Joseph Misdraji

Appendiceal mucinous neoplasms: A clinicopathologic analysis of 107 cases

The classification of appendiceal mucinous tumors is controversial and terminology used for them inconsistent, particularly when they lack overtly malignant features but are associated with extra-appendiceal spread. We reviewed 107 appendiceal mucinous neoplasms and classified them as low-grade appendiceal mucinous neoplasm (LAMN) (n = 88), mucinous adenocarcinomas (MACAs) (n = 16), or discordant (n = 3) based on architectural and cytologic features. LAMNs were characterized by a villous or flat proliferation of mucinous epithelium with low-grade atypia. Thirty-nine tumors were confined to the appendix, but 49 had extra-appendiceal tumor spread, including 39 with peritoneal tumor characterized by mucin pools harboring low-grade mucinous epithelium, usually dissecting in a hyalinized stroma. Eight of the 16 MACAs lacked destructive invasion of the appendiceal wall and eight showed an infiltrative pattern of invasion. Extra-appendiceal tumor spread was present in 12 MACAs (four peritoneum, seven peritoneum and ovaries; one ovaries only). In MACAs with an infiltrative pattern, peritoneal tumor consisted of glands and single cells in a desmoplastic stroma. The peritoneal tumor in the remaining cases consisted of mucin pools that contained mucinous epithelium with high-grade atypia and, in some cases, increased cellularity compared with that seen in peritoneal spread in cases of LAMN. Three cases were classified as discordant because the appendiceal tumors were LAMNs but the peritoneal tumors were high-grade. Follow-up was available for 49 LAMNs, 15 MACAs, and 2 discordant cases. None of the patients with LAMNs confined to the appendix experienced recurrence (median follow-up 6 years). LAMNs with extra-appendiceal spread were associated with 3-, 5-, and 10-year survival rates of 100%, 86%, and 45%, respectively. Patients with MACA had 3- and 5-year survival rates of 90% and 44%, respectively (p = 0.04). The bulk of peritoneal disease correlated with prognosis among patients with MACA (p = 0.04) and, to a lesser degree, among patients with LAMNs (p = 0.07). We conclude that: 1) appendiceal mucinous neoplasms can be classified as either low-grade mucinous neoplasms or mucinous adenocarcinoma based on architectural and cytologic features; 2) tumors that can be confidently placed in the low-grade group (which requires rigorous pathologic evaluation of the appendix) and are confined to the appendix are clinically benign in our experience to date; 3) low-grade tumors confined to the appendix are morphologically identical to those with extra-appendiceal spread (except for the usual identification of breach of the wall in the latter cases) and the same designation is appropriate for the appendiceal neoplasia in each situation; 4) the long-term outlook for patients with low-grade tumors and peritoneal spread is guarded with just over half dying of disease after 10 years; 5) appendiceal mucinous tumors with destructive invasion of the appendiceal wall, complex epithelial proliferations, or high-grade nuclear atypia generally pursue an aggressive clinical course and should be classified as mucinous adenocarcinomas; 6) peritoneal tumor can be classified as involvement by LAMN or MACA, and this distinction is of prognostic significance; 7) bulky peritoneal tumor worsens prognosis; and 8) LAMNs associated with high-grade peritoneal tumor behave as adenocarcinoma.

Sessile Serrated Adenoma: Challenging Discrimination From Other Serrated Colonic Polyps

Sessile serrated adenoma (SSA) is the proposed precursor for microsatellite unstable colorectal carcinomas and some authorities recommend that SSAs should be managed similar to adenomas. The aim of our study was to determine whether serrated polyps can be classified with sufficient consistency to support current treatment recommendations. One hundred eighty-five serrated polyps were classified as hyperplastic polyp (HP), SSA, or traditional serrated adenoma (TSA) by 5 pathologists blinded to clinical data. The observers documented which histologic features they considered most helpful in reaching their diagnosis in each case. In a second round, the observers were provided with polyp site and size. After reaching a consensus on minimum criteria for SSA and TSA, the pathologists classified another set of 50 polyps. The interobserver concordance was calculated using κ statistics. In the first round, the overall interobserver agreement was moderate (κ=0.55). Concordance for HP and SSA was moderate whereas it was nearly perfect for TSA. In the second round, there was no improvement in the concordance. All observers relied more often on architectural features than on cytologic ones to distinguish SSA from HP and agreement was reached that architectural features should provide the basis for the diagnosis of SSA. Subsequently, interobserver concordance was slightly improved but remained moderate (κ=0.58). Interobserver agreement for the diagnosis of serrated polyps is moderate. However, this level of variability is acceptable because the presence of SSA indicates increased risk of developing additional serrated polyps and carcinoma, and surveillance is appropriate.

