Notch Signaling Mediates Differentiation in Barrett's Esophagus and Promotes Progression to Adenocarcinoma.

BACKGROUND & AIMS: Studies are needed to determine the mechanism by which Barrett's esophagus (BE) progresses to esophageal adenocarcinoma (EAC). Notch signaling maintains stem cells in the gastrointestinal tract and is dysregulated during carcinogenesis. We explored the relationship between Notch signaling and goblet cell maturation, a feature of BE, during EAC pathogenesis. METHODS: We measured goblet cell density and levels of Notch messenger RNAs in BE tissues from 164 patients, with and without dysplasia or EAC, enrolled in a multicenter study. We analyzed the effects of conditional expression of an activated form of NOTCH2 (pL2.Lgr5.N2IC), conditional deletion of NOTCH2 (pL2.Lgr5.N2fl/fl), or loss of nuclear factor κB (NF-κB) (pL2.Lgr5.p65fl/fl), in Lgr5+ (progenitor) cells in L2-IL1B mice (which overexpress interleukin 1 beta in esophagus and squamous forestomach and are used as a model of BE). We collected esophageal and stomach tissues and performed histology, immunohistochemistry, flow cytometry, transcriptome, and real-time polymerase chain reaction analyses. Cardia and forestomach tissues from mice were cultured as organoids and incubated with inhibitors of Notch or NF-kB. RESULTS: Progression of BE to EAC was associated with a significant reduction in goblet cell density comparing nondysplastic regions of tissues from patients; there was an inverse correlation between goblet cell density and levels of NOTCH3 and JAG2 messenger RNA. In mice, expression of the activated intracellular form of NOTCH2 in Lgr5+ cells reduced goblet-like cell maturation, increased crypt fission, and accelerated the development of tumors in the squamocolumnar junction. Mice with deletion of NOTCH2 from Lgr5+ cells had increased maturation of goblet-like cells, reduced crypt fission, and developed fewer tumors. Esophageal tissues from in pL2.Lgr5.N2IC mice had increased levels of RelA (which encodes the p65 unit of NF-κB) compared to tissues from L2-IL1B mice, and we found evidence of increased NF-κB activity in Lgr5+ cells. Esophageal tissues from pL2.Lgr5.p65fl/fl mice had lower inflammation and metaplasia scores than pL2.Lgr5.N2IC mice. In organoids derived from pL2-IL1B mice, the NF-κB inhibitor JSH-23 reduced cell survival and proliferation. CONCLUSIONS: Notch signaling contributes to activation of NF-κB and regulates differentiation of gastric cardia progenitor cells in a mouse model of BE. In human esophageal tissues, progression of BE to EAC was associated with reduced goblet cell density and increased levels of Notch expression. Strategies to block this pathway might be developed to prevent EAC in patients with BE.

Imaging features of solitary fibrous tumors.

OBJECTIVE: The goal of this pictorial essay is to illustrate the multimodality imaging features of pleural and extrapleural solitary fibrous tumors. CONCLUSION: Solitary fibrous tumors tend to be well-defined, ovoid, heterogeneously enhancing lesions. MRI characteristically depicts areas of low signal intensity that correspond to dense collagen. The findings of lesion multiplicity and hypermetabolism on PET images should raise the suspicion of malignancy.

Case report: unicameral bone cysts in a young patient with acquired generalized lipodystrophy.

We report the case of a 13-year-old boy with bilateral distal femoral unicameral bone cysts (UBCs) associated with acquired generalized lipodystrophy. As opposed to congenital generalized lipodystrophy, cystic bone lesions in acquired generalized lipodystrophy are rare. After radiographic and histologic confirmation of the UBCs, we performed percutaneous intramedullary decompression, curettage, and grafting. UBCs can be an important manifestation of acquired generalized lipodystrophy. Cystic bone lesions appear to be less common in acquired generalized lipodystrophy than in congenital generalized lipodystrophy, and intramedullary adipose tissue loss may be a predisposing factor for the development of bone lesions in patients with acquired generalized lipodystrophy. When evaluating a patient with lipodystrophy, doctors should recognize the clinical course may include the development of UBCs.

