Daniel D. Wong

Oncocytic adrenocortical neoplasms—a clinicopathologic study of 13 new cases emphasizing the importance of their recognition

Oncocytic adrenocortical neoplasms (OANs) are a rare but important subtype of adrenal tumors with unique clinical and morphological features. We present 13 previously unpublished cases, of which 3 were classified as benign, 2 as having borderline malignant potential, and 8 as malignant according to the Lin-Weiss-Bisceglia criteria. Seven tumors (54%) showed evidence of endocrine activity. All were composed of more than 90% oncocytes confirmed immunohistochemically using the antimitochondrial antibody mES-13 and ultrastructurally in 4 cases. Small oncocytes were a frequent finding that challenges the conventional notion of oncocytes as necessarily having abundant cytoplasm. Most cases were immunoreactive for vimentin, synaptophysin, inhibin-α, melan A, and calretinin, the latter being a novel finding in this group of neoplasms. Cytokeratin positivity with AE1/AE3 and CAM5.2 was variable. The literature was comprehensively reviewed to identify all cases of OANs reported to date. Hormone production is not as uncommon as previously believed, occurring in 30%. The Lin-Weiss-Bisceglia criteria were retrospectively applied to all published cases with sufficient information and were shown to effectively separate tumors according to their future risk of recurrence and survival using Kaplan-Meier survival curves (log-rank test, P < .001 for both). The estimated overall median survival for malignant oncocytic neoplasms is 58 months (95% confidence interval = 27.5-88.5 months), providing the first preliminary evidence that the prognosis of malignant OANs is likely to be more favorable than conventional adrenocortical carcinomas, in which the reported median survival is between 14 and 32 months.

Oncocytic Adrenocortical Tumors: Diagnostic Algorithm and Mitochondrial DNA Profile in 27 Cases.

The pathologic diagnosis of adrenocortical carcinoma (ACC) relies on microscopic features that are sometimes equivocal in special variants, including oncocytic adrenocortical tumors (OACTs). We report a series of 27 unpublished OACTs (15 pure and 12 mixed or focal) and assess for the first time in OACTs the diagnostic utility of an algorithm recently proposed by our group (“reticulin” algorithm) for conventional ACCs on the basis of a combination of reticulin staining and assessment of only 3 Weiss parameters. Overall, 12 cases were malignant according to the Lin-Weiss-Bisceglia (L-W-B) system for pure tumors and the original Weiss system for mixed or focal tumors; extensive or focal disruption of the reticulin network was found in 16 of 27 OACTs. This was associated with either a high mitotic index, presence of necrosis, and/or vascular invasion in 14 of these, which were thus considered malignant according to our algorithm. From a clinical standpoint, OACTs, at least in the pure form, are “low grade” lesions with a low mean Weiss score, mitotic and Ki-67 indices, and uncommon capsular or vascular invasion. They, including unequivocal morphologically malignant cases, generally pursue an indolent clinical course. In addition, the 4977 bp mitochondrial DNA “common deletion” was detected using real-time polymerase chain reaction in 54% of cases from this study and an additional validation series of 23 OACTs, with a heterogenous (heteroplasmic) intratissue and intracellular distribution (as detected by a modified FISH procedure) and a marked association with the presence of intact reticulin framework.

HER2 testing in malignant effusions of metastatic gastric carcinoma: Is it feasible?

