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; Shaomin Hu, MD, PhD, staff pathologist, Cleveland Clinic; S. Emily Bachert, MD, breast pathology fellow, Brigham and Women’s Hospital, Boston; and Amarpreet Bhalla, MD, assistant professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center.

Histological regression in melanoma: impact on SLN status and survival

April 2022—Regression in melanoma is an immunological phenomenon that results in vascular fibrous tissue partially or completely replacing the tumor and is often accompanied by pigment-laden macrophages and chronic inflammation. In many cases, tumor-infiltrating lymphocytes (TILs), which permeate the tumor and disrupt nests or directly appose tumor cells, represent the earliest phase of this process. The prognostic significance of regression has long been debated, with inconsistent findings reported in the literature. The authors conducted a study to determine whether regression in primary cutaneous melanomas predicted sentinel lymph node status and survival outcomes in a large cohort of patients managed at a single medical center in Australia. Clinical and pathological parameters for 8,693 consecutive cases were retrieved for the study. Associations between regression and sentinel lymph node status, overall survival, melanoma-specific survival, and recurrence-free survival were investigated using logistic and Cox regression. Histological evidence of regression was present in 1,958 (22.5 percent) cases. Regression was significantly associated with lower Breslow thickness, lower mitotic rate, and absence of ulceration (p<0.0001). Multivariable analysis showed that regression in combination with TILs independently predicted a negative sentinel lymph node biopsy (odds ratio, 0.33; 95 percent confidence interval [CI], 0.20–0.52; p<0.0001). Patients whose tumors showed regression and TILs had the highest 10-year overall survival (65 percent), melanoma-specific survival (85 percent), and recurrence-free survival (60 percent). On multivariable analysis, the concurrent presence of regression and TILs independently predicted the lowest risk of death from melanoma (hazard ratio, 0.69; 95 percent CI, 0.51–0.94; p=0.0003) and the lowest rate of disease recurrence (hazard ratio, 0.71; 95 percent CI, 0.58–0.85; p<0.0001). However, in the subgroup analysis of stage III patients, regression predicted the lowest overall and recurrence-free survival, with melanoma-specific survival showing a similar trend. The findings indicate that regression plays a prognostically favorable role in primary cutaneous melanoma. However, in stage III melanoma patients, regression may be a marker of more aggressive disease.

Aivazian K, Ahmed T, El Sharouni MA, et al. Histological regression in melanoma: impact on sentinel lymph node status and survival. Mod Pathol. 2021;34(11):1999–2008.

Correspondence: Dr. Richard Scolyer at richard.scolyer@health.nsw.gov.au

CERTAIN study results: use of adjunctive p16 IHC in cervical biopsies

The Lower Anogenital Squamous Terminology (LAST) Project recommends using p16 IHC as an adjunct to morphologic assessment of cervical biopsies according to a specific set of criteria. The authors analyzed the effect of adjunctive p16 according to LAST criteria in a U.S.-based diagnostic utility study involving 70 surgical pathologists who provided a cumulative total of 38,500 reads on cervical biopsies. Compared with the results obtained using only H&E-stained slides, adding p16-stained slides per LAST criteria increased the sensitivity and specificity for diagnosing histologic high-grade squamous intraepithelial lesions across all cases by 8.1 percent (95 percent confidence interval [CI], 6.5–9.7; P< 0.0001) and 3.5 percent (95 percent CI, 2.8–4.2; P< 0.0001), respectively, using expert consensus diagnoses on H&E plus p16 as a reference. Within the subset of cases classified by the pathologists as fulfilling the LAST criteria, adding p16 increased sensitivity by 11.8 percent (95 percent CI, 9.5–14.0; P< 0.0001) and specificity by 9.7 percent (95 percent CI, 7.8–11.5; P< 0.0001). However, a comparable improvement in sensitivity (11.0 percent; 95 percent CI, 7.8–14.1; P< 0.0001) was found when p16 was used in cases in which p16 staining was not ordered by the pathologists per LAST, whereas specificity decreased by 0.8 percent (95 percent CI, -1.1 to -0.5; P< 0.0001) in these cases. The study demonstrated a clinically and statistically significant increase in sensitivity and specificity for high-grade squamous intraepithelial lesion when p16 was used according to LAST criteria. Extending the use of p16 to non-LAST cases led to a comparable improvement in sensitivity within this subgroup of biopsies at the cost of a minimal but statistically significant difference in specificity.

