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Anatomic Pathology Abstracts, 1/18

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Editors: Rouzan Karabakhtsian, MD, PhD, associate professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Rachel Stewart, DO, PhD, molecular genetic pathology fellow, University of Utah/ARUP Laboratories, Salt Lake City; Nicole Panarelli, MD, associate professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center; and Shaomin Hu, MD, PhD, pathology resident, Albert Einstein College of Medicine, Montefiore Medical Center.

Analysis of desmoplastic pattern at the tumor front in colorectal cancer subtypes

Clinicopathological and molecular analysis of GISTs of the oesophagus

Classifying papillary renal cell carcinoma into subtypes

Link between tumor budding in GAC and nodal metastasis and recurrence

Comparison of axillary versus sentinel lymph node dissection in breast cancer

P16/Ki-67 dual-stained cytology as a triage test for high-risk HPV-positive women

Analysis of desmoplastic pattern at the tumor front in colorectal cancer subtypes

Although recent findings of cancer biology research indicate that prognostic power arises from genes expressed by stromal cells rather than epithelial cells, desmoplastic reaction has not been completely examined as a prognostic marker for colorectal cancer. The authors conducted a pathologic review of 821 stage II and III patients who underwent R0 resection for colorectal cancer at four independent institutions. Desmoplastic reaction was classified as mature, intermediate, or immature based on the presence of hyalinized keloid-like collagen and myxoid stroma at the extramural desmoplastic front. In total, 325, 282, and 214 patients were classified as having mature, intermediate, and immature desmoplastic reaction, respectively. Desmoplastic reaction significantly influenced recurrence rate in the liver, lung, and peritoneum (P≤.0001 to .01). The five-year relapse-free survival rate was highest in the mature group (85.7 percent), followed by the intermediate (77.3 percent) and immature (50.4 percent) groups. A significant adverse impact of immature stroma on relapse-free survival was observed in subset analyses from the four institutions. Multivariate analysis revealed that desmoplastic reaction, along with T and N stages, is an independent prognostic factor. On the basis of Harrell’s concordance index, the prognostic power of desmoplastic reaction categorization (0.67) in stratifying relapse-free survival was greater than any other conventional prognostic factors, including TNM (0.64), N (0.62), and T stages (0.59), venous invasion (0.59), and tumor grade (0.54). The authors concluded that characterizing desmoplastic reaction based on the histologic products of activated fibroblasts is valuable for evaluating prognostic outcomes.

Ueno H, Kanemitsu Y, Sekine S, et al. Desmoplastic pattern at the tumor front defines poor-prognosis subtypes of colorectal cancer. Am J Surg Pathol. 2017;41:1506–1512.

Correspondence: Dr. Hideki Ueno at ueno_surg1@ndmc.ac.jp

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Clinicopathological and molecular analysis of GISTs of the oesophagus

Gastrointestinal stromal tumors may arise anywhere in the gastrointestinal tract but are rare in the oesophagus. The authors described the clinical, pathological, and molecular characteristics of 27 primary oesophageal GISTs, the largest series to date. DNA was extracted, and exons 9, 11, 13, and 17 of KIT, exons 12, 14, and 18 of PDGFRA, and exon 15 of BRAF were amplified and sequenced. Oesophageal GISTs occurred in 14 men and 13 women who were between 22 and 80 years of age (mean, 56 years). All 27 cases were immunohistochemically positive for KIT, and 92 percent and 47 percent co-expressed CD34 or smooth muscle actin, respectively. Fifteen (71 percent of the analyzed cases) harbored KIT exon 11 mutations and one case each had a mutation in KIT exon 13 (K642E) or BRAF exon 15 (V600E). Long-term follow-up data (median, 96.5 months) were obtained for 20 cases. Two patients had metastases at presentation, and seven had developed local recurrence or metastasis after surgery, or both of the latter. A large tumor size (10 cm or greater), high mitotic rate (greater than 5/5 mm2), presence of a deletion mutation in KIT exon 11 involving codons 557–558, and a positive microscopic margin were associated with recurrence and metastasis. The KIT mutations identified in oesophageal GISTs are similar to those observed in gastric GISTs. The authors concluded that complete surgical resection with clear margins is recommended, if technically feasible. Genotyping can help improve diagnosis and further patient management in oesophageal GISTs.

Kang G, Kang Y, Kim KH, et al. Gastrointestinal stromal tumours of the oesophagus: a clinicopathological and molecular analysis of 27 cases. Histopathol. 2017;71:805–812.