Anthropometric, serologic, and laboratory correlation with villous blunting in pediatric celiac disease: diabetics are different.

OBJECTIVES: We evaluated the correlation between level of tissue transglutaminase (TTG) and endomysial antibodies (EMAs) to different degrees of intestinal damage in celiac disease (CD) children with [presence of diabetes mellitus (DM)+] and without [absence of diabetes mellitus (DM-)] type I diabetes. We also assessed the correlation between albumin, hemoglobin (hgb), transaminases, symptom presence, age of cereal introduction, and body mass index (BMI) to different degrees of intestinal damage. METHODS: Retrospective review of patients seen at the Children's Hospital of Philadelphia between January 2002 and June 2006 revealed 60 children (mean age 9.8 y) who had TTG, EMA, and other laboratory tests performed at time of histologic CD diagnosis from duodenal biopsies. Twenty-one of 60 children had DM. All children were stratified for histologic damage according to Marsh classification. RESULTS: Overall, Marsh (M) I lesions were seen in 2 (3.3%), MII in 2 (3.3%), IIIa in 14 (23.3%), IIIb in 15 (25%), and IIIc in 27 (45%); no differences in DM- versus DM+ groups. TTG was positive in all and EMA was positive in all but 1 child. Among DM- and DM+ children, median TTG and EMA values were higher with MIIIa-c, respectively. For DM-, BMI percentile, hgb, and mean corpuscular volume were lower with advancing histology. However, in DM+, no significant correlation of BMI percentile, hgb, or mean corpuscular volume with grade was observed. Cereal introduction age, hypoalbuminemia, and hepatitis did not differ between MIIIa-c in any group. CONCLUSIONS: TTG and EMA mean serum values are higher in CD children with severe enteropathy (MIIIc) than in those with mild enteropathy (MIIIa). CD in DM is accompanied by serologic and histologic findings identical to that of a non-DM CD population. As CD is identified through screening in DM, it is often silent and not associated with symptoms, growth abnormalities, or anemia. Clinical parameters (height, weight, hgb, symptoms) are not helpful in identifying silent CD in DM.

Downregulation of Friend Leukemia Integration 1 (FLI1) follows the stepwise progression to gastric adenocarcinoma.

Gastric adenocarcinoma (GC) is a leading cause of cancer-related deaths worldwide. The transcription factor gene Friend Leukemia Integration 1 (FLI1) is methylated and downregulated in human GC tissues. Using human GC samples, we determined which cells downregulate FLI1, when FLI1 downregulation occurs, if FLI1 downregulation correlates with clinical-pathologic characteristics, and whether FLI1 plays a role in invasion and/or proliferation of cultured cells. We analyzed stomach tissues from 98 patients [8 normal mucosa, 8 intestinal metaplasia (IM), 7 dysplasia, 91 GC] by immunohistochemistry for FLI1. Epithelial cells from normal, IM, and low-grade dysplasia (LGD) showed strong nuclear FLI1 staining. GC epithelial cells showed significantly less nuclear FLI1 staining as compared to normal epithelium, IM and LGD (P=1.2×10-5, P=1.4×10-6 and P=0.006, respectively). FLI1 expression did not correlate with tumor stage or differentiation, but was associated with patient survival, depending on tumor differentiation. We tested the functional role of FLI1 by assaying proliferation and invasion in cultured GC cells. Lentiviral-transduced FLI1 overexpression in GC AGS cells inhibited invasion by 73.5% (P = 0.001) and proliferation by 31.5% (P = 0.002), as compared to controls. Our results support a combined role for FLI1 as a suppressor of invasiveness and proliferation in gastric adenocarcinoma, specifically in the transition from pre-cancer lesions and dysplasia to invasive adenocarcinoma, and suggest that FLI1 may be a prognostic biomarker of survival in gastric cancers.

