Catherine Hagen

Predictors Of Treatment Failure After Radiofrequency Ablation For Intramucosal Adenocarcinoma in Barrett Esophagus: A Multi-institutional Retrospective Cohort Study.

Radiofrequency ablation (RFA), with or without endoscopic mucosal resection (EMR), is a safe, effective, and durable treatment option for Barrett esophagus (BE)–associated dysplasia (DYS), but few studies have identified predictors of treatment failure in BE-associated intramucosal adenocarcinoma (IMC). The aim of this study was to determine the rate of IMC eradication when using RFA±EMR and to identify clinical and pathologic predictors of treatment failure. A retrospective review of medical records and a central review of index histologic parameters were performed for 78 patients who underwent RFA±EMR as the primary treatment for biopsy-proven IMC at 4 academic tertiary medical centers. Complete eradication (CE) (absence of IMC/DYS on first follow-up endoscopy) was achieved in 86% of patients, and durable eradication (DE) (CE with no recurrence of IMC/DYS until last follow-up) was achieved in 78% of patients, with significant variation between the 4 study sites (P=0.03 and 0.09 by analysis of variance for DE and CE, respectively). Use of EMR before RFA significantly reduced the risk for treatment failure for IMC/DYS (hazard ratio, 0.15; 95% confidence interval, 0.05-0.48; P=0.001), whereas IMC involving ≥50% of the columnar metaplastic area on index examination significantly increased the risk for treatment failure (hazard ratio, 4.24; 95% confidence interval, 1.53-11.7; P=0.005). Endoscopic and pathologic factors associated with treatment failure in BE-associated IMC treated with RFA±EMR may help identify the subset of IMC patients for whom a more aggressive initial approach may be justified.

Syphilis presenting as inflammatory tumors of the liver in HIV-positive homosexual men.

Syphilis, a sexually transmitted infection caused by the spirochete Treponema pallidum, has seen a resurgence since 2001, particularly in men who have sex with men. Syphilis can affect the liver during the secondary stage as syphilitic hepatitis and during the tertiary stage as gummas. We describe 3 cases of syphilis in human immunodeficiency virus–positive homosexual men that presented as hepatic mass lesions clinically suspected of being malignant tumors. Histologically, 2 of the 3 cases showed a plump spindle cell proliferation, mixed inflammatory infiltrate with numerous neutrophils, and abscesses, whereas the third case showed granulomas and pericholangitis/cholangitis. Immunohistochemical staining for T. pallidum showed innumerable organisms in 2 of the cases. Pathologists must be aware of the possibility of syphilis causing hepatic inflammatory masses in human immunodeficiency virus–positive men who have sex with men in order to avoid misdiagnosis or delayed treatment.

CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 41-2015. A 14-Year-Old Boy with Immune and Liver Abnormalities.

Dr. Timothy P. Lax (Pediatric Allergy and Immunology): A boy who was 14 years 8 months of age and had multiple chronic illnesses was seen in the gastroenterology clinic of this hospital because he had had abnormal results on liver-function tests for approximately 1.5 years. The patient was born by vaginal delivery after a full-term uncomplicated gestation. He was noted to have an undescended testis. He received diagnoses of gastroesophageal reflux disease and failure to thrive at infancy, followed by type 1 diabetes mellitus (at 2 years of age), primary hypothyroidism (at 4 years of age), mild speech delay, learning disabilities, recurrent infections (including sinusitis, streptococcal pharyngitis, and pneumonias), nocturia, and leukoplakia of the tongue. At 2 years of age, he underwent genetic evaluation at another hospital, and the chromosomes were reportedly normal. Dr. Steven M. Sharatz: When the patient was 10 years of age, magnetic resonance imaging (MRI) of the head (Fig. 1A) was performed because of chronic headaches From the Divisions of Pediatric Allergy Immunology (J.E.W.), Pediatric Gastro‐ enterology (U.S.), Pediatric Hematology– Oncology (A.M.F.), Bone Marrow Trans‐ plantation (T.S.), Radiology (S.M.S.), and Pathology (C.H.), Massachusetts General Hospital, and the Departments of Pediat‐ rics ( J.E.W., U.S., A.M.F., T.S.), Radiology (S.M.S.), and Pathology (C.H.), Harvard Medical School — both in Boston; and the Department of Medical Oncology, Johns Hopkins University School of Med‐ icine, Baltimore (M.A.).

