for intraductal carcinoma. Intraductal carcinoma occurring with concurrent invasive tumor showed the highest rate of PTEN loss, with 76% (38/50) lacking PTEN and 58% (29/50) expressing ERG. Of biopsies containing isolated intraductal carcinoma, 61% (20/33) showed PTEN loss and 30% (10/33) expressed ERG. Of the borderline intraductal proliferations, 52% (11/21) showed PTEN loss and 27% (4/15) expressed ERG. Of the borderline cases with PTEN loss, 64% (7/11) had carcinoma in a subsequent needle biopsy specimen, compared with 50% (5/10) of PTEN-intact cases. In contrast, none of the PIN cases showed PTEN loss or ERG expression (0/19). On needle biopsy, PTEN loss is common in morphologically identified intraductal carcinoma yet is very rare in high-grade PIN. Borderline intraductal proliferations, especially those with PTEN loss, have a high rate of carcinoma on resampling. If confirmed in larger prospective studies, these results suggest that PTEN and ERG immunostaining may provide a useful ancillary assay to distinguish intraductal carcinoma from high-grade PIN in this setting.

Gleason pattern 5 is frequently underdiagnosed on prostate needle-core biopsy.

OBJECTIVE: To assess underdiagnosing Gleason pattern 5 on needle biopsy and discuss the potential consequences for patient management. MATERIAL AND METHODS: We retrieved 300 consecutive prostate biopsy cases from the consultation files at The Johns Hopkins Hospital (JHH) from 2009-2010 in which we identified Gleason pattern 5. All of these cases were diagnosed by one of the authors and all were sent in as a final diagnosis for which the outside pathologist was not requesting consultation because of difficulty with the diagnosis. The Gleason grades assigned to these cases at our institution were compared with the grade rendered by the submitting pathologists from the outside institution. RESULTS: In 146 (48.7%) of the cases, Gleason pattern 5 was not identified by the outside pathologists. Of the 146 cases, the outside Gleason score was ≤7 in 61 (20.3%) and 4+4=8 in 85 (28.4%). Even when the tumor was diagnosed at JHH as Gleason score 5+5=10, only 26 (41.3%) were diagnosed as the same by the outside pathologists; Gleason score 9 was graded in 27 (42.8%). CONCLUSION: Considering the important prognostic and therapeutic implication of misdiagnosing Gleason pattern 5, efforts should be made by the pathology community to acknowledge this as a problem and improve on individual pathologists' accuracy by diverse medical education programs. In addition, urologists should not hesitate in sending biopsies with high-grade prostate cancer for expert genitourinary pathology second opinions.

Epithelial proliferations in prostatic stromal tumors of uncertain malignant potential (STUMP).

Stromal tumors of uncertain malignant potential (STUMPs) are rare tumors characterized by an atypical, unique stromal proliferation of the prostate. Various stromal proliferations of STUMPs have been described; however, epithelial proliferations occurring within the STUMP have not been systematically described to date. We reviewed 89 cases of STUMP from our consultation service from 1990 to 2010. Nineteen cases without a glandular component were excluded. We next evaluated the glandular component of the remaining 70 cases of STUMP for glandular crowding and complexity, prostatic intraepithelial neoplasia (PIN), squamous metaplasia, urothelial metaplasia, basal cell hyperplasia, adenosis, and clear cell cribriform hyperplasia. In 58 cases (83%), the glandular component differed from glands on the same biopsy specimen uninvolved by STUMP. The most common abnormalities were glandular crowding in 35 of 70 (50%) and a very prominent basal cell layer in some glands in 32 of 70 (46%) cases. The next most frequent glandular variation from normal was prominent papillary infolding in 13 of 70 (19%) cases. Less-frequent epithelial changes within the STUMP were as follows: 10 of 70 (14%) showed cystically dilated glands; 7 of 10 (10%) had basal cell hyperplasia; 6 of 70 (9%) had urothelial metaplasia; 6 of 70 (9%) showed squamous metaplasia; 3 of 70 (4%) had cribriform hyperplasia; 3 of 70 (4%) had adenosis; and 1 case each showed high-grade PIN, low-grade PIN, and partial atrophy. The glandular component of STUMP was histologically normal in 12 (17%) cases. There was a tendency toward urothelial and squamous metaplasia in STUMPs with a phyllodes pattern, and a prominent basal cell layer in STUMPs with degenerative and cellular stroma. This is the first study to systematically describe the epithelial proliferations occurring in STUMP. This study suggests that, within STUMPs, there is epithelial-mesenchymal crosstalk, as has been described in benign prostate and in prostatic carcinogenesis. In unusual cases of STUMP, the epithelial proliferation may predominate to the extent that it can mask the diagnosis of STUMP.

