Anatomic pathology Abstracts

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Xing D, Banet N, Sharma R, et al. Aberrant Pax-8 expression in well-differentiated papillary mesothelioma and malignant mesothelioma of the peritoneum: a clinicopathologic study. Hum Pathol. 2018;72:160–166.

Correspondence: Dr. P. B. Illei at pillei1@jhmi.edu

Association of HER2 ITH with incomplete response to anti-HER2 neoadjuvant chemotherapy in breast carcinoma

Anti-HER2 neoadjuvant chemotherapy has been widely used in HER2-positive breast cancer patients, yet pathologic complete response is achieved in only 40 to 50 percent of patients. The authors conducted a study to investigate the association of HER2 intratumoral heterogeneity (ITH) with response to anti-HER2 neoadjuvant chemotherapy. They assessed HER2 ITH on whole tissue sections of pretreatment samples from a cohort of 64 invasive breast carcinoma cases originally considered positive for HER2 and treated with anti-HER2 neoadjuvant chemotherapy. They simultaneously evaluated HER2 gene signal and protein expression using a single-slide dual assay, designated a HER2 gene-protein assay. The HER2 gene-protein assay was also used on surgical resection tissue from 25 cases with incomplete therapeutic response. Nineteen of 64 (30 percent) cases showed HER2 ITH. Significantly more cases with HER2 ITH were found in the incomplete response group (56 percent; 14 of 25) than in the pathologic complete response group (13 percent; five of 39). Patients in whom ITH was not detectable by gene-protein assay had a 76 percent pathologic complete response outcome (34 of 45), as compared with a 26 percent outcome (five of 19) for those with detectable ITH. Multivariate analysis demonstrated that HER2 ITH, progesterone receptor positivity, and relatively low HER2/chromosome 17 centromere ratio are significantly associated with incomplete response. HER2 ITH analyses conducted with the gene-protein assay method revealed that HER2 ITH is an independent factor, predicting incomplete response to anti-HER2 neoadjuvant chemotherapy.

Hou Y, Nitta H, Wei L, et al. HER2 intratumoral heterogeneity is independently associated with incomplete response to anti-HER2 neoadjuvant chemotherapy in HER2-positive breast carcinoma. Breast Cancer Res Treat. 2017;166(2):447–457.

Correspondence: Dr. Zaibo Li at zaibo.li@osumc.edu

Use of dual staining to distinguish colorectal carcinomas from other tumors

Small sample size limits the number of immuno­stains that may be attempted in colorectal carcinoma biopsy specimens. The authors investigated the utility of dual stain with special AT-rich sequence binding protein 2 (SATB2) or caudal-type homeobox 2 (CDX2) and cytokeratin 20 (CK20) or villin in identifying colorectal carcinoma (CRC). They built tissue microarrays with 222 CRCs and 375 other carcinomas and performed dual stain, pairing the nuclear stains CDX2 or SATB2 with CK20 or villin. The authors found that all four single stains showed excellent sensitivity (93–99 percent) but variable specificity (56–88 percent) for CRC. The four dual stains also showed excellent sensitivity (90–96 percent) and much improved specificity (88–98 percent) when compared with the single stains. SATB2 dual stain with CK20 or villin showed a higher specificity than CDX2 dual stain with CK20 or villin and comparable sensitivity. SATB2 dual stain demonstrated the greatest potential clinical utility in identifying CRC and was superior to CDX2 dual stain. More importantly, SATB2 dual stain could be helpful for specimens with limited tissue or having a nonclassic staining pattern.

Li Z, Rock JB, Roth R, et al. Dual stain with SATB2 and CK20/villin is useful to distinguish colorectal carcinomas from other tumors. Am J Clin Pathol. 2018;149:241–246.

Correspondence: Dr. Wendy L. Frankel at wendy.frankel@osumc.edu

Relationship between KRAS mutation and implants of serous borderline tumor

In contrast to noninvasive extraovarian implants, invasive implants of ovarian serous borderline tumor/atypical proliferative serous tumor are associated with adverse outcome and have been reclassified as low-grade serous carcinoma. Mutations of KRAS or BRAF, or both, have been reported in up to 50 percent of serous borderline tumor/atypical proliferative serous tumors. The authors investigated KRAS and BRAF mutation frequencies in the two types of implants of serous borderline tumor/atypical proliferative serous tumor in correlation with clinical outcome. They included in the study 42 implants of serous borderline tumor from 39 patients (invasive implants/low-grade serous carcinoma, n = 20; noninvasive implants, n = 22). KRAS mutation was found in 12 of 20 (60 percent) invasive implants and three of 22 (14 percent) noninvasive implants. BRAF V600E mutation was found in one of 22 (five percent) noninvasive implants and no invasive implants. Invasive implants were more frequently associated with higher stage disease. Nine of 14 (64 percent) patients with KRAS mutation were found to have stage IIIC disease, while five of 24 (20 percent) patients without the mutation had stage IIIC disease. Patients with invasive implants had higher recurrence rates compared to those with noninvasive implants (60 versus 14 percent, P = .0003, log-rank test) and worse disease-specific survival (P = .0008, log-rank test). Regardless of histological subtypes, patients with KRAS mutation-positive implants had significantly higher recurrence rates than those without the mutation (71 versus 21 percent, P = .0021, log-rank test) and unfavorable disease-specific survival (P = .0104, log-rank test). The authors concluded that compared to those with noninvasive implants, patients with invasive implants present with higher stage disease, higher recurrence rates, and worse survival rates. KRAS mutation, but not BRAF V600E mutation, is significantly associated with invasive implants of serous borderline tumor. Regardless of the histological subtypes of the implants, KRAS mutation is a significant prognostic indicator for high risk of tumor recurrence and worse disease-specific survival.