Whole-Slide Imaging Digital Pathology as a Platform for Teleconsultation: A Pilot Study Using Paired Subspecialist Correlations

CONTEXT -Whole-slide imaging technology offers promise for rapid, Internet-based telepathology consultations between institutions. Before implementation, technical issues, pathologist adaptability, and morphologic pitfalls must be well characterized. OBJECTIVE -To determine whether interpretation of whole-slide images differed from glass-slide interpretation in difficult surgical pathology cases. DESIGN -Diagnostically challenging pathology slides from a variety of anatomic sites from an outside laboratory were scanned into whole digital format. Digital and glass slides were independently diagnosed by 2 subspecialty pathologists. Reference, digital, and glass-slide interpretations were compared. Operator comments on technical issues were gathered. RESULTS -Fifty-three case pairs were analyzed. There was agreement among digital, glass, and reference diagnoses in 45 cases (85%) and between digital and glass diagnoses in 48 (91%) cases. There were 5 digital cases (9%) discordant with both reference and glass diagnoses. Further review of each of these cases indicated an incorrect digital whole-slide interpretation. Neoplastic cases showed better correlation (93%) than did cases of nonneoplastic disease (88%). Comments on discordant cases related to digital whole technology focused on issues such as fine resolution and navigating ability at high magnification. CONCLUSIONS -Overall concordance between digital whole-slide and standard glass-slide interpretations was good at 91%. Adjustments in technology, case selection, and technology familiarization should improve performance, making digital whole-slide review feasible for broader telepathology subspecialty consultation applications.

Primary lymphoma of peripheral nerve: Report of four cases

Lymphoma presenting as a solitary tumor of peripheral nerve is exceedingly rare, with only six previously reported cases. The authors describe an additional four cases of primary lymphoma of peripheral nerve involving the sciatic nerve (two cases), the radial nerve, and the sympathetic chain and spinal nerve. The patients were two men and two women with an average age of 55.5 years. All tumors were high-grade B-cell lymphomas. Two patients experienced relapse of disease with involvement of other nervous system sites and died of lymphoma. One patient is alive with stable local disease at 57 months. The fourth patient is alive with no evidence of disease at 54 months. Expression of neural cell adhesion molecule (CD56) has been reported to correlate with an increased incidence of central nervous system involvement in peripheral T-cell lymphoma; all their cases were CD56 negative. Recent reports indicate a high proportion of primary brain lymphomas show loss of CDKN2A/p16 gene expression. Therefore, CDKN2A/p16 was evaluated in their patients both by polymerase chain reaction and by immunohistochemistry for the p16 protein. The authors found homozygous deletion of the CDKN2A/p16 gene in one of three patients studied, confirmed immunohistochemically by absent staining for p16. The fourth patient showed absent staining for p16, suggesting inactivation of the gene in this case as well. The two patients with p16 loss both died of lymphoma, whereas the two patients with normal p16 expression are alive. Primary lymphoma of peripheral nerve is a rare neoplasm, usually of large B-cell type, has a variable prognosis, and appears to have less consistent loss of p16 expression than primary central nervous system lymphoma.

Appendiceal Mucinous Neoplasms: Controversial Issues

Low grade appendiceal mucinous neoplasms can spread to the peritoneum as pseudomyxoma peritonei even though they are not obviously invasive in the appendix. During the past several decades, several problematic issues surrounding this enigmatic tumor have been debated in the literature, including appropriate nomenclature for the appendiceal tumors and their peritoneal metastases. In this article, the most contentious issues in the area of appendiceal mucinous tumors are examined. First, the classification systems that have been proposed for these tumors are compared in the context of whether the appendiceal mucinous tumors are ruptured adenomas or invasive carcinomas. The controversy about the nature of pseudomyxoma peritonei and its classification systems is discussed in the following section. A brief discussion follows that examines the issue of localized pseudomyxoma peritonei and its clinical significance. Next reviewed is the largely resolved controversy about whether ovarian mucinous tumors in this setting are separate primaries or are metastases from the appendiceal tumor. Finally, the controversy about the most effective treatment of patients with pseudomyxoma peritonei is discussed.

Prognostic Significance of Localized Extra-appendiceal Mucin Deposition in Appendiceal Mucinous Neoplasms

