Anatomic pathology selected abstracts

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Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology and director of the Women’s Health Pathology Fellowship, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Rachel Stewart, DO, PhD, assistant professor, Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington; 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.

ALK-rearranged tumors in the STUMP subcategory of uterine tumors

May 2019—Smooth muscle tumor of uncertain malignant potential is a rare diagnosis rendered when there is uncertainty concerning the biological potential of a smooth muscle tumor. The initial differential diagnosis is often broad, as tumors in this subgroup are morphologically heterogeneous. Recent data suggest that uterine inflammatory myofibroblastic tumors (IMTs) with anaplastic lymphoma kinase (ALK) rearrangement may be misclassified as smooth muscle tumor of uncertain malignant potential (STUMP), but the extent to which this occurs has not been examined. The authors identified 60 female patients with tumors previously diagnosed as STUMP (48 cases) or prospectively considered for the diagnosis of STUMP (12 cases). Each case underwent histologic review, ALK immunohistochemistry, and confirmatory break-apart FISH for ALK if immunoreactive. Six of the 43 (14 percent) uterine and cervical tumors were ALK IHC positive, whereas tumors at all other sites were ALK IHC negative. Myxoid features, although limited in some cases, were present in all six ALK IHC-positive tumors, representing 35 percent (six of 17) of tumors displaying myxoid features at uterine and cervical sites. All ALK-immunoreactive tumors were confirmed to have ALK rearrangements by FISH, with one tumor showing numerous (three to eight) 3′ ALK signals, an unusual FISH pattern not previously described in uterine inflammatory myofibroblastic tumors. Two patients developed recurrent disease and were treated with ALK-targeted therapy, with initial response. The data demonstrate that a significant proportion of uterine and cervical tumors considered to be STUMPs are ALK-positive by IHC and FISH. Future screening of all uterine and cervical mesenchymal tumors under consideration for the diagnosis of STUMP, particularly those with myxoid features, is recommended to identify ALK-rearranged inflammatory myofibroblastic tumors that could potentially be treated with targeted therapy using tyrosine kinase inhibitors.

Devereaux KA, Kunder CA, Longacre TA. ALK-rearranged tumors are highly enriched in the STUMP subcategory of uterine tumors. Am J Surg Pathol. 2019;43(1):64–74.

Correspondence: Dr. T. A. Longacre at longacre@​stanford.edu

Study of molecular changes preceding endometrial and ovarian cancer

Molecular alterations preceding endometrial and ovarian cancer and their sequence of events are unknown. The authors profiled specimens from patients with lifelong surveillance for Lynch syndrome, a prevalent cancer predisposition syndrome associated with hereditary defects in DNA mismatch repair, to define the molecular trajectories of endometrial and ovarian cancer and guide patient management. They identified DNA mismatch repair gene mutation carriers with endometrial or ovarian carcinoma or endometrial hyperplasia from a nationwide registry. The authors collected endometrial biopsy specimens taken from these women during 20 years of screening. They retrieved 213 endometrial and ovarian specimens from Lynch syndrome mutation carriers and 197 histology-matched (nonserous) samples from sporadic cases. The specimens were profiled for markers linked to endometrial and ovarian tumorigenesis, including ARID1A protein expression, mismatch repair status, and tumor suppressor gene promoter methylation. In Lynch syndrome-associated endometrial and ovarian carcinomas, ARID1A protein was lost in 61 to 100 percent and mismatch repair was deficient in 97 to 100 percent, compared with none to 17 percent and 14 to 44 percent, respectively, in sporadic carcinomas (P = .000). ARID1A loss appeared in complex hyperplasia and deficient mismatch repair and tumor suppressor gene promoter methylation in histologically normal endometrium. Despite quantitative differences between Lynch syndrome and sporadic cases, ARID1A expression, mismatch repair, and tumor suppressor gene promoter methylation divided endometrial samples from both patient groups into three categories of increasing abnormality, comprising normal endometrium and simple hyperplasia, complex hyperplasia with or without atypia, and endometrial cancer. Complex hyperplasias without atypia and with atypia were molecularly indistinguishable. The authors concluded that surveillance specimens from Lynch syndrome identify mismatch repair deficiency, tumor suppressor gene promoter methylation, and ARID1A loss as early changes in tumor development. These findings are clinically relevant for classifying endometrial hyperplasias and have potential implications for cancer prevention in Lynch syndrome patients.

Niskakoski A, Pasanen A, Lassus H, et al. Molecular changes preceding endometrial and ovarian cancer: a study of consecutive endometrial specimens from Lynch syndrome surveillance. Mod Pathol. 2018;31:1291–1301.

Correspondence: Anni Niskakoski at anni.niskakoski@helsinki.fi

Prognostic significance of tumor-infiltrating lymphocytes in DCIS of breast

Tumor-infiltrating lymphocytes provide prognostic value in invasive breast cancer, and there are published guidelines for assessing them. The authors conducted a study to evaluate methods of tumor-infiltrating lymphocyte (TIL) assessment and the prognostic significance of TILs in breast ductal carcinoma in situ (DCIS). They assessed hematoxylin-and-eosin–stained sections from two clinically annotated DCIS cohorts—a training set (n =150 pure DCIS) and a validation set (n = 666 comprising 534 pure DCIS and 132 cases wherein DCIS and invasive breast carcinoma coexisted). Seven scoring methods were applied to the training set to identify the optimal reproducible method associated with the strongest prognostic value. Among the methods, TILs touching the ducts’ basement membrane or one lymphocyte cell thickness away from it provided the strongest significant association with outcome and highest concordance rate (inter-cluster correlation coefficient, 0.95). The assessment of periductal TILs at increasing distances from DCIS (0.2, 0.5, and 1 mm) and percentage of stromal TILs was challenging and showed lower concordance rates than for touching TILs. TIL hotspots and lymphoid follicles did not exhibit prognostic significance. Within the pure DCIS validation set, dense TILs were associated with younger age, symptomatic presentation, larger size, higher nuclear grade, comedo necrosis, estrogen receptor negativity, and shorter recurrence-free interval (P = .002). In multivariate survival analysis, dense TILs were independent predictors of shorter recurrence-free interval (P = .002) in patients treated with breast conservation. DCIS associated with invasive carcinoma showed denser TILs than pure DCIS (P = 9.0 × 10^-13). Dense TILs are an independent prognostic variable in DCIS. Touching TILs provide a reproducible method for their assessment that potentially can be used to guide management.

Toss MS, Miligy I, Al-Kawaz A, et al. Prognostic significance of tumor-infiltrating lymphocytes in ductal carcinoma in situ of the breast. Mod Pathol. 2018;31:1226–1236.