Joshua A. Hanson

Adult testicular granulosa cell tumor: a review of the literature for clinicopathologic predictors of malignancy.

Adult testicular granulosa cell tumors are rare sex cord-stromal tumors of which only 28 have been previously reported. As compared with their ovarian counterparts, these tumors may follow a more aggressive course because the proportion of malignant cases is higher. To date, there are no clinical or pathologic features that definitively predict malignancy. We reviewed all prior case reports for features that may predict their malignant potential. Tumor size greater than 5.0 cm is the only feature statistically associated with malignancy. Mitotic count, tumor necrosis, patient age, and the presence of gynecomastia do not, at present, predict benign versus malignant behavior.

Blockade of MK2 is protective in inflammation-associated colorectal cancer development.

Chronic inflammation is a risk factor for colorectal cancer. The MAPK‐activated protein kinase 2 (MK2) pathway controls multiple cellular processes including p38‐dependent inflammation. This is the first study to investigate the role of MK2 in development of colitis‐associated colon cancer (CAC). Herein, we demonstrate that MK2−/− mice are highly resistant to neoplasm development when exposed to AOM/DSS, while wild type (WT) C57BL/6 develop multiple neoplasms with the same treatment. MK2‐specific cytokines IL‐1, IL‐6 and TNF‐α were substantially decreased in AOM/DSS treated MK2−/− mouse colon tissues compared with WT mice, which coincided with a marked decrease in macrophage influx. Restoring MK2‐competent macrophages by injecting WT bone marrow derived macrophages into MK2−/− mice led to partial restoration of inflammatory cytokine production with AOM/DSS treatment; however, macrophages were not sufficient to induce neoplasm development. These results indicate that MK2 functions as an inflammatory regulator to promote colonic neoplasm development and may be a potential target for CAC.

Solitary Gastric Carcinoid Tumor Associated with Long-Term Use of Omeprazole: A Case Report and Review of the Literature

Gastrin exerts trophic effects on all cells of the gastric oxyntic mucosa including enterochromaffin-like (ECL) cells. Hypergastrinemia may result from hypoor achlorhydria due to chronic atrophic gastritis, from longterm drug-induced acid suppression or from gastrinoma occurring as part of the multiple endocrine neoplasia (MEN) 1 syndrome [1]. We describe here a man who developed an atypical, benign gastric carcinoid or neuroendocrine tumor (NET), after being treated with a proton pump inhibitor (PPI) for 20 years.

Intestinal barrier dysfunction in human necrotizing enterocolitis

BACKGROUND Intestinal barrier dysfunction has been implicated in necrotizing enterocolitis (NEC), but has not been directly measured in human NEC. METHODS Small intestines removed during surgery were immediately mounted in an Ussing chamber. mRNA expression of tight junction (TJ) proteins was measured with RT-PCR. RESULTS Fifteen infants were included, 5 with NEC and 10 with other diagnoses. Average transepithelial resistance (TER) was 11.61±1.65Ω/cm2 in NEC specimens, 23.36±1.48Ω/cm2 at resection margin, and 46.48±5.65Ω/cm2 in controls. Average flux of permeability marker mannitol was 0.23±0.06μMol/cm2 per h in NEC, 0.04±0.01 μMol/cm2 per h at resection margin, and 0.017±0.004 μMol/cm2 per h in control tissue (p<0.05). RT-PCR analysis showed marked decrease in mRNA expression of a TJ protein occludin in NEC affected tissue (p<0.03 vs. control). Additionally, mRNA expression of myosin light chain kinase (MLCK), an important regulator of TJ permeability, was increased in NEC specimens. CONCLUSION These studies show for the first time that NEC intestinal tissue have increased intestinal permeability, even at grossly healthy-appearing resection areas. The increase in intestinal permeability in NEC appeared to be related in part to a decrease in occludin and an increase in MLCK expression. LEVEL OF EVIDENCE Level 2.

Diffuse glutamine synthetase overexpression restricted to areas of peliosis in a β-catenin-activated hepatocellular adenoma: a potential pitfall in glutamine synthetase interpretation

Hepatocellular adenomas have recently been classified into four subtypes based on molecular findings: hepatocyte nuclear factor 1α (HNF1α) inactivated, inflammatory/telangiectatic, β-catenin activated, and unclassifiable. β-catenin-activated adenomas have the potential for malignant transformation and are thus important to recognize. Diffuse glutamine synthetase immunohistochemical positivity has been shown to be a reliable surrogate marker for β-catenin activation, though variations in staining patterns may be difficult to interpret. We report a case of a peliotic adenoma that was morphologically consistent with a β-catenin wild-type hepatocellular adenoma but harbored a β-catenin mutation by molecular analysis. The tumor lacked nuclear β-catenin positivity and demonstrated a hitherto undescribed pattern of glutamine synthetase overexpression restricted to areas of peliosis with mostly negative staining in non-peliotic areas. This pattern was initially interpreted as physiologic and may represent a potential pitfall in glutamine synthetase interpretation.

Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use.

CONTEXT Mastocytic enterocolitis is a recently described entity defined by chronic diarrhea of unknown etiology and normal colon biopsy results with increased mast cells (MCs) seen on special stains. These patients may benefit from mast cell stabilizers; however, the clinical utility of MC counts remains unknown. OBJECTIVE To determine the clinical utility of colonic MC counts on normal biopsies in patients with chronic diarrhea of unknown etiology. DESIGN Blinded MC counts using a c-Kit stain were performed in 76 consecutive patients with chronic diarrhea of unknown etiology who had normal colon biopsy results and in 89 consecutive control patients presenting for screening colonoscopy. Mast cells were counted per single high-power field in the highest-density area. A t test was used to compare the counts, and receiver operating characteristic curves were generated to examine sensitive and specific cutoff values. RESULTS Overall, MC counts averaged 31 MCs per high-power field in the study group versus 24 MCs per high-power field in the control group (P < .001). When stratified by location, a significant increase was seen in biopsies from the left colon only. Receiver operating characteristic analysis revealed that overall MC counts, left-sided MC counts, and the difference between right- and left-sided MC counts did not yield discriminatory cutoff values (area under the curve, 0.68, 0.74, and 0.81, respectively). CONCLUSIONS Mast cell counts were increased in patients with chronic diarrhea of unknown etiology, primarily in the left colon. However, receiver operating characteristic analysis demonstrates no discriminatory cutoff values. Quantitative MC stains yield little useful diagnostic information, and further studies are necessary to determine whether mastocytic enterocolitis truly represents a distinct entity.

Radiology Estimates of Viable Tumor Percentage in Hepatocellular Carcinoma Ablation Cavities Correlate Poorly With Pathology Assessment

CONTEXT No study has evaluated radiology/pathology correlation of percentage viable tumor (PVT) estimates in ablated hepatocellular carcinoma (HCC) to examine the reliability of radiologic estimates. OBJECTIVE To determine how well interdisciplinary PVT estimates correlate and identify pathologic factors that influence this correlation. DESIGN Pathologists and radiologists established blinded PVT estimates in 22 HCC ablation cavities. Paired sample t tests examined the differences between the interdisciplinary estimates. RESULTS Fifteen cavities had pathologic viable tumor (VT) (68%) and 6 had radiographic VT (22%). Radiologys sensitivity for detecting VT was 40% and the specificity was 100%. Pathology detected significantly more VT than radiology (pathology mean = 22.3% versus radiology mean = 2.6%; P = .005). Five cavities had tumor growth in a discontinuous rim pattern, 7 in a nodular pattern, and 3 in a solid pattern. Radiology did not detect VT in cavities with a discontinuous rim pattern (sensitivity = 0%) but did detect VT in 3 cavities with a nodular pattern (sensitivity = 43%), and in all cavities with a solid pattern (sensitivity = 100%). There was no significant difference in PVT estimates in cavities 3.5 cm or larger (P = .07), but there was a significant difference in cavities smaller than 3.5 cm (P = .01). CONCLUSION This study clarifies that the risk of underestimation by imaging is greatest in small lesions (<3.5 cm), though the sensitivity of detection depends primarily on the tumor growth pattern within the cavity. This underestimation raises the question of whether basing treatment decisions on a radiologic impression of complete ablation is valid.

Squamoid Cyst of Pancreatic Ducts: A Case Series Describing Novel Immunohistochemistry, Cytology, and Quantitative Cyst Fluid Chemistry

Squamoid cyst of pancreatic ducts (SCPD) is a benign pancreatic cyst often misdiagnosed preoperatively as a mucinous cyst. The histopathologic features are well described but the cytology and quantitative fluid chemistry profiles from fine-needle aspiration have not been reported. This case series discusses the cytology and cyst fluid chemistry profiles in 2 SCPDs and describes morphologic and immunohistochemical features that have not been previously reported. Fine-needle aspiration of 2 SCPDs yielded acellular debris lacking mucin or exfoliated squamous cells. Two cysts had elevated fluid carcinoembryonic antigen (CEA) and amylase levels. Positive immunohistochemical staining included cytokeratin 5/6, pCEA, synaptophysin, and chromogranin (both focal). MUC2 and MUC5AC showed negativity in all cases, while PAX8 showed negative nuclear staining. An accurate preoperative diagnosis of SCPD is potentially difficult in the setting of elevated fluid CEA levels, and acellular cytology as a mucinous cyst cannot be confidently excluded.

