Distinguishing Autoimmune Hepatitis From Steatohepatitis in Adolescents With Obesity and Positive Screening Alanine Aminotransferase.

Screening children with obesity for nonalcoholic fatty liver disease leads to identification of elevated alanine aminotransferase (ALT) and is a common cause for referral to pediatric gastroenterology. Guidelines recommend that children with positive screening ALT be evaluated for causes of ALT elevation beyond nonalcoholic fatty liver disease. One clinical challenge is that autoantibodies can be present in patients with obesity and thus may or may not represent autoimmune hepatitis. This case series highlights the importance of a comprehensive evaluation to reach an accurate diagnosis.

Primary Female Urethral Carcinoma: Proposed Staging Modifications Based on Assessment of Female Urethral Histology and Analysis of a Large Series of Female Urethral Carcinomas.

Primary female urethral carcinoma is rare. Limited clinicopathologic information has hindered development of staging criteria in this disease. We analyzed 29 primary female urethral carcinoma resections from 3 academic medical centers to characterize histopathologic features, clinical outcomes, and applicability of current and a novel modified staging criteria. We complemented this analysis with review of fully embedded female autopsy urethras to detail anterior and posterior urethral wall histology. Primary female urethral carcinoma subtypes included urothelial carcinoma in situ (3/29, 10%), adenocarcinoma in situ (1/29; 3%), invasive urothelial carcinoma (13/29, 45%), clear cell carcinoma (5/29, 17%), adenocarcinoma not otherwise specified (4/29, 14%) and squamous cell carcinoma (3/29, 10%). Only 6/29 cases (21%) were originally assigned a stage at diagnosis. Using histologic landmarks specific to the female urethra, we modified existing eighth edition American Joint Committee on Cancer urethral staging to a histology-based female urethral carcinoma staging (UCS) system. UCS stages were defined as pTa/pTisUCS (noninvasive carcinoma), pT1UCS (subepithelial tissue invasion), pT2UCS (periurethral muscle invasion), pT3UCS (vaginal adventitia or surrounding fibrovascular tissue), and pT4UCS (anterior wall fibroadipose tissue or posterior vaginal wall). UCS staging was applicable to all cases and showed stepwise changes in disease recurrence with increasing stage and was statistically significant for disease-specific and overall survival in contrast to the American Joint Committee on Cancer staging system. This study of one of the largest cohort of primary female urethral carcinomas provides a modified histology-based staging system specific to female urethral anatomy that provides outcomes-related information, which may be further validated by larger multi-institutional studies.

Urothelial Proliferation of Unknown Malignant Potential Involving the Bladder: Histopathologic Features and Risk of Progression in De Novo Cases and Cases With Prior Neoplasia.

CONTEXT.­: Urothelial proliferation of unknown malignant potential (UPUMP) is a 2016 World Health Organization classifier that encompasses prior categories of flat and papillary urothelial hyperplasia. In addition, UPUMP occurs in settings of both de novo and prior bladder neoplasia. OBJECTIVE.­: To identify UPUMP features associated with subsequent neoplastic development. DESIGN.­: Sixty-eight patients were identified from the archives, including 26 patients with de novo and 42 patients with prior bladder neoplasia. Patient slides and clinical course were reviewed. RESULTS.­: Patients with de novo UPUMP were detected through clinical findings (26/26; 100%), whereas surveillance cystoscopy primarily detected UPUMP in patients with prior neoplasia (29/42; 69%). Histopathologic criteria evaluated included urothelial hyperplasia, urothelial cytology, vascular ingrowth, denudation, inflammation, edema, and fibrosis. Mean clinical follow-up was 68.9 months in patients with de novo neoplasia and 69.5 months in patients with prior neoplasia. Subsequent neoplasia developed in 4 of 26 (15.4%) of patients with de novo UPUMP and was associated with cystoscopic papillary appearance (P = .02) or microscopic thin papillary ingrowths or papillations (P = .02; median time to progression, 4.1 months). Of 42 patients with prior neoplasia, 17 (40.5%) had subsequent neoplasia, significantly associated with an absence of prominent lamina propria edema (P < .001; median time to progression, 11.0 months). A higher rate of progression to high-grade disease was present in patients with a prior neoplasia versus those with de novo disease (58.9% versus 25%). CONCLUSIONS.­: Urothelial proliferation of unknown malignant potential shows subsequent risk of neoplastic development of 17% in patients with de novo disease and 40% in patients with prior neoplasia. The greatest risk of progression is associated with early papillary formation.

Loss of ARID1A expression is associated with DNA mismatch repair protein deficiency and favorable prognosis in advanced stage surgically resected esophageal adenocarcinoma.