Wright Jr TC, Stoler MH, Ferenczy A, et al. The CERTAIN study results: adjunctive p16 immunohistochemistry use in cervical biopsies according to LAST criteria. Am J Surg Pathol. 2021;45:1348–1356.

Correspondence: Dr. Thomas C. Wright Jr. at tcw1@columbia.edu

Measurement of depth of invasion vs. tumor thickness in early oral tongue squamous cell carcinoma

The eighth edition of the American Joint Committee on Cancer (AJCC) cancer staging manual introduced depth of invasion into the pT category of oral cavity squamous cell carcinoma. However, the authors of this study noted multiple practical obstacles that hindered accurate measurement of depth of invasion in their daily practice. To compare the prognostic effects of depth of invasion and tumor thickness, the authors conducted a pathology review of a retrospective cohort of 293 patients with pT1/T2 oral tongue squamous cell carcinoma, as defined by the AJCC cancer staging manual seventh edition. Overall survival and nodal metastasis rate at initial resection were the primary and secondary outcomes, respectively. The authors found that tumor thickness and depth of invasion were highly correlated (correlation coefficient, 0.984). They also found that the upstage rate was only six percent (18 of 293 patients) when using tumor thickness in lieu of depth of invasion in the pT stage. More importantly, depth of invasion and tumor thickness, as well as pT stage using depth of invasion and tumor thickness, performed identically in predicting risk of nodal metastasis and overall survival. Therefore, the authors propose replacing depth of invasion, a complicated measurement with many challenges, with tumor thickness in the pT staging system.

Salama AM, Valero C, Katabi N, et al. Depth of invasion versus tumour thickness in early oral tongue squamous cell carcinoma: which measurement is the most practical and predictive of outcome? Histopathology. 2021;79(3):325–337.

Correspondence: Dr. Bin Xu at xub@mskcc.org

Loss of expression of YAP1 C-terminus as an ancillary marker for EHE variant with YAP1-TFE3 fusion

Epithelioid hemangioendothelioma (EHE) with YAP1-TFE3 fusion is a recently characterized distinctive variant of EHE that accounts for less than five percent of cases. It is composed of nests of epithelioid cells with voluminous pale cytoplasm and often shows focally vasoformative architecture. While TFE3 IHC can be used to support the diagnosis, studies have questioned its specificity. Yes-associated protein 1 (YAP1), part of the Hippo signaling pathway, is expressed in normal endothelial cells but becomes disrupted in the EHE variant with YAP1-TFE3, such that only a small N-terminal region of YAP1 is expressed in the fusion protein. A recent study reported YAP1 rearrangements in a subset of retiform and composite hemangioendotheliomas (RHE and CHE, respectively). The authors conducted a study in which they evaluated the diagnostic utility of an antibody directed against the C-terminus of YAP1 (YAP1-CT) for EHE with YAP1-TFE3, RHE, and CHE. The study included 78 tumors: EHE variant with YAP1-TFE3 (n=13), conventional (CAMTA1-positive) EHE (n=20), pseudomyogenic hemangioendothelioma (n=10), epithelioid hemangioma (n=19), epithelioid angiosarcoma (n=10), RHE (n=4), and CHE (n=2). IHC was performed using a rabbit monoclonal anti-YAP1 C-terminus antibody. EHE variant showed complete loss of YAP1-CT expression in 10 of 13 (77 percent) cases. All cases of RHE and CHE with previously confirmed YAP1 rearrangements also showed loss of YAP1-CT expression. Loss of YAP1-CT was seen in one conventional EHE (one of 20; five percent). All other epithelioid vascular tumors retained YAP1-CT expression. Loss of YAP1-CT expression appears to be associated with good sensitivity and specificity for the EHE variant with YAP1-TFE3 fusion and, along with TFE3 and CAMTA1 IHC, may provide additional support in challenging cases. This marker also may be useful in the diagnosis of RHE and CHE.

Anderson WJ, Fletcher CDM, Hornick JL. Loss of expression of YAP1 C-terminus as an ancillary marker for epithelioid hemangioendothelioma variant with YAP1-TFE3 fusion and other YAP1-related vascular neoplasms. Mod Pathol. 2021;
34(11):2036–2042.