Zuo T, Wong S, Buza N, et al. KRAS mutation of extraovarian implants of serous borderline tumor: prognostic indicator for adverse clinical outcome. Mod Pathol. 2018;31:350–357.

Correspondence: Dr. P. Hui at pei.hui@yale.edu

Tumor-infiltrating lymphocytes and prognosis in breast cancer

Tumor-infiltrating lymphocytes are predictive for response to neoadjuvant chemotherapy in triple-negative breast cancer and HER2-positive breast cancer. However, their role in luminal breast cancer and the effect of tumor-infiltrating lymphocytes (TILs) on prognosis in all subtypes is less clear. The authors conducted a study in which they assessed the relevance of TILs for chemotherapy response and prognosis in patients with triple-negative breast cancer, HER2-positive breast cancer, and luminal HER2-negative breast cancer. The study included primary breast cancer patients who were treated with neoadjuvant combination chemotherapy and who were from six randomized trials conducted by the German Breast Cancer Group. Pretherapeutic core biopsies from 3,771 patients who participated in these studies were assessed for the number of stromal TILs by standardized methods according to the guidelines of the International TILs Working Group. TILs were analyzed as a continuous parameter and in predefined groups of low (zero to 10 percent immune cells in stromal tissue within the tumor), intermediate (11–59 percent), and high (60 percent or more). The authors used these data in univariable and multivariable statistical models to assess the association between TIL concentration and pathologic complete response in all patients and between the amount of TILs and disease-free survival and overall survival in 2,560 patients from five of the six clinical trial cohorts. In the luminal HER2-negative breast cancer subtype, a pathologic complete response was achieved in 45 of 759 (six percent) patients with low TILs, 48 of 435 (11 percent) with intermediate TILs, and 49 of 172 (28 percent) with high TILs. In the HER2-positive subtype, pathologic complete response was observed in 194 of 605 (32 percent) patients with low TILs, 198 of 512 (39 percent) with intermediate TILs, and 127 of 262 (48 percent) with high TILs. Finally, in the triple-negative breast cancer subtype, pathologic complete response was achieved in 80 of 260 (31 percent) patients with low TILs, 117 of 373 (31 percent) with intermediate TILs, and 136 of 273 (50 percent) with high TILs (P< .0001 for each subtype, χ2 test for trend). In the univariable analysis, a 10 percent increase in TILs was associated with longer disease-free survival in triple-negative breast cancer (hazard ratio [HR], 0.93; 95 percent confidence interval [CI], 0.87–0.98; P = .011) and HER2-positive breast cancer (HR, 0.94; 95 percent CI, 0.89–0.99; P = .017) but not in luminal HER2-negative tumors (HR, 1.02; 95 percent CI,  0.96–1.09; P = .46). The increase in TILs was also associated with longer overall survival in triple-negative breast cancer (HR, 0.92; 95 percent CI, 0.86–0.99; P = .032) but had no association in HER2-positive breast cancer (HR, 0.94; 95 percent CI, 0.86–1.02; P = .11) and was associated with shorter overall survival in luminal HER2-negative tumors (HR, 1.10; 95 percent CI, 1.02–1.19; P = .011). Increased TIL concentration predicted response to neoadjuvant chemotherapy in all molecular subtypes assessed and was associated with a survival benefit in HER2-positive and triple-negative breast cancer. By contrast, increased TILs were an adverse prognostic factor for survival in luminal HER2-negative breast cancer, suggesting a different biology for the immunological infiltrate in this subtype. The authors’ data support the hypothesis that breast cancer is immunogenic and might be targetable by immune-modulating therapies. In light of the results for luminal breast cancer, additional research investigating the interaction of the immune system with different types of endocrine therapy is warranted.

Denkert C, von Minckwitz G, Darb-Esfahani S, et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2018;19:40–50.

Correspondence: Dr. Carsten Denkert at carsten.denkert@​charite.de