Case 41-2015

Dr. Timothy P. Lax (Pediatric Allergy and Immunology): A boy who was 14 years 8 months of age and had multiple chronic illnesses was seen in the gastroenterology clinic of this hospital because he had had abnormal results on liver-function tests for approximately 1.5 years. The patient was born by vaginal delivery after a full-term uncomplicated gestation. He was noted to have an undescended testis. He received diagnoses of gastroesophageal reflux disease and failure to thrive at infancy, followed by type 1 diabetes mellitus (at 2 years of age), primary hypothyroidism (at 4 years of age), mild speech delay, learning disabilities, recurrent infections (including sinusitis, streptococcal pharyngitis, and pneumonias), nocturia, and leukoplakia of the tongue. At 2 years of age, he underwent genetic evaluation at another hospital, and the chromosomes were reportedly normal. Dr. Steven M. Sharatz: When the patient was 10 years of age, magnetic resonance imaging (MRI) of the head (Fig. 1A) was performed because of chronic headaches From the Divisions of Pediatric Allergy Immunology (J.E.W.), Pediatric Gastro‐ enterology (U.S.), Pediatric Hematology– Oncology (A.M.F.), Bone Marrow Trans‐ plantation (T.S.), Radiology (S.M.S.), and Pathology (C.H.), Massachusetts General Hospital, and the Departments of Pediat‐ rics ( J.E.W., U.S., A.M.F., T.S.), Radiology (S.M.S.), and Pathology (C.H.), Harvard Medical School — both in Boston; and the Department of Medical Oncology, Johns Hopkins University School of Med‐ icine, Baltimore (M.A.).

Biliary Adenofibroma of Liver: Morphology, Tumor Genetics, and Outcomes in 6 Cases

Biliary adenofibroma is a rare primary hepatic neoplasm, recognized in the World Health Organization classification, although only 14 cases have been reported to date. This series includes extended follow-up from 2 of the early case reports and 4 novel cases. Clinical history and histology were reviewed in all 6 cases. Tumor DNA was analyzed for point mutations by multiplex polymerase chain reaction and copy number alterations by array comparative genomic hybridization. The patients included 4 females and 2 males presenting between 46 and 83 years of age, with tumors ranging from 7 to 16 cm in diameter. The tumors had similar morphology, with tubules and cysts lined mainly by bland to mildly atypical cuboidal epithelium embedded in fibrous stroma. Multiplex polymerase chain reaction did not identify mutations in 4 tumors tested. Three tumors tested by array comparative genomic hybridization showed chromosomal copy number alterations, including 1 with amplifications of CCND1 and ERBB2. Three patients underwent resection with no recurrence at 21, 20, and 3 years of follow-up. One patient is alive after 14 months with no resection. Two patients with margin-positive resections had local recurrence at 1 and 6 years after surgery. No patient had distant metastasis. The distinct morphology and multiple clonal cytogenetic alterations in biliary adenofibromas indicate that the lesions are neoplastic. Amplifications of CCND1 and ERBB2 are not typical of benign neoplasms, and suggest that these tumors may have the ability to behave aggressively. However, the clinical outcomes in these patients suggest the neoplasms are only slowly progressive.

Barrett esophagus: Diagnostic challenges

The incidence of esophageal adenocarcinoma and associated mortality has risen dramatically over the past several decades, and, thus, it is increasingly important to understand its pathogenesis and risk factors. Barrett esophagus is the established precursor to esophageal adenocarcinoma that progresses through a metaplasia-dysplasia-carcinoma sequence. Its risk of transforming to carcinoma is not as high as previously reported and there appears to be a biological heterogeneity among patients with this disease. The overall prevalence of Barrett esophagus in the United States ranges from 1% to 25% and is closer to 5% in patients with gastroesophageal reflux disease. Because of the frequency of Barrett esophagus and associated implications, it is important for the practicing pathologist to have a thorough understanding of this disease and its diagnostic pitfalls. In this review, we will discuss issues associated with the diagnosis of Barrett esophagus, including the definition of Barrett esophagus and its distinction from carditis with intestinal metaplasia. We will also discuss challenges in the grading of dysplasia and new variants of dysplasia, including crypt dysplasia and foveolar-type dysplasia. Finally, we will touch upon the evaluation of dysplasia in endoscopic mucosal resection specimens.