Correspondence: Dr. Kyoung-Mee Kim at kkmkys@skku.edu

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Classifying papillary renal cell carcinoma into subtypes

Papillary renal cell carcinoma has two histologic subtypes. Almost half the cases fail to meet all morphologic criteria for either type and, therefore, are characterized as papillary renal cell carcinoma not otherwise specified (PRCC NOS). There are no markers to resolve the PRCC NOS category. However, accurate classification can better guide management of these patients. In their previous PRCC study, the authors identified markers that can distinguish between the subtypes. A PRCC patient cohort of 108 cases was selected for the current study. A panel of potentially distinguishing markers was chosen from the authors’ previous genomic analysis and assessed by immunohistochemistry. The panel exhibited distinct staining patterns between the two classic PRCC subtypes and successfully reclassified the NOS (45 percent) cases. Moreover, these immunomarkers revealed a third subtype, PRCC3, in 35 percent of the cohort. Molecular testing using miRNA expression and copy number variation analysis confirmed the presence of three distinct molecular signatures corresponding to the three subtypes. On univariate analysis, disease-free survival was significantly enhanced in PRCC1 versus PRCC2 and PRCC3 (P = .047). The subtype stratification was also significant on multivariate analysis (P = .025; hazard ratio, 6; 95 percent confidence interval, 1.25–32.2). The authors proposed a new classification system for PRCC integrating morphologic, immunophenotypical, and molecular analysis. The newly described PRCC3 has overlapping morphology between PRCC1 and PRCC2 and, therefore, would be subtyped as NOS in the current classification. PRCC3 has a distinct molecular signature and clinical behavior similar to that of PRCC2. The new classification stratifies PRCC patients into clinically relevant subgroups and has significant implications for the management of PRCC.

Saleeb RM, Brimo F, Farag M, et al. Toward biological subtyping of papillary renal cell carcinoma with clinical implications through histologic, immunohistochemical, and molecular analysis. Am J Surg Pathol. 2017;41(12):1618–1629.

Correspondence: Dr. G. M. Yousef at yousefg@smh.ca

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Link between tumor budding in GAC and nodal metastasis and recurrence

Gastric adenocarcinoma, a common cause of cancer-related death worldwide, can be classified as intestinal or diffuse. Intestinal-type cancers are common and are reported to have a better prognosis than diffuse cancers. Studies have shown that the amount of tumor budding in intestinal carcinomas of the colon and esophagus predicts nodal metastasis and recurrence. The authors conducted a study to determine if tumor budding in intestinal-type GAC correlates with prognostic features. They identified 104 patients treated with primary surgical excision between 1999 and 2013 and evaluated histologic type (intestinal, diffuse, or mixed), tumor grade, T stage, and lymph node status. They assigned tumor bud scores to all intestinal-type cancers using methods previously described for colorectal adenocarcinoma. Scores of less than one were designated as low and one or more as high. Tumor characteristics included 52 (50 percent) intestinal, 36 (35 percent) diffuse, and 16 (15 percent) mixed. Of the 52 cases with intestinal histology, four (eight percent) were well differentiated, 28 (54 percent) were moderately differentiated, and 20 (38 percent) were poorly differentiated. Thirty-three (63 percent) of the intestinal tumors had high tumor bud scores. Cases with high scores were associated with higher T stage, N stage, and grade (P< .001, P< .001, and P = .002, respectively). They also had a higher likelihood of recurrence (P = .007). In the authors’ cohort, high tumor bud scores in intestinal-type GAC had higher T stage, N stage, grade, and likelihood of recurrence. The authors concluded that assessment of tumor budding may guide clinical management in a subset of patients.

Olsen S, Jin L, Fields RC, et al. Tumor budding in intestinal-type gastric adenocarcinoma is associated with nodal metastasis and recurrence. Hum Pathol. 2017;68:26–33.

Correspondence: Dr. I. Nalbantoglu at inalbantoglu@path.wustl.edu

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Comparison of axillary versus sentinel lymph node dissection in breast cancer