Cytology diagnosis of metastatic clear cell renal cell carcinoma, synchronous to pancreas, and metachronous to thyroid and contralateral adrenal: Report of a case and literature review.

Renal cell carcinoma metastases to pancreas, thyroid, and contralateral adrenal gland are decidedly uncommon. Clear cell renal cell carcinoma (CCRCC) is the most frequent subtype. Cytology diagnosis may be challenging. A 74-year-old male with remote history of vocal cord malignancy and hypertension presented with abdominal pain. Computed tomography (CT) revealed 8.4 cm left renal mass highly suspicious for renal cell carcinoma, a 1.8 cm mass within vessels near left adrenal and a 2.5 cm mass in pancreatic tail. Right pulmonary middle lobe showed two small nodules. Metastatic CCRCC was diagnosed on preoperative transgastric, endoscopic ultrasound guided fine-needle aspiration cytology of pancreatic tail mass. Left radical nephrectomy and distal pancreatectomy and splenectomy confirmed CCRCC (pT3bNxM1), with metastases in adrenal and pancreatic tail. The 3p deletion identification in pancreatic tumor suggested CCRCC origin. Follow-up positron emission tomography-CT (PET-CT) scan revealed left thyroid lower pole mass. Thyroid ultrasound showed three clustered 6 mm nodules in left mid pole. Ultrasound-guided fine needle aspiration (US-FNA) biopsies, 4-month post-nephrectomy, were consistent with metastatic renal cell carcinoma in lower, and atypia of undetermined significance in mid poles respectively. Left lobectomy and isthmus and pyramidal lobe resections confirmed metastatic renal cell carcinoma. One year post-radical nephrectomy, contralateral adrenal lesion noted on PET-CT was interpreted as metastatic CCRCC on CT-guided core biopsy with touch imprints. Rapid on-site evaluation was implemented, and immunoprofile typical of CCRCC substantiated cytomorphology at all three sites. Previously reported cases of renal cell carcinoma metastases to organs as in the described case are reviewed as well. Diagn. Cytopathol. 2017;45:161-167. © 2016 Wiley Periodicals, Inc.

Cytomorphology of Recurrent Osseous Extracranial Meningioma of Right Pubic Ramus:: Report of a Case and Literature Review.

Meningiomas are well-recognized neoplasms of the central nervous system. Primary extracranial meningiomas (ECMs) are extremely rare and arise in various anatomic sites. We present a 56-year-old female with 13-year history of primary grade I meningothelial meningioma of right pubic symphysis, orthotopic heart transplant, and right total hip arthroplasty, who presented with progressive right hip pain for 3 weeks. Primary intracranial, intraspinal and other tumors were excluded. Imaging revealed a destructive lytic lesion at right superior and inferior pubic rami and body, associated with extensive bone destruction and soft tissue mass. Touch imprint (TI) cytology of computed tomography (CT)-guided core biopsy from the right pubic ramus (PRA) lesion showed a spindle cell neoplasm, with classical syncytial, lobular, and whorling cellular arrangement, composed of spindle, oval or round nuclei with occasional pseudoinclusions, consistent with known history of osseous meningioma. Tumor was further characterized by histopathology as grade 1 meningioma with meningothelial features. To our knowledge, primary osseous ECM arising specifically at the PRA has not been reported previously. ECM at this site may pose a diagnostic challenge for cytologists as its features may resemble other more commonly observed lesions. Accurate diagnosis requires awareness of occurrence of ECM at PRA and recognition of its characteristic cytomorphology. TI cytological features of our case are presented and previously described cytology of ECMs and diagnostic pitfalls are reviewed. Diagn. Cytopathol. 2016;44:618-622. © 2016 Wiley Periodicals, Inc.