Colonic graft-vs.-host disease in autologous versus allogeneic transplant patients: earlier onset, more apoptosis, and lack of regulatory T-cell attenuation

Histologic characterization of graft-vs.-host disease in autologous stem cell transplant patients has been limited. The aims of this study were to characterize colonic graft-vs.-host disease in autologous stem cell transplant patients and compare to a control group of allogeneic stem cell transplant patients, to determine whether graft-vs.-host disease can be diagnosed < 21 days post transplantation in autologous stem cell transplant recipients, and to quantify colonic T-cell populations in autologous stem cell transplant patients. Colonic biopsies taken to evaluate for graft-vs.-host disease in both allogenic and autologous stem cell transplant patients were reviewed for the maximum number of apoptotic bodies per 10 contiguous crypts. Immunohistochemical stains for CD4, CD8, and FoxP3 were performed. Clinical information was collected from chart review. The study group consisted of 122 colonic biopsies from 84 patients. Sixteen patients underwent autologous stem cell transplant and 68 allogeneic stem cell transplant. Autologous stem cell transplant patients underwent biopsy significantly earlier compared with allogeneic stem cell transplant patients (median 20 vs. 87 days, p = 0.0002), had significantly higher apoptotic counts compared with matched-related donor patients (7.5 vs. 3.9, p = 0.03), and had higher FoxP3-positive lamina propria lymphocytes counts compared to allogeneic stem cell transplant patients (9.2 vs. 5.3, p = 0.03). In patients undergoing biopsy < 21 days post transplantation, allogeneic stem cell transplant patients showed less CD8-positive lamina propria lymphocytes and a trend of less FoxP3- and CD4-positive lamina propria lymphocytes compared with autologous stem cell transplant patients. Autologous stem cell transplant patients have more prominent crypt apoptosis compared with allogenic stem cell transplant patients and do not have numerically decreased FoxP3-positive lamina propria lymphocytes. Presence of robust T-cell populations in the early period following transplantation suggest that the 21-day cutoff for diagnosis of graft-vs.-host disease is not applicable to autologous stem cell transplant patients.

Liver biopsy findings in patients with hematopoietic cell transplantation

Liver dysfunction is a frequent complication after hematopoietic cell transplantation. Liver biopsy has an important role for confirming the diagnosis of graft-versus-host disease (GVHD) or other liver diseases. The histological features of GVHD are not specific, and GVHD and other coexisting diseases may be present in the same biopsy, which makes the histologic interpretation of the liver biopsy more complex and challenging. The aim of the study is to improve the present diagnostic criteria. Fifty-two liver biopsies were studied. Most biopsies (47, 92%) showed some features of GVHD. Five (9.6%) had no GVHD, 20 (38.5%) had possible GVHD, and 27 (51.9%) had likely GVHD. Histologic features were analyzed semi-quantitatively and scored. Bile duct damage and intraepithelial lymphocytes were significantly more frequent in likely GVHD groups. Bile duct injury score calculated as the sum of bile duct damage and intraepithelial lymphocytes score was 2.3 in no GVHD and possible GVHD groups, and 4.2 in likely GVHD group (P<.001). A bile duct injury score ≥4 correlated well with a diagnosis of GVHD, with sensitivity 74% and specificity 88%. Many cases (36; 70.6%) had a concurrent disease process. Drug-induced liver injury (8, 16%) and sinusoidal obstruction syndrome (6, 12%) are particularly important causes of liver dysfunction. Moderate degree of bile duct injury and intraepithelial lymphocytes were the most helpful histologic findings to confirm the diagnosis of GVHD. In addition, it is important for the pathologist to be aware of the etiologies of liver dysfunction other than GVHD.

A Fatal Case of Erdheim-Chester Disease with Hepatic Involvement

Erdheim-Chester disease (ECD) is a rare form of systemic histiocytosis, typically presenting with striking osseous involvement characterized by bilateral osteosclerosis and involvement of organs such as the lung, pituitary gland, heart, and brain. Liver involvement with ECD is extremely uncommon. We report a 56-year-old woman presenting with newly diagnosed cirrhosis and signs concerning for intra-abdominal malignancy, including omental caking and peritoneal thickening. Liver biopsy demonstrated xanthogranulomatous infiltration from ECD. The patient showed initial improvement with interferon therapy, but she developed severe depression, which led to the discontinuation of the treatment. Shortly afterward, she died from progressive liver dysfunction resulting in hepatorenal syndrome.

Diagnostic phrasing is independently correlated with the decision to treat for graft-versus-host disease: retrospective review of colon biopsies with rare apoptosis.

The risks of immunosuppression and the non‐specific nature of rare crypt apoptosis has led to debate over the lower threshold for histological diagnosis of colonic graft‐versus‐host disease (GVHD). A recent study proposed the diagnostic category of indeterminate for GVHD (iGVHD) for cases with six or fewer apoptotic bodies per 10 crypts. Our aim was to assess colon biopsies with iGVHD histology to determine whether the diagnosis was retrospectively predictive of the decision to treat, and to correlate these findings with endoscopic and clinical findings.