The results of the American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial were first reported in 2005, with a median followup of 6.3 years. Longer followup was necessary because the majority of the patients had estrogen receptor–positive tumors that may recur later in the disease course. (The ACOSOG is now part of the Alliance for Clinical Trials in Oncology.) The authors analyzed the ACOSOG Z0011 trial to determine whether the 10-year overall survival of patients with sentinel lymph node metastases treated with breast-conserving therapy and sentinel lymph node dissection (SLND) alone, without axillary lymph node dissection (ALND), is noninferior to that of women treated with axillary dissection. The ACOSOG Z0011 phase three randomized clinical trial enrolled 115 patients at academic and community medical centers from May 1999 to December 2004. The last date of followup in the ACOSOG Z0011 (Alliance) trial was Sept. 29, 2015. Eligible patients were women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, and one or two sentinel lymph nodes containing metastases. All patients had planned lumpectomy, planned tangential whole-breast irradiation, and adjuvant systemic therapy. Third-field radiation was prohibited. The primary outcome was overall survival with a noninferiority hazard ratio (HR) margin of 1.3; the secondary outcome was disease-free survival. Among 891 women (446 in the SLND alone group and 445 in the ALND group; median age, 55 years) who were randomized, 856 (96 percent) completed the trial. At a median followup of 9.3 years (interquartile range, 6.93–10.34 years), the 10-year overall survival was 86.3 percent in the SLND alone group and 83.6 percent in the ALND group (HR, 0.85 [one-sided 95 percent coefficient of variation, 0–1.16]; noninferiority, P = .02). The 10-year disease-free survival was 80.2 percent in the SLND alone group and 78.2 percent in the ALND group (HR, 0.85 [95 percent CI, 0.62–1.17]; P = .32). Between years five and 10, one regional recurrence was seen in the SLND alone group versus none in the ALND group. Ten-year regional recurrence did not differ significantly between the two groups. The authors concluded that among women with T1 or T2 invasive primary breast cancer, with no palpable axillary adenopathy and one or two sentinel lymph nodes containing metastases, the 10-year overall survival for patients treated with sentinel lymph node dissection alone was noninferior to overall survival for those treated with axillary lymph node dissection. These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes.

Giuliano AE, Ballman KV, McCall L, et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: the ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA. 2017;318(10):918–926.

Correspondence: Dr. Armando E. Giuliano at armando.giuliano@cshs.org

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P16/Ki-67 dual-stained cytology as a triage test for high-risk HPV-positive women

The authors conducted a study to evaluate the clinical utility of p16/Ki-67 dual staining for identifying cervical intraepithelial neoplasia (CIN) in high-risk HPV-positive women from a nonresponder screening cohort. P16/Ki-67 dual staining, Pap cytology, and HPV16/18 genotyping were performed on physician-obtained liquid-based samples from 495 women who tested high-risk HPV positive on self-sampled material (Protection by Offering HPV Testing on Cervicovaginal Specimens Trial-3B [PROHTECT-3B study]). Different triage strategies involving p16/Ki-67 dual staining were evaluated for sensitivity, specificity, and predictive value for ≥CIN2 and ≥CIN3 and compared to Pap cytology with a threshold of atypical cells of undetermined significance. Centrally revised histology or an adjusted endpoint with combined high-risk HPV-negative and cytology-negative followup at six months was used as the gold standard. Pap cytology (threshold of atypical cells of undetermined significance) triage of high-risk HPV-positive samples showed a sensitivity of 93 percent (95 percent confidence interval [CI], 85–98) and a specificity of 49 percent (95 percent CI, 41–56) for ≥CIN3. Three triage strategies with p16/Ki-67 showed a significantly increased specificity and similar sensitivity. P16/Ki-67 triage of all high-risk HPV-positive samples had a sensitivity of 92 percent (95 percent CI, 84–97) and a specificity of 61 percent (95 percent CI, 54–69) for ≥CIN3. Applying p16/Ki-67 triage to only high-risk HPV-positive women with low-grade Pap cytology showed a similar sensitivity of 92 percent (95 percent CI, 84–97) and a specificity for ≥CIN3 of 64 percent (95 percent CI, 56–71). For high-risk HPV-positive women with low-grade and normal Pap cytology, triage with p16/Ki-67 showed a sensitivity of 96 percent (95 percent CI, 89–99) and a specificity of 58 percent (95 percent CI, 50–65). HPV16/18 genotyping combined with Pap cytology showed a sensitivity and specificity for ≥CIN3 similar to Pap cytology with an atypical cells of undetermined significance threshold. The authors concluded that because the quality of Pap cytology varies worldwide and differences in sensitivity and specificity are limited between the three selected strategies, p16/Ki-67 triage of all high-risk HPV-positive samples would be the more reliable strategy in the triage of high-risk HPV-positive women with an increased specificity and similar sensitivity when compared with Pap cytology triage.

Ebisch RM, van der Horst J, Hermsen M, et al. Evaluation of p16/Ki-67 dual-stained cytology as triage test for high-risk human papillomavirus-positive women. Mod Pathol. 2017;30:1021–1031.

Correspondence: Dr. R. M. Ebisch at renee.ebisch@radboudumc.nl

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