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.
HPV-independent precursors mimicking HSIL of the vulva
June 2021—Two etiopathogenic types of vulvar squamous cell carcinoma have been described: human papillomavirus associated and HPV independent. HPV-associated vulvar squamous cell carcinoma (VSCC) develops from the precursor high-grade squamous intraepithelial lesions (HSILs). HPV-independent VSCC develops from the precursors vulvar intraepithelial neoplasia (dVIN) or vulvar acanthosis with altered differentiation. HPV-independent precursors mimicking HSIL have been described in the vulva, but their frequency and morphologic spectrum have not been completely characterized. The authors conducted a study in which they explored the frequency and histologic features of precursor lesions mimicking HSIL in a large series of HPV-independent VSSC. They included in the study 779 DNA HPV-negative/p16-negative VSCC with at least 1 cm of adjacent skin. They evaluated the histologic and immunohistochemical (p16 and p53) characteristics of the intraepithelial lesions, focusing on precursors mimicking HPV-associated vulvar HSIL. A total of 254 (33 percent) tumors had adjacent premalignant lesions. Of that group, 186 (73 percent) had dVIN, 22 (nine percent) had vulvar acanthosis with altered differentiation, and 46 (18 percent) had lesions that mimicked HSIL. The patients with these HSIL-like lesions were a mean age of 72 ±15 years. Twenty-six of these HSIL-like lesions had basaloid morphology, while 13 had warty and seven had mixed basaloid/warty features. All HSIL-like precursors were DNA HPV negative/p16 negative. Seventy-four percent of them showed p53 abnormal staining and 35 percent had areas of conventional dVIN. The authors concluded that their study shows that at least one-fifth of HPV-independent vulvar precursors mimic HSIL, exhibiting basaloid or warty features. Older age and areas of typical HPV-independent intraepithelial lesions, together with p16 negativity, should raise suspicion of an HPV-independent etiology.
Rakislova N, Alemany L, Clavero O, et al. HPV-independent precursors mimicking high-grade squamous intraepithelial lesions (HSIL) of the vulva. Am J Surg Pathol. 2020;44(11):1506–1514.
Correspondence: Dr. Jaume Ordi at jordi@clinic.cat
Characterization of myocarditis associated with immune checkpoint inhibitor therapy
Cardiac complications of immune checkpoint inhibitor therapy are rare, but reports of myocarditis are increasing. The findings have been described in case reports as lymphocytic myocarditis, but the histopathology of this diffuse lymphohistiocytic myocarditis is underreported. The authors conducted a study to review the histology of myocardial biopsy-proven cases of immune checkpoint-associated myocarditis and provide IHC characterization of the inflammatory infiltrate. They identified six patients with biopsy-proven myocarditis receiving therapy using anti-programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) agents with and without cytotoxic T-lymphocyte–associated protein 4 inhibitors and characterized their histopathology and immune cell profiles. The myocarditis was multifocal/diffuse and characterized by a predominant CD163-positive histiocytic infiltrate with an associated CD8+ and PD-1+ T-lymphocytic infiltrate, some of which were granzyme B positive. Cardiac myocytes showed immunoreactivity for PD-L1 in areas of injury, which was confirmed using two different anti–PD-L1 clones. Four of six patients recovered from their cardiac injury. One patient had residual tachycardia-bradycardia syndrome and one patient expired. The authors concluded that diffuse lymphohistiocytic myocarditis associated with this therapy is relatively distinctive. This diagnosis is strongly suggested based on histopathologic findings in the correct clinical setting.
Sobol I, Chen CL, Mahmood SS, et al. Histopathologic characterization of myocarditis associated with immune checkpoint inhibitor therapy. Arch Pathol Lab Med. 2020;144(11):1392–1396.