Cystic struma ovarii presenting with ascites and an elevated CA-125 level. A case report.

BACKGROUND: Struma ovarii is a monodermal teratoma that usually presents as a solid pelvic mass. Occasionally the lesions are cystic. Rare cases present with ascites or pseudo-Meigs' syndrome. The association of a cystic struma ovarii with ascites and an elevated CA-125 level is exceptionally rare. CASE: A 51-year-old woman presented with ascites and a cystic pelvic mass. There was marked elevation of her CA-125 level. The clinical impression was ovarian carcinoma. Frozen section revealed a multicystic struma ovarii. CONCLUSION: Struma ovarii can mimic ovarian carcinoma clinically, particularly if cystic and associated with ascites and an elevated CA-125 level.

Anorectal melanoma--3 case reports and a review of the literature.

Anorectal melanoma is an uncommon disease. Histologically, the tumor may mimic adenocarcinomas, small cell carcinomas, and sarcomas; grossly, the lesion often mimics hemorrhoids. We report 3 cases of anorectal melanoma: a 40-year-old woman with anorectal melanoma with local recurrence after an abdominoperineal resection (APR); a 30-year-old woman with anorectal melanoma and multiple liver metastases returning with multiple masses in the rectum and 2 nodules above and below the left clavicle after receiving chemotherapy; and a 62-year-old woman with inguinal node metastases. The histologic findings in all 3 cases revealed malignant tumor composed of atypical melanocytes diagnosed as malignant melanoma of the rectum. In the first case, APR with pararectal lymphadenectomy was performed. Histopathology revealed nodal metastasis. The patient was noncompliant with chemotherapy and died after several months. In the second case, chemotherapeutic treatment was begun. Seven months after receiving chemotherapy, the patient returned with multiple metastases. The final case was lost to follow-up after referral to an oncologist. Anorectal melanoma is highly aggressive and unresponsive to both radical surgery and local control. Although supplemental therapy may improve quality of life and prolong survival, the 5-year survival rate is 10% with a mean survival time of 15 to 25 months. In the 3 cases presented, metastatic disease was present at the time of diagnosis. At this stage, APR with lymphadenectomy followed by some form of adjuvant therapy is our recommended treatment.

Intraventricular hemorrhage induces deposition of proteoglycans in premature rabbits, but their in vivo degradation with chondroitinase does not restore myelination, ventricle size and neurological recovery.

Intraventricular hemorrhage (IVH) results in white matter injury and hydrocephalus in premature infants. Chondroitin sulfate proteoglycans (CSPGs)-neuorcan, brevican, versican, aggrecan and phosphacan-are unregulated in the extracellular matrix after brain injury, and their degradation enhances plasticity of the brain. Therefore, we hypothesized that CSPG levels were elevated in the forebrain of premature infants with IVH and that in vivo degradation of CSPGs would enhance maturation of oligodendrocyte, augment myelination, promote neurological recovery, and minimize hydrocephalus. We found that levels of neurocan, brevican, aggrecan, phosphacan, and versican were elevated, whereas NG2 expression was reduced in premature rabbit pups and human infants with IVH compared to controls. Intracerebroventricular chondroitinase ABC (ChABC) reduced the expression of neuorcan, brevican, versican and aggrecan, but not NG2. However, ChABC treatment did not enhance maturation of oligodendrocytes, myelination, or neurological recovery in the pups with IVH. Moreover, ChABC did not reduce gliosis or ventriculomegaly. Our results demonstrate that IVH induces distinct changes in the components of CSPGs, and that reversing these changes by in vivo ChABC treatment neither promotes clinical recovery, myelination, nor reduces ventriculomegaly in preterm rabbit pups.

Effect of prenatal exposure to anticonvulsant drugs on dermal ridge patterns of fingers.