Esophageal adenocarcinoma often presents at an advanced stage and has a dismal prognosis. Current prognostic markers have limited utility. ARID1A is implicated as a tumor suppressor gene in esophageal adenocarcinoma. Loss of ARID1A expression correlates with DNA mismatch repair (MMR) protein deficiency in other tumors. We hypothesized that ARID1A loss is associated with prognosis and DNA MMR protein deficiency in esophageal adenocarcinoma. Tissue microarrays representing 316 surgically resected esophageal adenocarcinomas without neoadjuvant treatment were evaluated for ARID1A and MMR proteins by immunohistochemistry. Loss of ARID1A expression (ARID1A-loss) was detected in 41 of 316 (13%) adenocarcinomas. MMR deficiency was identified in 5% (17/316) but was detected more frequently in ARID1A-loss adenocarcinomas (13/41, 32%) than in ARID1A-retained adenocarcinomas (4/275, 1%; P < .001). Morphologically, ARID1A-loss adenocarcinomas frequently demonstrated peritumoral lymphoid aggregates (90%) and tumor infiltrating lymphocytes (51%). In patients with locally advanced or metastatic disease (stages III or IV, N = 169), patients with ARID1A-loss adenocarcinomas (N = 22) had longer overall survival than patients with ARID1A-retained adenocarcinomas (median [month]: 26 vs. 16, P = .010). In these patients, ARID1A-loss correlated with a 56% reduction in mortality independent of other prognostic factors (P = .007). In summary, loss of ARID1A expression is associated with DNA MMR protein deficiency in esophageal adenocarcinoma. Furthermore, ARID1A loss is independently associated with a more favorable prognosis for patients with locally advanced or metastatic esophageal adenocarcinomas.

SATB2 Is Superior to CDX2 in Distinguishing Signet Ring Cell Carcinoma of the Upper Gastrointestinal Tract and Lower Gastrointestinal Tract.

Signet ring cell carcinomas of the gastrointestinal (GI) tract are clinically aggressive neoplasms with frequent intra-abdominal metastases at initial presentation. Currently available immunohistochemistry (IHC) markers cannot distinguish signet ring cell carcinomas of the lower GI tract and upper GI tract, suggesting the need for more specific diagnostic markers. SATB2 is a novel, sensitive marker for colorectal carcinoma. We hypothesized that SATB2 IHC can reliably identify primary and metastatic signet ring cell carcinomas of lower GI tract origin. SATB2 and CDX2 IHC was performed on 159 primary (n=93) and metastatic (n=66) signet ring cell carcinomas of GI tract origin and 13 metastatic breast carcinomas with signet ring cell features. Positive SATB2 expression (SATB2) was identified in 82% (27/33) of appendiceal, 88% (43/49) of colorectal, 13% (7/54) of gastric, and 35% (8/23) of esophageal/esophagogastric junction signet ring cell carcinomas. Primary and metastatic signet ring cell carcinomas of lower GI tract origin were more frequently SATB2 than those from upper GI tract (70/82, 85% vs. 15/77, 19%, P<0.01). Compared with CDX2, SATB2 and dual-positive staining for SATB2 and CDX2 both had higher specificities for signet ring cell carcinomas from the lower GI tract (81% vs. 49% and 86% vs. 49%, respectively, P<0.01 for both). Two (15%) metastatic breast carcinoma were SATB2, but all 13 demonstrated negative CDX2 staining. In summary, our results show SATB2 is a relatively specific immunohistochemistry marker for both metastatic and primary signet ring cell carcinomas of lower GI tract origin.

Loss of SATB2 Expression in Colorectal Carcinoma Is Associated With DNA Mismatch Repair Protein Deficiency and BRAF Mutation.

The special AT-rich sequence binding protein (SATB2) has been reported to be a specific immunohistochemical marker for colorectal carcinoma; however, correlation of SATB2 expression with molecular alterations commonly assessed in colorectal carcinoma has not been performed. We examined the immunohistochemical expression of SATB2 in 586 adenocarcinomas of the gastrointestinal (GI) tract and pancreas to assess its utility in diagnosis and analyze the clinicopathologic and molecular characteristics of colorectal carcinoma stratified by SATB2 expression. SATB2 and CDX2 expression were evaluated in 266 adenocarcinomas of lower GI tract origin (246 colorectal and 20 appendiceal mucinous), 208 adenocarcinomas of upper GI tract and small intestinal origin (74 esophagus/esophagogastric junction, 103 stomach, 20 duodenal, and 11 jejunoileal), and 112 pancreatic ductal adenocarcinomas. SATB2 expression was more frequently identified in adenocarcinomas of lower GI tract origin (222/266, 83%) compared with upper GI tract, small intestinal, or pancreatic origin (26/320, 8%) (P<0.001). Compared with CDX2 alone, dual positive expression for SATB2 and CDX2 (SATB2/CDX2) has a significantly higher specificity for adenocarcinoma of lower GI tract origin (94% vs. 57%, P<0.001). In colorectal carcinoma, loss of SATB2 expression was more frequently observed in DNA mismatch repair (MMR) protein deficient tumors (31%) compared with MMR protein proficient tumors (13%) (P<0.01). A BRAF V600E mutation was more frequently identified in colorectal carcinomas with loss of SATB2 expression compared with those with positive SATB2 expression (29% vs. 3%) (P<0.001). In summary, SATB2 expression is a relatively specific marker of lower GI tract origin; however, loss of SATB2 expression is more commonly seen in colorectal carcinoma with MMR protein deficiency and BRAF mutation.