Correspondence: Dr. Alain C. Borczuk at alb9003@med.cornell.edu
Significance of chromogranin A expression in rectal neuroendocrine tumors
Although rectal neuroendocrine tumors with an L-cell phenotype and small size are generally less clinically serious than their non-L-cell type counterparts, the 2019 World Health Organization classification system has categorized all of these lesions as malignant. Therefore, identifying biomarkers of rectal neuroendocrine tumors (NETs) is important for stratifying their clinical behavior. The authors conducted a study in which they assessed chromogranin A protein expression in 538 endoscopically or surgically resected rectal NETs and compared it to clinicopathologic factors to determine its clinical and prognostic significance. All of the rectal NETs were synaptophysin positive, but chromogranin A labeling was detected in only 111 (20.6 percent) cases. Chromogranin A expression in the rectal NETs was more commonly associated with older age (50 years and older; P = .013), male gender (P = .002), radical resection (P = .003), large tumor size (≥1 cm; P = .038), muscularis propria invasion (P = .002), lymphovascular (P = .014) and perineural (P < .001) invasion, involved resection margin (P = .028), and lymph node metastasis (P = .003). Patients with chromogranin A expression had higher plasma chromogranin A levels (P = .023) than those without chromogranin A expression during follow-up. The 10-year disease-free survival rate in rectal NET patients with chromogranin A expression (91.5 percent) was significantly shorter than in the negative cases (99.7 percent) based on univariate (hazard ratio, 14.438; 95 percent confidence interval [CI], 2.911–71.598; P < .001) and multivariate (hazard ratio, 12.099; 95 percent CI, 2.044–71.608; P = .006) analyses. The authors concluded that rectal NETs that are positive for chromogranin A are less common than those with synaptophysin expression and show more aggressive clinical behavior. Therefore, chromogranin A is a prognostic indicator of higher recurrence risk in patients with endoscopically or surgically resected rectal NETs.
Kim J, Kim JY, Oh EH, et al. Chromogranin A expression in rectal neuroendocrine tumors is associated with more aggressive clinical behavior and a poorer prognosis. Am J Surg Pathol. 2020;44(11):1496–1505.
Correspondence: Dr. S-M Hong at smhong28@gmail.com
A unique monocyte-macrophage phenotype in Rosai-Dorfman disease
Rosai-Dorfman disease is a rare histiocytosis with heterogenous clinical features. The authors conducted a study to characterize its histologic and phenotypic features to better define its pathologic diagnosis. The study involved 33 patients with Rosai-Dorfman disease (RDD)—24 patients with extracutaneous disease (R group) and nine patients with lesions limited to the skin or subcutaneous tissue (C group). The authors identified OCT2 as a novel marker for the monocyte-macrophage phenotype of RDD. It was expressed in 97 percent of RDD cases. In contrast, OCT2 expression was not seen in any cases of Erdheim-Chester disease and was seen in 6.7 percent of cases of Langerhans cell histiocytosis. Other markers that were useful in the diagnosis of RDD included S100 (100 percent), CD163 (88 percent), and cyclin D1 (97 percent). In a subset of cases, RDD showed moderate to strong expression of factor 13a (30 percent), p16 (64 percent), and phosphorylated extracellular signal-regulated kinase (45 percent). It was uniformly negative for ZBTB46, CD1a, and langerin. Within the R group of RDD, increased expression of factor 13a or phosphorylated extracellular signal-regulated kinase showed a statistically significant association with multifocal disease (P< .05). The authors concluded that identification of the unique monocyte-macrophage phenotype of RDD with OCT2 expression furthers the medical community’s understanding of Rosai-Dorfman disease and allows for more uniform classification.
Ravindran A, Goyal G, Go RS, et al. Rosai-Dorfman disease displays a unique monocyte-macrophage phenotype characterized by expression of OCT2. Am J Surg Pathol. 2021;45(1):35–44.