BACKGROUND: An altered frequency of specific dermal ridge patterns on fingertips, such as an increased number of arches, has been observed in children exposed in utero to anticonvulsants and other teratogens. Asymmetry of the distribution of dermal ridge patterns has been attributed to environmental exposures and genetic factors. METHODS: We evaluated all of the dermal ridge patterns of 66 children who had been exposed to either the anticonvulsant phenytoin alone or phenytoin and phenobarbital. We determined the frequency of each pattern, concordance between the fingers on the left and right hands, sex differences and total ridge counts in the drug-exposed children and compared them to the findings in 716 unexposed comparison children. The frequency of each pattern was established in comparison to the most common type of pattern (ulnar loop), which showed that there were alterations in the frequency of arches, radial loops and whorls on specific fingers. RESULTS: Eight (12.1%) of 66 children had three or more arch patterns, with all but one having been exposed to phenytoin and phenobarbital. Only one of these eight children was considered by the masked examiner to have fingernail hypoplasia. There was no evidence of asymmetry in the anticonvulsant-exposed children. There were minor differences in the distribution of total ridge count. CONCLUSIONS: Subtle differences in several dermal ridge patterns, not just arch patterns, were present in anticonvulsant-exposed children, primarily in those exposed to polytherapy: phenytoin and phenobarbital.

Subglottic ductal cysts associated with complete tracheal ring deformity: coexistence of two rare airway abnormalities with fatal outcome.

Subglottic cysts are rare and may cause airway obstruction. Most cases are acquired secondary to endotracheal intubation, even short-term, particularly in the premature neonate. Complete tracheal rings are rare anomalies associated with tracheal stenosis. To our knowledge, the two have not been reported coexisting. A 16-month-old ex-premature boy was found unresponsive, with his tracheostomy tube dislodged. Tracheomalacia, subglottic stenosis, and a laryngeal cyst had been diagnosed shortly after birth, and the cyst was surgically treated at that time. At autopsy, a complete tracheal ring was noted in the subglottic region, above the tracheostomy site, and the tracheal diameter was markedly decreased in this area. In addition, multiloculated cysts were present at that level, arising from both anterolateral tracheal walls. These completely occluded the airway. To our knowledge, this is the first case of a combination of tracheal ring anomaly and subglottic cysts. Pediatric pathologists must be aware of iatrogenic lesions associated with care of the premature neonate, particularly as the age of viability continues to decrease.

Effects on toes from prenatal exposure to anticonvulsants.

BACKGROUND: Changes in the distal phalanges of the fingers, including coned epiphyses and hypoplasia of the phalanges, are recognized teratogenic effects of the anticonvulsant drugs phenytoin and phenobarbital. We hypothesized that the frequency of these changes would also be increased in the toes of children exposed to these drugs in comparison to unexposed children. METHODS: We report on the findings in an analysis of radiographs of the feet of 63 children exposed in utero to either phenytoin alone, phenobarbital alone or both drugs and 56 unexposed comparison children. RESULTS: Only subtle changes were identified. The frequency of coned epiphyses and hypoplasia of phalanges of the toes was the same in both the anticonvulsant and unexposed children. Among the anticonvulsant-exposed children, however, there was a strong association between the presence of coned epiphyses in the feet and in the hands: all five children with coned epiphyses in the hands, as described previously in the same individuals by Lu et al. ([2000] Teratology 61:277-283) had coned epiphyses in their feet (P = 0.0012). Measurements showed a shortening of metatarsals in all three treatment groups, but this was significant only in the phenytoin monotherapy-exposed children. CONCLUSIONS: Subtle changes are present in the phalanges and metatarsals of the feet of anticonvulsant-exposed children, but the overall frequency is much less than occurred in the hands of the same children. We conclude that the presence of either coned epiphyses or hypoplasia of the phalanges of the toes cannot be considered a distinctive feature of the teratogenicity of the anticonvulsant drugs phenytoin and phenobarbital.