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Anatomic Pathology Abstracts

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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.

Impact of pattern of invasion in invasive endocervical adenocarcinoma

Inflammatory myofibroblastic tumor of the uterus: an analysis of 13 cases

Influence of tumor stage on value of Ki-67 index and mitotic count in SINETs

Analysis of T1 bladder cancer to predict progression to muscularis propria invasion

Composite analysis of markers defines subtypes of triple-negative breast cancer

Discordance between HER2 IHC and FISH in invasive breast carcinoma

Rapid virtual H&E histology of breast tissue specimens

Impact of pattern of invasion in invasive endocervical adenocarcinoma

The pattern-based classification system for human papillomavirus-related endocervical adenocarcinoma, which classifies tumors based on the destructiveness of stromal invasion, can be used in predicting the risk of nodal metastases and adverse outcome. Previous studies have demonstrated clinically important molecular alterations in endocervical adenocarcinoma, including KRAS and PIK3CA mutations. However, the correlation between molecular landscape and pathological variables, including pattern of invasion, has not been explored thoroughly. To this end, the authors conducted a study in which they classified 20 endocervical adenocarcinomas using the pattern-based classification system. They subjected the adenocarcinomas to targeted sequencing using the Ion AmpliSeq Cancer Hotspot Panel v2 (Thermo Fisher Scientific), which surveys hotspot regions of 50 oncogenes and tumor-suppressor genes. Single-nucleotide polymorphisms were correlated with clinical and pathologic variables, including pattern of invasion. Five (25 percent), six (30 percent), and nine (45 percent) cases were classified as patterns A, B, and C, respectively. Lymph node metastases, advanced stage at presentation, and mortality from disease were exclusively seen in destructively invasive tumors (pattern B or C). Prevalent mutations in the cohort involved PIK3CA (30 percent), KRAS (30 percent), MET (15 percent), and RB1 (10 percent). Most (94 percent) relevant genomic alterations were present in destructively invasive tumors, with PIK3CA, KRAS, and RB1 mutations seen exclusively in pattern B or C subgroups. KRAS mutations correlated with advanced stage at presentation (FIGO [International Federation of Obstetrics and Gynecology] stage II or higher). These findings indicate that the pattern of stromal invasion correlates with genomic abnormalities detected by next-generation sequencing, suggesting that tumors without destructive growth (pattern A) are biologically distinct from those with destructive invasion (patterns B and C) and that pattern B endocervical adenocarcinoma is more closely related to its pattern C counterpart. The authors concluded that the pattern-based classification may be used as a triage tool when considering molecular testing for prognostic or therapeutic purposes.

Hodgson A, Amemiya Y, Seth A, et al. Genomic abnormalities in invasive endocervical adenocarcinoma correlate with pattern of invasion: biologic and clinical implications. Mod Pathol. 2017;30:1633–1641.

Correspondence: Dr. C. Parra-Herran at carlos.parraherran@utoronto.ca

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Inflammatory myofibroblastic tumor of the uterus: an analysis of 13 cases

Inflammatory myofibroblastic tumors of the uterus are rare, and although most have a favorable prognosis, a small subset exhibit extrauterine disease, recur, or cause death. The authors conducted a study in which they evaluated the morphology and immunoprofile of 13 uterine inflammatory myofibroblastic tumors, including four with aggressive behavior. ALK rearrangements were detected by FISH and fusion partners by anchored multiplex assay. Patients ranged from eight to 63 (mean, 39) years and tumors from 2.5 to 20 (mean, 7.4) cm. Myxoid, compact, and hyalinized patterns were noted in 13, 12, and two tumors, ranging from one to 100 percent, five to 99 percent, and zero to five percent, respectively. Nuclear atypia was mild in six (46 percent) tumors, moderate in five (38 percent), and severe in two (15 percent), with ganglion-like cells in two tumors. Mitoses ranged from zero to 24 (mean, five) per 10 high-power fields. Inflammation was mild in five (38 percent), moderate in three (23 percent), and marked in five (38 percent), consisting of a lymphoplasmacytic infiltrate that was lymphocyte-predominant in six (46 percent). Lymphovascular invasion was noted in two (15 percent), and necrosis was noted in eight (62 percent). All but one tumor were ALK positive by immunohistochemistry, with granular cytoplasmic staining in nine (82 percent). ALK rearrangements (tested for in 10) were detected in eight tumors and absent in one. The remaining tumor showed an isolated green 5′ ALK signal. Fusion partners were identified in 10 (77 percent) and included THBS1 (n = 3), IGFBP5 (n = 2), DES (n = 2), SEC31 (n = 1), TPM3 (n = 1), and TIMP3 (n = 1). Tumor size of 8 cm or more was predictive of aggressive behavior (P<.01), with increased mitoses (seven or more per 10 high-power fields), lymphovascular invasion, and compact-predominance approaching statistical significance. These data show that inflammatory myofibroblastic tumors of the uterus are morphologically heterogenous with frequent ALK expression and a variety of ALK fusion partners. Recognizing this rare mesenchymal neoplasm is crucial as those with aggressive behavior potentially can be treated with tyrosine kinase inhibitors.

