Beth Z. Clark

Objectives: Whole-slide digital imaging technology paired with artificial intelligence is transforming the practice of cervical cancer screening. We aimed to evaluate the performance of the Hologic Genius Digital Diagnostics System (HGDDS) for detection of neoplasia and to investigate interobserver variability among users who have undergone HGDDS training. Methods: A total of 110 ThinPrep Papanicolaou tests were selected, with original diagnoses that included 47 cases of low-grade squamous intraepithelial lesion or worse (LSIL+); 4 cases of unsatisfactory findings; and 59 cases negative for intraepithelial lesion or malignancy (NILM), including 23 cases with microorganisms. All cases were reviewed by 16 cytologists or cytopathologists using the HGDDS. Interobserver variability and correlation with original diagnoses were assessed. Results: The HGDDS showed greater than 95% sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for LSIL+ disease. The overall misinterpretation rate was 5.5%. In total, 3 cases had poor interpretation (≥7/16 misinterpretations), including a high-grade squamous intraepithelial lesion case with 2 adenocarcinoma responses, an LSIL response, and 4 unsatisfactory responses, as well as 2 NILM cases interpreted as unsatisfactory by most participants due to borderline cellularity. Of 23 cases with microorganisms, organisms were not present in the 60-image gallery for 4 cases. Sensitivity was highest for Trichomonas (93.8%) but was low for other microorganisms (58.9%-68.8%). Conclusions: In a large academic cytology laboratory, HGDDS review by trained users demonstrated high concordance with adjudicated diagnoses for detection of LSIL+, supporting its effectiveness for identifying epithelial abnormalities. However, user experience with digital morphology is important. During early implementation, laboratories should monitor discordance and consider temporary dual review, with particular attention to borderline cellularity cases and microorganism detection.

Objective: This study assesses the effectiveness of Magee Equation 3 (ME3) in predicting response to neoadjuvant chemotherapy (NACT) and its prognostic value. Methods: In total, 263 clinical stage I to III estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancers diagnosed between 2014 and 2020 were assessed for response to NACT. Pathologic complete response (pCR) was defined as no invasive carcinoma in the breast or regional lymph nodes. Results: The pCR rate for the 4 different categories of ME3 scores (25 to <31, and ≥31) was 0% (0 of 44), 4% (4 of 96), 10% (7 of 68), and 31% (17 of 55), respectively. The ME3 score inversely correlated with residual cancer burden (RCB) score (Pearson correlation coefficient, –0.374; P < .001; 95% CI, –0.473 to –0.265). The pCR group also had a lower rate of multifocality (P = .007) and smaller tumor size (P = .008). Patients who achieved pCR (RCB-0) experienced favorable outcomes. In patients with residual disease after NACT, worse recurrence-free survival (RFS), distant recurrence-free survival (DRFS), overall survival (OS), or breast cancer–specific survival (BCSS) was noted for patients with a pretherapy ME3 score greater than 25. In the group with substantial residual disease (RCB-3), an increasing ME3 score was associated with significantly worse RFS (hazard ratio [HR], 1.103; 95% CI, 1.038-1.171), DRFS (HR, 1.086; 95% CI, 1.020-1.156), OS (HR, 1.069; 95% CI, 1.002-1.140), and BCSS (HR, 1.088; 95% CI, 1.002-1.182) in the multivariable analysis. The RCB index and posttherapy grade were also prognostic in the RCB-3 group. Conclusions: The ME3 score is predictive of response to neoadjuvant chemotherapy and is prognostically informative, particularly for RCB-3 cases.

Objective: We examined the utility of preferentially expressed antigen in melanoma (PRAME) immunohistochemistry (IHC) in distinguishing breast angiosarcoma from benign or atypical vascular lesions (AVLs) of the breast. Methods: There were 26 breast angiosarcomas (24 radiation related and 2 primary), 6 radiation-related AVLs of the breast, and 16 other benign vascular lesions of the breast retrieved from our institutional archive and stained with PRAME IHC. Results: Twenty-four of 26 (92%) breast angiosarcomas were positive for PRAME with moderate to strong staining intensities (median HScore, 255 [range, 90-300]), while 0 of 22 benign or atypical vascular lesions of the breast were PRAME positive (sensitivity, 92.3% [95% CI, 75.9%-98.6%]; specificity, 100% [95% CI, 85.1%-100%]); c-MYC was positive in all angiosarcoma cases but showed weak staining in several cases (median HScore, 155 [range, 30-280]). PRAME was negative in 1 of 2 primary angiosarcomas and negative in only 1 of 24 secondary angiosarcomas of the breast. None of the benign or atypical vascular lesions was stained with PRAME. Conclusions: It appears that PRAME expression occurs in a high proportion of radiation-related angiosarcomas and not in benign breast vascular lesions or AVLs. PRAME IHC is diagnostically useful in distinguishing benign from malignant vascular proliferations in patients with a history of radiation to the breast.

