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Anatomic Pathology Selected Abstracts, 4/14

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Anatomic pathology abstracts editors: Michael Cibull, MD, professor of pathology, University of Kentucky, Lexington; Rouzan Karabakhtsian, MD, attending pathologist, Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; Thomas Cibull, MD, dermatopathologist, Evanston Hospital, NorthShore University HealthSystem, Evanston, Ill.; and Rachel Stewart, DO, resident physician, Department of Pathology and Laboratory Medicine, University of Kentucky.

Clear cell papillary renal cell carcinoma: diagnosis and immunohistochemical profile

Clear cell papillary renal cell carcinoma is a recently recognized renal neoplasm composed of cells with clear cytoplasm lining cystic, tubular, and papillary structures. These tumors have immunohistochemical and genetic profiles distinct from clear cell renal cell carcinoma and papillary renal cell carcinoma. The authors studied morphologic and immunohistochemical features (cytokeratin 7 [CK7], carbonic anhydrase IX [CAIX], CD10, alpha-methylacyl-CoA racemase [AMACR], smooth muscle actin, desmin, and estrogen and progesterone receptors) in 55 tumors from 34 patients, eight of whom had end-stage renal disease. The tumors comprised three percent of all adult renal cell carcinoma resections over three years. Patients’ ages ranged from 33 to 87 years (mean, 61 years). Multiple tumors (two to eight) were present in nine patients. Other renal tumors were present concurrently in four patients and subsequently in two patients, including oncocytoma, clear cell renal cell carcinoma, and multilocular cystic renal cell carcinoma. Sizes ranged from 0.2 to 7.5 cm (mean, 2 cm); 87 percent were Fuhrman grade 2 and 96 percent were stage pT1a. Papillary architecture was usually limited to focal branching papillae (51 percent of 55 tumors) or small, blunt papillae (35 percent). Large areas of extensively branched papillae were present in only 14 percent of tumors. Almost all tumors (98 percent) included cysts, and 18 tumors were extensively (90 percent or greater) cystic. Immunoprofile showed CK7+, AMACR−, CD10−, and CAIX+ in the tubular and papillary components of all tumors. However, CD10 labeled the apical cell membrane of cyst epithelium in 59 percent. The stroma was focally actin positive (94 percent), with infrequent desmin expression (13 percent). Estrogen receptor and progesterone receptor were negative. During a median followup period of 56 months, no patient developed local recurrence or distant or lymph node metastasis or died of cancer. The authors concluded that branched tubules, small papillae, and immunohistochemical and molecular profiles aid in distinguishing clear cell papillary renal cell carcinoma from clear cell renal cell carcinoma and multilocular cystic renal cell carcinoma.

Williamson SR, Eble JN, Cheng L, et al. Clear cell papillary renal cell carcinoma: differential diagnosis and extended immunohistochemical profile. Mod Pathol. 2013;26:697–708.

Correspondence: Dr. D. J. Grignon at dgrignon@iupui.edu

Breast cancer subtypes defined by ER signaling and prognostic relevance of PR loss

The majority of luminal type breast carcinomas are slow-growing tumors with an overall favorable prognosis. However, a proportion of cases (luminal B tumors) are characterized by coactivation of growth factor receptors or noncanonical estrogen receptor signaling and a poorer clinical outcome. The authors conducted a study to evaluate whether the expression of proteins that are part of the estrogen receptor signaling network may be used to distinguish low-risk from high-risk luminal tumors. Unsupervised hierarchical clustering of a set of proteins involved in estrogen receptor signaling or associated with resistance to endocrine therapy was performed in a series of 443 postmenopausal breast carcinomas. Using this approach, the authors were able to reproduce the established classification with two distinct groups of luminal (estrogen receptor-positive) tumors, one group of HER2-associated tumors, and one group of triple-negative tumors. However, progesterone receptor expression, and not proliferation or expression of one or more of the estrogen receptor cofactors or resistance-associated factors, was identified as the most important stratifier distinguishing between the two luminal groups. Not only were the four identified clusters shown to be significantly associated with patient outcome, but progesterone receptor expression alone or in combination with Ki-67 stains stratified estrogen receptor-positive tumors into a low-risk and high-risk group. The authors concluded that these data indicate that defining luminal B tumors by the presence of criteria for high risk (loss of progesterone receptor expression or increased proliferation) provides a robust and highly significant stratification of estrogen receptor-positive breast carcinomas into luminal A and B.

Braun L, Mietzsch F, Seibold P, et al. Intrinsic breast cancer subtypes defined by estrogen receptor signaling—prognostic relevance of progesterone receptor loss. Mod Pathol. 2013;26:1161–1171.

Correspondence: Dr. S. Aulmann at sebastian.aulmann@med.uni-heidelberg.de

Comparison of PAM50 risk of recurrence score with Oncotype DX and IHC4

Risk of distant recurrence among women with estrogen receptor-positive early breast cancer is the major determinant of recommendations for or against chemotherapy. It is frequently estimated using the Oncotype DX recurrence score. The PAM50 risk of recurrence (ROR) score provides an alternative approach and also identifies intrinsic subtypes. The authors conducted a study in which the mRNA from 1,017 patients with estrogen receptor-positive primary breast cancer treated with anastrozole or tamoxifen in the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial was assessed for ROR using the NanoString nCounter. Likelihood ratio tests and concordance indices (c indices) were used to assess the prognostic information provided beyond that of a clinical treatment score by recurrence score, ROR, or IHC4, an index of risk of distant recurrence derived from immunohistochemical assessment of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and Ki67. The authors found that ROR added significant prognostic information beyond clinical treatment score in all patients (ΔLR-χ(2)=33.9; P<0.001). In all four subgroups—node negative, node positive, HER2 negative, and HER2 negative/node negative—more information was added by ROR than by recurrence score. C indices in the HER2-negative/node-negative subgroup were 0.73, 0.76, and 0.78 for clinical treatment score, clinical treatment score plus recurrence score, and clinical treatment score plus ROR, respectively. More patients were scored as high risk and fewer as intermediate risk by ROR than by recurrence score. Relatively similar prognostic information was added by ROR and IHC4 for all patients but more by ROR in the HER2-negative/node-negative group. The authors concluded that ROR provides more prognostic information for endocrine-treated patients with estrogen receptor-positive, node-negative disease than does recurrence score, with better differentiation of intermediate- and higher-risk groups.

Dowsett M, Sestak I, Lopez-Knowles E, et al. Comparison of PAM50 risk of recurrence score with Oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol. 2013;31: 2783–2790.

Correspondence: Dr. Mitch Dowsett at mitch.dowsett@icr.ac.uk

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