Bennett JA, Nardi V, Rouzbahman M, et al. Inflammatory myofibroblastic tumor of the uterus: a clinicopathological, immunohistochemical, and molecular analysis of 13 cases highlighting their broad morphologic spectrum. Mod Pathol. 2017;30:1489–1503.

Correspondence: Dr. J. A. Bennett at jennifer.a.bennett@lahey.org

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Influence of tumor stage on value of Ki-67 index and mitotic count in SINETs

Tumor cell proliferation rate determined by Ki-67 index or mitotic count has been identified as a prognostic factor for gastrointestinal neuroendocrine tumors in general. After being incorporated into the 2010 World Health Organization tumor grading system, it has become mandatory in pathology reports for all gastrointestinal neuroendocrine tumors, regardless of tumor location. Nevertheless, the clinical significance of the Ki-67 index and mitotic count has not been well demonstrated in small intestinal neuroendocrine tumors (SINETs), particularly those SINETs without distant metastasis, the majority of which have very low proliferation rates. The authors assessed the clinical behavior of 130 SINETs in relation to stage, Ki-67 index, mitotic count, and other pathologic features. Eighty-six percent of SINETs were grade 1 and 14 percent were grade 2. None were grade 3 tumors or poorly differentiated neuroendocrine carcinomas. On multivariate analysis, age, Ki-67 index of more than five percent, mitotic count greater than 10 per 50 high-power fields, stage IV, and liver metastases were associated with increased risk of death in all patients. When both stage and grade were considered, Ki-67 index of more than five percent was associated with a nearly four-fold increased risk of death in stage IV cases (n=60). In contrast, Ki-67 index did not show prognostic value for patients with stages I to III disease (n=70), although mitotic count greater than one per 50 high-power fields was significantly associated with death on multivariable analysis. This study confirms that liver metastasis and increased tumor cell proliferation rate are independent prognostic factors for SINETs, but it also shows that most SINETs have a very low proliferation rate, which limits its value for predicting tumor behavior. By combining stage and grade information, the authors demonstrated different roles and cutoff values for Ki-67 index and mitotic count in SINETs of varying stages.

Sun Y, Lohse C, Smyrk T, et al. The influence of tumor stage on the prognostic value of Ki-67 index and mitotic count in small intestinal neuroendocrine tumors. Am J Surg Pathol. 2018;42(2):247–255.

Correspondence: Dr. Lizhi Zhang at zhang.lizhi@mayo.edu

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Analysis of T1 bladder cancer to predict progression to muscularis propria invasion

Urothelial carcinoma of the bladder invasive into lamina propria on biopsy or transurethral resection of bladder tumor, termed T1 disease, progresses to muscularis propria invasion in a subset of patients. Studies have proposed histopathologic metrics to predict progression, although methods vary widely and it is unclear which method is most robust. This poses a challenge since recent World Health Organization and American Joint Commission on Cancer editions encourage some attempt to substratify T1 disease. To address this problem, the authors analyzed T1 specimens to test which T1 quantification method is best to predict progression and establish the optimal cutoff. Progression was analyzed for all patients or those with definitive muscularis propria only. Multivariate analysis and outcomes modeling controlled for additional histopathologic features. The authors’ results suggest that aggregate linear length of invasive carcinoma (ALLICA) measured by optical micrometer is far superior to other methods (P = 3.067×10) and could be applied to all specimens. ALLICA retained significance in multivariate analysis and eliminated the contribution of other histopathologic features to progression. The best cutoff for ALLICA was 2.3 mm using a 30 percent false-positive threshold and 25 mm using a 10 percent false-positive threshold, although the number of patients who could achieve the latter threshold was severely limited. After comparing all proposed methods of T1 quantification, the authors recommended adopting the ALLICA measurement and a cutoff of 2.3 mm or more as the best predictor of progression, acknowledging that additional nonhistopathologic methods may be required to increase broad applicability and further reduce the false-positive threshold.

Leivo MZ, Sahoo D, Hamilton Z, et al. Analysis of T1 bladder cancer on biopsy and transurethral resection specimens: comparison and ranking of T1 quantification approaches to predict progression to muscularis propria invasion. Am J Surg Pathol. 2018;42(1):e1–e10.