MammaPrint (MP) is a multigene assay utilized for prognostic and predictive use in early stage ER+/HER2-negative breast cancer (BC). There is limited data on MP correlation to histopathologic variables, including multivariable model Magee Equations (MEs). We compared pathologic variables to MP on 365 ER+/HER2-negative BCs in the adjuvant setting. Further, we analyzed MP and ME results in 26 core biopsy-proven ER+/HER2-negative BCs subjected to neoadjuvant chemotherapy (NACT). Post-NACT response was assessed by residual cancer burden (RCB) score. In the adjuvant cohort (n=365), high-risk (HR) MP correlated with high Nottingham score, low progesterone receptor H-score, ductal morphology, high Ki-67 index, and high ME score. In the neoadjuvant cohort (n=26), 24 were MP-HR and 2 were MP low-risk (MP-LR). The 2 MP-LR cases correlated with average ME scores of ≤25 and showed RCB scores of 2 or 3. Of the 24 MP-HR, 2 showed RCB-0 or RCB-1. Average ME>25 was seen in both of these cases and 7 others corresponding to an RCB-0 and RCB-1 rate of 22% (2 of 9) with ME>25 compared with 8% (2 of 24) with MP-HR. Lack of significant benefit from NACT (RCB-2 or RCB-3) was accurately predicted by average ME≤25 in 17 of 26 cases (65%) compared with only 2 of 26 cases (8%) with MP-LR. MP correlates with aggressive histopathologic features. While both MP and ME identified cases with robust chemotherapeutic response, MP overpredicted cases that would benefit. Therefore, MEs may more accurately predict response to NACT.

Objectives: The objective of this study was to evaluate SOX17, a transcription factor from the Sry high-mobility group–related box superfamily, as a diagnostic marker to determine site of origin using both whole-tissue sections and tissue microarrays (TMAs). Methods: SOX17 immunohistochemistry was performed on gynecologic and nongynecologic tissues (N = 1004) using whole-tissue sections and both internally constructed and commercially available TMAs. SOX17 nuclear reactivity was scored as positive or negative on the whole-tissue sections and using the semiquantitative H score method on TMAs. Results: Using both whole-tissue sections and TMAs, SOX17 was positive in 94% (n = 155) of endometrial tumors and 96% (n = 242) of ovarian tumors. All breast cases (n = 241) and vulvar/cervical squamous cell carcinomas (n = 150) were negative. Among 1004 tumors from 20 sites, the only organs with positive tumors were ovary, uterus, and testis. Conclusions: SOX17 is a sensitive and specific marker for gynecologic origin in the tissues tested and may be a valuable adjunct to PAX8 and other commonly used markers to confirm endometrial or ovarian origin. SOX17 expression is lower in mucinous tumors, endocervical adenocarcinoma, high-grade neuroendocrine tumors, and undifferentiated/dedifferentiated endometrial carcinoma.

This study describes “lobular-like invasive mammary carcinomas” (LLIMCas), a group of low- to intermediate-grade invasive mammary carcinomas with discohesive, diffusely infiltrative cells showing retained circumferential membranous immunoreactivity for both E-cadherin and p120. We analyzed the clinical-pathologic features of 166 LLIMCas compared to 104 classical invasive lobular carcinomas (ILCs) and 100 grade 1 and 2 invasive ductal carcinomas (IDCs). Tumor size and pT stage of LLIMCas were intermediate between IDCs and ILCs, and yet often underestimated on imaging and showed frequent positive margins on the first resection. Despite histomorphologic similarities to classical ILC, the discohesion in LLIMCa was independent of E-cadherin/p120 immunophenotypic alteration. An exploratory, hypothesis-generating analysis of the genomic features of 14 randomly selected LLIMCas and classical ILCs (7 from each category) was performed utilizing an FDA-authorized targeted capture sequencing assay (MSK-IMPACT). None of the seven LLIMCas harbored CDH1 loss-of-function mutations, and none of the CDH1 alterations detected in two of the LLIMCas was pathogenic. In contrast, all seven ILCs harbored CDH1 loss-of-function mutations coupled with the loss of heterozygosity of the CDH1 wild-type allele. Four of the six evaluable LLIMCas were positive for CDH1 promoter methylation, which may partially explain the single-cell infiltrative morphology seen in LLIMCa. Further studies are warranted to better define the molecular basis of the discohesive cellular morphology in LLIMCa. Until more data becomes available, identifying LLIMCas and distinguishing them from typical IDCs and ILCs would be justified. In patients with LLIMCas, preoperative MRI should be entertained to guide surgical management.

Objectives: This study examined the accuracy of radioactive seed localization (RSL) of lymph nodes (LNs) following neoadjuvant chemotherapy (NAC) for invasive breast carcinoma, recorded pathologic features of LNs following NAC, evaluated concordance of response between breast and LNs, and identified clinicopathologic factors associated with higher risk of residual lymph node involvement. Methods: Clinical records, imaging, and pathology reports and slides were retrospectively reviewed for 174 breast cancer patients who received NAC. Chi-square and Fisher’s exact tests were used to compare differences in risk of residual lymph node disease. Results: Retrieval of biopsied pre-therapy positive LN was confirmed in 86/93 (88%) cases overall, and in 75/77 (97%) of cases utilizing RSL. Biopsy clip site was the best pathologic feature to confirm retrieval of a biopsied lymph node. Pre-therapy clinical N stage > 0, positive pre-therapy lymph node biopsy, estrogen and progesterone receptor positivity, Ki67 < 50%, HR + /HER2− tumors, and residual breast disease had higher likelihood of residual lymph node disease after NAC (p < 0.001). Conclusions: RSL-guided LN excision improves retrieval of previously biopsied LNs following NAC. The pathologist can use histologic features to confirm retrieval of targeted LNs, and tumor characteristics can be used to predict a higher risk of residual LN involvement.

Mural nodules are rarely identified in cystic ovarian neoplasms, and have been categorized into sarcoma-like, sarcomatous, and anaplastic carcinomatous types. Most reports of these mural nodules have been described in mucinous ovarian tumors. In this case report, we describe an ovarian serous borderline tumor with mural nodules composed of high-grade carcinoma with anaplastic features and necrosis, including the morphologic features, immunoprofile, and results of tumor DNA sequencing. Omental involvement was also identified. Recognition of this phenomenon in serous tumors is important, so that thickened areas of cyst wall in ovarian serous tumors will be thoroughly examined.