Cytomegalovirus prostatitis: a series of 4 cases.

Cytomegalovirus (CMV) prostatitis is very rare with only 1 report of biopsy-proven CMV prostatitis in the literature. The authors report 4 cases, 3 detected on needle biopsy and 1 detected on transurethral resection. Patients were 36, 41, 48, and 71 years old. All patients were immunosuppressed, including 1 with AIDS and 3 undergoing immunosuppressive therapy following organ transplantation. CMV inclusions were seen in secretory cells of the prostatic glands, endothelial cells of small vessels, and prostatic stromal cells associated with a dense lymphoid inflammation. Only very rarely is CMV prostatitis detected on clinical specimens, typically in immunosuppressed hosts undergoing immunosuppressive therapy following organ transplantation. Patients with CMV prostatitis may harbor multiple infections or have other serious medical conditions adversely affecting their prognosis.

Gastrointestinal manifestations of amyloidosis.

Amyloidosis is characterized by extracellular deposition of abnormal protein. There are six types: primary, secondary, hemodialysis-related, hereditary, senile, and localized. Primary (AL) amyloidosis is associated with monoclonal light chains in serum and/or urine with 15% of patients having multiple myeloma. Secondary (AA) amyloidosis is associated with inflammatory, infectious, and neoplastic diseases. The presentation is protean, including macroglossia, a dilated and atonic esophagus, gastric polyps or enlarged folds, and luminal narrowing or ulceration of the colon. Amyloid deposition in the gastrointestinal (GI) tract is greatest in the small intestine. The symptoms include diarrhea, steatorrhea, or constipation. Pseudo-obstruction carries a particularly grave prognosis, often not responding to pro-motility agents. Hepatic involvement is common, but the clinical manifestations are usually mild with hepatomegaly and an elevated alkaline phosphatase level. Biopsies to diagnose amyloidosis can be taken from the fat, kidney, intestine, or bone marrow. The safety of liver biopsies is controversial. With Congo Red stain, amyloid appears red in normal light and apple-green in polarized light. Treatment for AL amyloidosis is chemotherapy and stem cell transplantation; treatment for AA amyloidosis is control of the underlying disease. Amyloidosis should be considered in patients with proteinuria, cardiomyopathy, hepatomegaly (with mildly abnormal liver tests), peripheral and autonomic neuropathy, weight loss, and GI symptoms.

Extracorporeal shock wave lithotripsy for large ureteral stones using HM3 lithotriptor.

PURPOSE: We assessed the efficacy of extracorporeal shock wave lithotripsy for large (more than 10 mm) ureteral calculi with the unmodified Dornier HM3 lithotriptor. MATERIALS AND METHODS: A total of 96 consecutive patients with large ureteral stones were treated with shock wave lithotripsy using an unmodified HM3 lithotriptor. Patients, stone characteristics, preliminary treatment before shock wave lithotripsy, additional procedures after shock wave lithotripsy, complications and clinical outcomes were assessed. RESULTS: Between 2000 and 2003 a total of 96 patients (75 males, 21 females, mean age 51 years [range 16 to 81]) with large ureteral stones underwent shock wave lithotripsy. Average stone size was 14 mm (range 10 to 22), 90 stones were calcified, and 66 stones were located in the upper ureter, 20 in the mid ureter and 10 in the distal ureter. A total of 77 (80.2%) patients underwent a single shock wave lithotripsy session, 18 (18.7%) underwent 2 sessions and 1 (1.1%) patient underwent 3 sessions. The overall stone-free rate was 86.5% (83 patients). Complications occurred in 10 (10.4%) patients. Shock wave lithotripsy failed in 13 (13.5%) patients who were successfully treated with ureteroscopy. CONCLUSIONS: Our data show that shock wave lithotripsy for large ureteral stones along the entire ureter with the unmodified HM3 lithotriptor has a high success rate with minimal morbidity. We recommend it as first line treatment.