HER2 testing on effusions of metastatic gastric carcinoma may provide a valuable alternative to testing on primary biopsies. This study assessed the feasibility of this method by immunohistochemistry (IHC) and silver in situ hybridization (SISH). Cell blocks from 46 effusions from metastatic gastric carcinoma were examined. IHC was scored using the modified criteria of Hofmann et al. An average of ≥6 signals per nucleus was considered amplification on SISH. Results were compared with histological specimens to assess HER2 status concordance. Cell blocks showed a poorly cohesive pattern in 30 (65%), aggregates in 7 (15%), and mixed pattern in 9 (20%). Seven (15%) showed an IHC 2+/3+ reaction with a membranous pattern, appearing more granular than in histology. Three (7%) showed HER2 amplification on SISH. In 18 cases (39%), HER2 status was compared with histological specimens, showing 100% concordance. Difficulties were encountered in distinguishing malignant cells from reactive mesothelial cells in 12 (26%). This study supports the feasibility of HER2 assessment on effusions. The incidence of HER2 positivity (7% with SISH+ and IHC 2+/3+) was lower than reported in histological samples. Further refinement and validation will enhance the use of this method in clinical practice and overcome difficulties encountered. Diagn. Cytopathol. 2015;43:80–85.

Concordance of HER2 expression in paired primary and metastatic sites of gastric and gastro-oesophageal junction cancers

Summary HER2 is amplified/overexpressed in a subset of gastric and gastro-oesophageal junction cancers. Addition of anti-HER2 therapy has been shown to provide survival benefit in this setting. However, there are limited data assessing the concordance of HER2 status between primary and metastatic sites. A total of 113 samples from 43 paired primary and metastatic tumours were tested for HER2 status, by immunohistochemistry (IHC) for protein expression and silver in situ hybridisation (SISH) for gene amplification. Primary sites tested included endoscopic biopsies (n = 30) and resections (n = 24). Metastatic samples included lymph nodes (n = 29), peritoneal effusions (n = 21) and miscellaneous sites (n = 9). The overall HER2+ rate was 11%. Of 41 (95%; 95% CI 88.5–100%) concordant cases, 38 were HER2– and three were HER2+. There were two (5%) discordant cases, one of which showed heterogeneity of HER2 expression. This series confirms a high concordance rate of 95%, supporting that testing of primary tumours and metastases is equally valid and providing clinical rationale for the addition of anti-HER2 therapy in HER2+ disseminated disease.

38. MDM2/CDK4 amplification in large and/or deep-seated lipomatous neoplasms without overtly atypical morphological features

Background: MDM2/CDK4 gene amplification has been shown to be sensitive and specific for the diagnosis of well-differentiated lipoma-like liposarcoma (WD-LLLPS). However, there are limited data on the incidence of these alterations in large and/or deep-seated lipomatous neoplasms (LN) in which the histological features do not fulfil criteria for WD-LLLPS. Aims: To assess the incidence of MDM2/CDK4 amplification in large and/or deep seated LN without overtly atypical morphological features and to examine the clinicopathological features of cases showing these alterations. Methods: All LN submitted for FISH analysis or conventional karyotyping from January 2009 to March 2013 were retrospectively identified from our database. Tumours measuring ≥50 mm in maximum extent and/or in deep-seated locations (excluding retroperitoneal cases) were included. FISH analysis was performed using in-house CDK4/MDM2/CEP12 probes. The clinical, radiological and pathological features of all cases with CDK4/MDM2 amplification were reviewed. Results: 81 cases were identified including 51 (63%) males and 30 females (37%) with a median age of 60 years (range 24–83). The most common site was the thigh (n = 20). FISH analysis was attempted in 77 (95%) cases and karyotyping in 4 (5%). Cytogenetic analysis could not be performed in 4 (5%) cases due to technical factors. Two (3%) cases showed dual MDM2/CDK4 amplification and 2 (3%) showed MDM2 amplification alone. All were deep seated with a median size of 95 mm (range 35–160 mm). Two had unusual radiological findings (intermediate signal intensity on MRI). Retrospective slide review confirmed the absence of diagnostic features of WD-LLLPS. Two cases showed marked degenerative changes and one showed prominent lymphocytic inflammation. Conclusions: The incidence of MDM2/CDK4 amplification was reassuringly low (5%) in this cohort of LN, despite their large and/or deep-seated nature. Features that may suggest a potentially more aggressive neoplasm include unusual radiological findings, degenerative changes and prominent inflammation.