Carbamazepine-Associated Hypersensitivity Colitis

A 26-year-old man with a history of bipolar disorder was transferred from an outside hospital with possible Stevens–Johnsons syndrome in the setting of worsening skin rash and subacute bloody diarrhea. Two months previously, he had been admitted to a psychiatric facility following a manic episode and was treated with carbamazepine 200 mg twice a day, lithium 900 mg at bedtime, gabapentin 100 mg three times a day, and mirtazapine 7.5 mg at bedtime. One month later, he developed raised flat lesions on his extremities that progressively spread to his entire body, including his face. Owing to these developments, his psychiatrist had started him prior to this admission on oral prednisone that did not improve his condition. Furthermore, he was taking over-the-counter ibuprofen 400 mg every 4–6 h and acetaminophen 500 mg daily for generalized pain of the rash and diffuse joint pain. He denied use of any herbal supplements or alcohol. Over the following 2 weeks, he had developed bloody diarrhea with associated abdominal cramping for which he was briefly evaluated at an outside hospital prior to rapid transfer to this medical center. On arrival, he was febrile with a temperature of 38.2 °C, a pulse rate of 92/min, a respiratory rate of 20/min, and a blood pressure of 145/62 mmHg. Physical examination revealed generalized skin erythema, with exfoliation encompassing his entire body from his face to the soles of his feet and multiple brown plate-like scales covering his face. Linear fissures with dry lips were noted along with tongue erythema. Eye examination revealed conjunctival injections with dry yellow crusts. Cardiovascular examination revealed tachycardia and pulmonary examination was normal. The abdomen was generally soft with mild tenderness on deep palpation of the lower abdomen. There was no rebound tenderness, distension, palpable mass, or splenomegaly; bowel sounds were normal. Rectal examination revealed some yellow mucous without blood or hemorrhoids. The skin around the anus was intact with no erosions. Laboratory evaluation revealed a white blood cell count 15.6 K/mm3 (4–10.6 K/mm3) with toxic neutrophilia and reactive lymphocytosis. Eosinophils constituted 16% of the white cell population with an absolute count of 2496 cells/μL (N < 300). Blood hemoglobin was 11.8 g/dL (14.5–17.7 g/ dL), hematocrit was 36% (42–53%), and platelet count was 194 K/mm3 (150–400 K/mm3), with serum concentrations of sodium 138 mmol/L (137–145 mmol/L), potassium 4.2 mmol/L (3.4–4.8 mmol/L), and creatinine 1.20 mg/ dL (0.66–1.25 mg/dL, baseline 0.8 mg/dL). Liver tests revealed serum concentrations of aspartate transaminase (AST) 151 U/L (17–59 U/L), alanine transaminase (ALT) 363 U/L (21–72 U/L), alkaline phosphatase (AP) 252 U/L (38–126 U/L), total bilirubin 2.2 mg/dL (0.2–1.3 mg/dL), indirect bilirubin 1.4 mg/dL (0.1–0.4 mg/dL), total protein 5.1 g/dL (6.1–8.2 g/dL), and albumin 2.5 g/dL (3.5–5 g/ dL). International normalized ratio (INR) was 1.4 (1.0–1.2). Serum lactate was 5 mmol/L (0.4–2 mmol/L) but improved to 2 mmol/L with hydration. Other test results, including autoimmune markers (antinuclear antibody, anti-mitochondrial antibody, anti-smooth muscle antibody, anti-neutrophil cytoplasmic antibodies, and anti-liver–kidney microsome-1 antibody), ceruloplasmin, alpha-1 antitrypsin, and tissue transglutaminase IgA, were negative. Serologic tests for acute viral infection (hepatitis A virus IgM antibodies, hepatitis B virus surface antigen, hepatitis B virus core IgM antibodies, hepatitis C virus antibodies, Epstein–Barr virus antibody to viral capsid antigen IgG, herpes simplex virus 1 and 2 IgM antibodies, and cytomegalovirus IgM antibody) were all negative. * Sarah Lee sleemd12@gmail.com

Selective staining of gastric biopsies for H. pylori does not affect detection rates or turnaround time and improves cost compared to reflexive staining

AIMS To evaluate how reflexive versus selective H. pylori stains affect detection rates, turnaround time (TAT), and cost savings in a real life practice environment following an institutional policy change. METHODS The aforementioned parameters were evaluated in all cases in the year preceding and the year following an institutional policy change from reflexive to selective staining. RESULTS 1497 patients comprised the reflexive stain (RS) group of which 228 (15.2%) were H. pylori positive. 1629 patients comprised the selective stain (SS) group of which 237 (14.5%) were H. pylori positive. There was no significant difference in H. pylori detection rates between the RS and SS groups (OR=0.95, 95% CI=0.78-1.15, p=0.59). TATs were similarly equivalent with a mean of 52.4h for the RS cohort and 53.7h for the SS cohort (p=0.344), both of which included a resident preview day. We calculated an average laboratory cost savings of