Appendiceal mucinous neoplasms confined to the mucosa are benign, whereas those with disseminated peritoneal mucin deposits often follow an indolent, but malignant, course. Not infrequently, appendiceal mucinous neoplasms are associated with localized periappendiceal mucin deposits, but lack diffuse peritoneal involvement. Mucin deposits in these cases may be acellular or contain neoplastic epithelium (cellular mucin). Although some investigators consider both acellular and cellular periappendiceal mucin to pose no, or minimal, risk for recurrent disease, the biologic importance of localized extra-appendiceal mucin has never been evaluated. We identified 65 patients with appendiceal mucinous neoplasms, all of whom had localized periappendiceal mucin deposits without diffuse peritoneal involvement, and assessed them for the presence of extra-appendiceal epithelium and clinical outcome. Forty-nine (75%) appendices were submitted in total for histologic evaluation. Most (77%) cases showed acellular periappendiceal mucin, but 15 (23%) had scant extra-appendiceal epithelium (range: 1 to 12 cell clusters). Upon follow-up (mean: 48 mo), 2 (4%) patients with acellular periappendiceal mucin developed diffuse peritoneal disease, but neither of these appendices was submitted in total for histologic evaluation. In contrast, 5 of 15 (33%) patients with cellular periappendiceal mucin developed mucinous ascites, including 1 who eventually died of disease (P=0.03). Thus, patients with appendiceal mucinous neoplasms and acellular periappendiceal mucin are unlikely to develop recurrent disease. However, microscopic examination of the entire appendix is necessary, as lesions with extra-appendiceal tumor cells are more likely to progress to disseminated disease and result in death of the patient, even if the mucin is paucicellular and confined to the periappendiceal region.

Autoimmune hepatitis with centrilobular necrosis.

Autoimmune hepatitis (AIH) is usually a chronic portal-based hepatitis with prominent plasma cells. Although necroinflammatory activity throughout the lobule is described, centrilobular necrosis (CN) is only rarely the predominant pattern of injury. Recognition of the possibility of AIH in zone 3 hepatitis will lead to prompt steroid therapy and may avert cirrhosis. We report the clinicopathologic features of 6 cases of AIH with CN. The 3 females and 3 males averaged 48 years of age (range 32–66 years). Four patients had a history of autoimmune disorders. All had elevated transaminases and negative serology for viral hepatitis B and C. One had a history of ethanol use. One patient was taking interferon-β and 1 patient was taking atorvastatin, but none of the patients was taking medication with a temporal relationship to suggest a drug hypersensitivity hepatitis. All patients had positive antinuclear antibody, anti-smooth muscle antibody, or both, although 1 patient was negative for autoantibodies at initial laboratory testing. Four biopsies showed confluent zone 3 necrosis, whereas two biopsies showed spotty CN. Portal inflammation was relatively mild in all cases. Plasma cells were few to numerous in both zone 3 and portal tracts in four biopsies; they were absent in 2 cases. All patients responded to steroid therapy. Two patients relapsed, and rebiopsy in 1 of them showed CN, bridging necrosis, and an increase in the degree of portal-based hepatitis. Another patient was not treated initially; a second biopsy 35 months after presenting revealed periportal hepatitis as well as CN. The histologic spectrum of AIH should be expanded to include zone 3 hepatitis. As with classic AIH, most patients with CN demonstrate serologic and clinical evidence of autoimmunity. Subsequent biopsies in patients with a centrilobular pattern may show evolution to portal-based hepatitis characteristic of AIH but may also show persistence of the zone 3 hepatitis. Unlike other causes of zone 3 hepatitis, AIH is steroid responsive; therefore, timely diagnosis is important.

Secondary causes of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is becoming the most common cause of chronic liver disease in the developing world, found in 17-30% of the population in Western countries and 2-4% worldwide. Defined as the accumulation of fatty acid content greater than 5% of liver weight, NAFLD is a spectrum of disease ranging from simple steatosis to nonalcoholic steatohepatitis. The pathophysiology of NAFLD involves increased de novo synthesis of fatty acids in hepatocytes, the retention of lipids due to impaired hepatocyte apolipoprotein secretion or beta-oxidation. The well-known primary causes of NAFLD are obesity, type II diabetes, dyslipidemia, and insulin resistance. However, other less common conditions can cause a similar clinical and histologic picture, and should be considered in patients who present with NAFLD but do not have traditional risk factors. In this review, we discuss uncommon but important causes of NAFLD, including inborn errors of metabolism, iatrogenic causes, viral hepatitis, and nutritional disorders to provide practicing clinicians with an understanding of the less well recognized causes of NAFLD.

2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody‐mediated liver allograft rejection at the 11th (Paris, France, June 5–10, 2011), 12th (Comandatuba, Brazil, August 19–23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5–10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody‐mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Follicle Center Lymphoma of the Ampulla of Vater Presenting with Jaundice: Report of a Case

We report the case of a 56-year-old woman who presented with biliary obstruction due to a neoplasm involving the duodenum in the area of the ampulla of Vater and the head of the pancreas. Clinically and radiographically, she was thought to have pancreatic carcinoma. Histologic examination of the specimen from a Whipple procedure revealed malignant lymphoma, follicle center type, follicular, grade 1 of 3 (follicular, predominantly small cleaved cell type), arising in the duodenum and invading the pancreas. Five peripancreatic lymph nodes were partially involved by lymphoma. Follicle center lymphoma presenting as a mass involving the ampulla of Vater with jaundice has not been described previously. Our case indicates that this type of lymphoma can occur in this location and can present with features that mimic pancreatic carcinoma.