Correspondence: Dr. D. E. Hansel at dhansel@ucsd.edu

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Composite analysis of markers defines subtypes of triple-negative breast cancer

Cancer biology is influenced by the tumor microenvironment, which impacts disease prognosis and therapeutic interventions. The authors evaluated the interrelationship of tumor-infiltrating lymphocytes, immune response regulators, and a glycolytic tumor environment in a cohort of 183 largely consecutive patients with a triple-negative breast cancer diagnosis. High levels of tumor-infiltrating lymphocytes were associated with improved survival in triple-negative breast cancer patients. However, elevated levels of PD-L1, CD163, and FOXP3 were individually associated with significantly decreased overall survival rates. These determinants were significantly correlated and could serve to differentiate the prognostic significance of tumor-infiltrating lymphocytes. Interestingly, a glycolytic tumor environment, as determined by the expression of MCT4 in the tumor stroma, was associated with the immune evasive environment and poor prognosis. Clustering of all markers defined four distinct triple-negative breast cancer subtypes that harbored prognostic significance in multivariate analysis. Immune and metabolic markers stratified triple-negative breast cancer into subtypes that have prognostic significance and implications for therapies targeting immune checkpoints and tumor metabolism.

Adams TA, Vail PJ, Ruiz A, et al. Composite analysis of immunological and metabolic markers defines novel subtypes of triple negative breast cancer. Mod Pathol. 2018;31:288–298.

Correspondence: Dr. Agnes K. Witkiewicz at awitki@email.arizona.edu

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Discordance between HER2 IHC and FISH in invasive breast carcinoma

The 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) recommendations for HER2 testing suggest that HER2 immunohistochemical staining that is intense but incomplete and would be considered 1+ may instead be HER2 amplified by FISH. Therefore, pathologists should consider reporting the immunohistochemistry (IHC) as equivocal (2+) and employ an alternative testing methodology. This recommendation is based largely on a study in which the authors reported testing a series of 22 micropapillary carcinomas that were considered 1+ by IHC and identifying HER2 amplification in one (five percent) case. To assess for discordance between HER2 IHC and FISH, the authors of this study evaluated 45 invasive carcinomas with micropapillary features using both methodologies. As described by the World Health Organization, invasive carcinomas with micropapillary features have small, hollow, or morula-like clusters of cells surrounded by clear stromal spaces. The authors performed HER2 IHC and FISH for all cases, and they employed an alternative chromosome 17 probe (RAI1) for cases with equivocal FISH results. All assays were scored according to the 2013 ASCO/CAP guidelines. IHC was scored irrespective of the presence of micropapillary features. Overall, the authors identified HER2 amplification in 21 (47 percent) of the cases assayed, with the corresponding immunohistochemistry being 1+ (n=9), 2+ (n=11), and 3+ (n=1). The ASCO/CAP recommendation that indicates that this morphology may deviate from the typical staining pattern is highlighted, as the authors found that 43 percent of cases with micropapillary features and HER2 staining that would otherwise be scored as 1+ were HER2 amplified by FISH. This study supports the ASCO/CAP recommendation that pathologists consider reporting IHC in this morphologic subtype as equivocal and perform reflex testing using in situ hybridization.

Stewart RL, Caron JE, Gulbahce EH, et al. HER2 immunohistochemical and fluorescence in situ hybridization discordances in invasive breast carcinoma with micropapillary features. Mod Pathol. 2017;30:1561–1566.

Correspondence: Dr. Rachel L. Stewart at rachel.stewart@aruplab.com

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Rapid virtual H&E histology of breast tissue specimens

Up to 40 percent of patients undergoing breast-conserving surgery for breast cancer require repeat surgeries due to close or positive margins. The lengthy processing required to evaluate surgical margins by standard paraffin-embedded histology precludes its use during surgery. Therefore, technologies to rapidly evaluate surgical pathology could improve breast cancer treatment by reducing the number of surgeries required. The authors demonstrated real-time histological evaluation of breast cancer surgical specimens by staining specimens with acridine orange (AO) and sulforhodamine 101 (SR101) analogously to H&E. They then imaged the specimens with fluorescence nonlinear microscopy (NLM) using a compact femtosecond fiber laser. The authors used a video-rate computational light-absorption model to produce realistic virtual H&E images of tissue in real-time and three dimensions. NLM imaging could be performed to depths of 100 μm below the tissue surface. This is important because many surgical specimens require subsurface evaluation due to contamination artifacts on the tissue surface caused by electrocautery, surgical ink, or debris from specimen handling. The authors validated this method by expert review of NLM images compared to formalin-fixed, paraffin-embedded (FFPE) H&E histology. Diagnostically important features, such as normal terminal ductal lobular units, fibrous and adipose stromal parenchyma, inflammation, invasive carcinoma, and in situ lobular and ductal carcinoma, were present in NLM images associated with pathologies identified on standard FFPE H&E histology. The authors demonstrated that AO and SR101 were extracted to undetectable levels after FFPE processing and that FISH HER2 amplification status was unaffected by the NLM imaging protocol. This method potentially enables cost-effective, real-time histological guidance of surgical resections.

Cahill LC, Giacomelli MG, Yoshitake T, et al. Rapid virtual hematoxylin and eosin histology of breast tissue specimens using a compact fluorescence nonlinear microscope. Lab Invest. 2018;98:150–160.

Correspondence: Dr. J. G. Fujimoto at jgfuji@mit.edu

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