Correspondence: Dr. K. L. Rech at rech.karen@mayo.edu
E-cadherin to P-cadherin switching in lobular breast cancer with tubular elements
Loss of E-cadherin expression due to mutation of the CDH1 gene is a characteristic feature of invasive lobular breast cancer. Beta-catenin, which binds to the cytoplasmic domain of E-cadherin, is simultaneously downregulated, reflecting disassembly of adherens junctions and loss of cell adhesion. E-cadherin to P-cadherin switching can rescue adherens junction formation and cell adhesion. However, P-cadherin has not been implicated in invasive lobular breast cancer (ILBC). The authors conducted a study to characterize 13 ILBCs with exceptional histomorphology, which they termed ILBCs with tubular elements. The CDH1 mutational status was determined by next-generation sequencing and whole genome copy number (CN) profiling. Expression of cadherins was assessed by immunohistochemistry. ILBCs with tubular elements were estrogen receptor positive (13 of 13) and HER2 negative (13 of 13), and they harbored deleterious CDH1 mutations (11 of 13) accompanied by loss of heterozygosity due to deletion of chromosome 16q22.1 (nine of 11). E-cadherin expression was lost or reduced in noncohesive tumor cells and admixed tubular elements (13 of 13). Beta-catenin expression was lost in noncohesive tumor cells but retained in tubular elements (11 of 13), indicating focal rescue of adherin junction formation. N-cadherin and R-cadherin were negative (zero of 13). P-cadherin was typically positive (12 of 13), and immunoreactivity was accentuated in tubular elements. Adjacent lobular carcinoma in situ was P-cadherin negative (zero of seven). In a reference cohort of lobular carcinoma in situ specimens, P-cadherin was not expressed (zero of 25). In a reference cohort of invasive mammary carcinomas, P-cadherin-positive cases (36 of 268) were associated with triple-negative nonlobular breast cancer (P< .001). P-cadherin expression was more common in ILBCs with tubular elements than in ILBCs from the reference cohort (12 of 13 versus seven of 84; P< .001). In summary, E-cadherin to P-cadherin switching occurs in a subset of ILBCs. P-cadherin is the molecular determinant of a mixed-appearing histomorphology in ILBCs with tubular elements.
Christgen M, Bartels S, van Luttikhuizen JL, et al. E-cadherin to P-cadherin switching in lobular breast cancer with tubular elements. Mod Pathol. 2020;33(12):2483–2498.
Correspondence: Dr. Matthias Christgen at christgen.matthias@mh-hannover.de
Invasive apocrine carcinoma of the breast: clinicopathologic features and genomic profiling
Pure invasive apocrine carcinoma is a rare type of primary breast cancer and constitutes approximately one percent of all breast cancers. Most pure invasive apocrine carcinomas are triple negative, and the lack of targeted therapies for triple-negative breast cancer has fostered efforts to discover actionable molecular targets in these tumors. The authors conducted a study in which they analyzed the clinicopathologic characteristics and comprehensive genomic profiling of 18 patients with pure triple-negative apocrine carcinomas (TNACs) using a 324-gene panel assay (FoundationOne CDx). The patients were a median age of 55.5 years, and the postmenopausal status rate was 77.8 percent. In total, 83.3 percent of patients were diagnosed with histological grade II TNACs and 16.7 percent were diagnosed with grade III. The majority of patients presented at an early tumor-node-metastasis (TNM) stage (I, 38.9 percent; II, 50 percent; and III, 11.1 percent). The mean Ki-67 index was 9.7 percent, and PD-L1 positivity was 11.7 percent. During a median follow-up period of 76.5 months, one patient died and two experienced distant metastases. There were 61 clinically relevant genomic alterations among all 18 TNAC patients, and the mean tumor mutation burden (TMB) was 3 Mut/Mb. The top-ranked altered genes were PIK3CA (72.2 percent), PTEN (33.3 percent), and TP53 (27.8 percent). There were four novel mutations found in PTEN and an actionable rearrangement involving FGFR2-TACC2 that had never been reported in breast cancer. In total, 88.9 percent, 50 percent, 44.4 percent, and 16.7 percent of TNACs had at least one clinically relevant genomic alteration in genes involved in the PI3K/mTOR, cell cycle, RAS/RAF/MEK, and growth factor receptor-related pathways, respectively. All patients had at least one clinically relevant genomic alteration, and 94.4 percent had at least one actionable alteration. To the best of the authors’ knowledge, this study is the largest genomic sequencing cohort of pure TNACs. Incorporating comprehensive genomic profiling into TNACs may shed light on potential therapeutic opportunities for targeted drugs and immune checkpoint inhibitors.
Sun X, Zuo K, Yao Q, et al. Invasive apocrine carcinoma of the breast: clinicopathologic features and comprehensive genomic profiling of 18 pure triple-negative apocrine carcinomas. Mod Pathol. 2020;33:2473–2482.
Correspondence: Dr. Wentao Yang at yangwt2000@163.com