Gastric Medullary Carcinoma with Sporadic Mismatch Repair Deficiency and a TP53 R273C Mutation: An Unusual Case with Wild-Type BRAF.

Medullary carcinoma has long been recognized as a subtype of colorectal cancer associated with microsatellite instability and Lynch syndrome. Gastric medullary carcinoma is a very rare neoplasm. We report a 67-year-old male who presented with a solitary gastric mass. Total gastrectomy revealed a well-demarcated, poorly differentiated carcinoma with an organoid growth pattern, pushing borders, and abundant peritumoral lymphocytic response. The prior cytology was cellular with immunohistochemical panel consistent with upper gastrointestinal/pancreaticobiliary origin. Overall, the histopathologic findings were consistent with gastric medullary carcinoma. A mismatch repair panel revealed a mismatch repair protein deficient tumor with loss of MLH1 and PMS2 expression. BRAF V600E immunostain (VE1) and BRAF molecular testing were negative, indicating a wild-type gene. Tumor sequencing of MLH1 demonstrated a wild-type gene, while our molecular panel identified TP53 c.817C>T (p.R273C) mutation. These findings were compatible with a sporadic tumor. Given that morphologically identical medullary tumors often occur in Lynch syndrome, it is possible that mismatch repair loss is an early event in sporadic tumors with p53 mutation being a late event. Despite having wild-type BRAF, this tumor is sporadic and unrelated to Lynch syndrome. This case report demonstrates that coordinate ancillary studies are needed to resolve sporadic versus hereditary rare tumors.

Giant Bullous Emphysema With Placental Transmogrification: A Case Report of a 14-Year-Old With Right Middle- and Lower-Lobe Involvement.

Giant bullous emphysema with placental transmogrification is an extremely rare entity, with 30 previously reported cases. Of these reported cases, it is typically identified with varied clinical and radiological impressions, presents in young adulthood to elderly, is always unilateral, and usually involves just one lobe. Despite the unknown pathogenesis, this diagnosis carries an excellent prognosis and is curative with complete resection. The pulmonary placental transmogrification is histologically indistinguishable from placental origin. Although not necessary to utilize because of the male predominance and no reported association, immunohistochemical stains can be used to prove lung origin. We report an extremely rare case of 2-lobe involvement of giant bullous emphysema with placental transmogrification in a boy 14 years of age, who is the youngest diagnosed patient with this lung abnormality.

Challenges in the Diagnosis of Urothelial Carcinoma Variants: Can Emerging Molecular Data Complement Pathology Review?

Urothelial carcinoma can exhibit a wide variety of histopathologic phenotypes or variant morphologies, classifications of which have recently been revised in the 2016 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs. Many of these variants not only present diagnostic challenges, but also have clinical implications that affect patient prognosis and treatment strategies. This review will discuss these variant morphologies and their relationship to current understanding of the underlying biology of urothelial carcinoma and molecular classification paradigms.

Association of pain and itch with depth of invasion and inflammatory cell constitution in skin cancer: results of a large clinicopathologic study.

IMPORTANCE: This study highlights a simple bedside evaluation of itch and pain for suspicious skin lesions. OBJECTIVE: To examine the correlation of pain and itch with histologic features of skin cancers. DESIGN, SETTING, AND PARTICIPANTS: This large, prospective, clinicopathologic study enrolled patients who filled out questionnaires that assessed itch and pain intensity of their skin tumors at the time of excision. Study participants were from the patient population presenting to the Department of Dermatology surgical unit at Wake Forest University Baptist Medical Center from July 1, 2010, through March 31, 2011. Study participants included 268 patients, representing 339 histopathologically confirmed cutaneous neoplasms. The following skin cancer subtypes were represented in this analysis: 166 basal cell carcinomas, 146 squamous cell carcinomas, and 27 melanomas. MAIN OUTCOMES AND MEASURES: Itch and pain associated with skin cancer at the time of excision ranked on an 11-point (score range, 0-10) numerical visual analog scale and histopathologic analysis for each neoplasm (assessment of the amount and type of inflammation, ulceration, perineural invasion, and depth of invasion). RESULTS: The prevalence of itch and pain across all skin cancers was 36.9% and 28.2%, respectively. However, these symptoms were mostly absent in melanomas. Pain intensity was significantly associated with the degree of inflammation (mild or none vs moderate or marked; P < .001), presence of neutrophils in the inflammatory infiltrate (predominantly mononuclear vs mixed or neutrophilic; P = .003), presence of eosinophils (present vs absent; P = .007), ulceration (yes vs no; P = .003), perineural invasion (yes vs no; P < .001), depth of invasion (P = .001), and largest diameter length of skin lesion (P < .003). Itch intensity was significantly associated with the degree of inflammation (mild or none vs moderate or marked; P = .001) and the presence of eosinophils (present vs absent; P = .02). CONCLUSIONS AND RELEVANCE: These findings support the theory that itch emanates from the upper layers of the skin, whereas pain is associated with deeper processes. This study also reports that a simple bedside assessment for the presence and intensity of pain or itch is an easily implementable tool for physicians evaluating suspicious skin lesions.