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.
SATB2 as a marker of appendiceal and rectosigmoid well-differentiated neuroendocrine tumors
November 2020—Neuroendocrine neoplasms range from well to poorly differentiated and indolent to highly aggressive. The site of origin in metastatic neuroendocrine neoplasms has therapeutic and prognostic implications. SATB2 is a transcriptional regulator involved in osteoblastic and neuronal differentiation and a sensitive and specific marker of colorectal epithelium. The authors conducted a study to evaluate the expression of SATB2 in neuroendocrine neoplasms from various primary sites and its utility as a marker for determining the site of origin of these neoplasms. SATB2 IHC was performed on 266 such neoplasms, including lung small cell carcinomas (n = 39) and carcinoids (n = 30), bladder (n = 21) and prostate (n = 31) small cell carcinomas, and gastrointestinal/pancreatic neuroendocrine neoplasms of various primary sites (n =145) consisting of well-differentiated neuroendocrine tumors (WDNET, n =124) and poorly differentiated neuroendocrine carcinomas (PDNEC, n = 21). SATB2 was expressed in prostatic (10 of 31, 32 percent) and bladder (eight of 21, 38 percent) small cell carcinomas, lung carcinoid tumors (one of 30, three percent), and lung small cell carcinomas (eight of 39, 21 percent). Among primary GI neuroendocrine neoplasms, SATB2 was expressed in 37 of 124 (30 percent) WDNETs and four of 21 (19 percent) PDNECs. Of the former, all 15 rectal/rectosigmoid and all 22 appendiceal neoplasms expressed SATB2. Using receiver operator characteristic analysis, SATB2 was a sensitive and specific marker for rectal (100 percent and 80 percent, respectively) and appendiceal (100 percent and 84.5 percent, respectively) WDNETs. The authors concluded that SATB2 is a sensitive and specific marker for rectal/rectosigmoid and appendiceal WDNETs and may represent a useful diagnostic tool when these sites of origin are considered in the differential diagnosis.
Hoskoppal D, Epstein JI, Gown AM, et al. SATB2 protein expression by immunohistochemistry is a sensitive and specific marker of appendiceal and rectosigmoid well differentiated neuroendocrine tumours. Histopathology. 2020;76(4):550–559.
Correspondence: Dr. G. A. Giannico at giovanna.giannico@vumc.org
Analysis of malignant gastrointestinal neuroectodermal tumor
Malignant gastrointestinal neuroectodermal tumors are rare and, therefore, not yet completely understood. The authors conducted a study to present the clinicopathologic features of gastrointestinal neuroectodermal tumors (GNET), including treatment information. The study included 19 patients with GNET (mean tumor size, 4.2 cm). The most common site of tumor origin was the small intestine (57.9 percent), followed by the stomach (15.8 percent), colon (10.5 percent), ileocecal junction (5.3 percent), lower esophagus (5.3 percent), and anal canal (5.3 percent). Microscopically, the tumors were composed of epithelioid cells with eosinophilic or clear cytoplasm arranged in nest, sheet-like, papillary, or pseudoalveolar patterns or spindle tumor cells with eosinophilic cytoplasm arranged in a fascicular pattern. Immunohistochemically, the tumor cells stained positively for S100 (19 of 19, 100 percent), SOX10 (14 of 15, 93.3 percent), vimentin (17 of 17, 100 percent), synaptophysin (seven of 17, 41.2 percent), CD56 (four of 13, 30.8 percent), CD99 (one of five, 20 percent), and CD117 (one of 15, 6.7 percent). They stained negatively for HMB45, melan-A, DOG1, CD34, AE1/AE3, CAM5.2, chromogranin A, smooth muscle actin, and desmin. Fourteen of 15 (93.3 percent) cases showed split Ewing sarcoma breakpoint region 1 gene (EWSR1) signals consistent with a chromosomal translocation involving EWSR1. Within a mean follow-up of 29.7 months (range, three to 63 months), two of 15 (13.3 percent) patients died of disease, five (33.3 percent) were alive with disease, and eight (53.3 percent) had no evidence of disease. Two patients showed partial response to apatinib and one patient showed partial response to anlotinib. The authors concluded that GNET has distinctive morphologic, IHC, and molecular genetic features and should be distinguished from other gastrointestinal tract malignancies. Apatinib and anlotinib might be effective for treating advanced GNET and could prolong patient survival.
Chang B, Yu L, Guo WW, et al. Malignant gastrointestinal neuroectodermal tumor: clinicopathologic, immunohistochemical, and molecular analysis of 19 cases. Am J Surg Pathol. 2020;44(4):456–466.
Correspondence: Dr. Jian Wang at softtissuetumor@163.com
Malignant transformation of liver fatty acid-binding protein-deficient hepatocellular adenomas
The molecular classification of hepatocellular adenomas highlights a distinctive genotype-phenotype correlation. Malignant transformation is an exceptionally rare complication of hepatocyte nuclear factor 1α (HNF1A)-inactivated hepatocellular adenomas. This subtype is characterized by loss of liver fatty acid-binding protein immunoexpression. The authors conducted a study in which they characterized the histopathologic spectrum of 13 liver fatty acid-binding protein-deficient hepatocellular adenoma cases showing malignant transformation and that were from multiple centers. The clinicopathologic characteristics of these patients were evaluated. Stains for reticulin, liver fatty acid-binding protein, β-catenin, and glutamine synthetase were applied to these lesions. The findings were compared to those of patients with β-catenin–mutated hepatocellular adenoma. Liver fatty acid-binding protein-deficient hepatocellular adenomas with borderline features/carcinoma were seen predominantly in females (77 percent) who were an average age of 46 ± 18 years and had multiple lesions (77 percent; five patients with adenomatosis). β-catenin–mutated hepatocellular adenoma with malignant transformation, on the other hand, was seen predominantly in males (67 percent, p = .018) with a single lesion (86 percent, p = .0009). The largest liver fatty acid-binding protein-deficient hepatocellular adenoma nodule in each patient ranged from 4 to 15.5 cm. Loss of liver fatty acid-binding protein, determined by IHC, was noted in all adenoma and borderline/carcinoma components. Features of malignant transformation were pseudoglandular architecture (85 percent), cytologic atypia (85 percent), architectural atypia (100 percent), and lack of steatosis (100 percent). Other findings included myxoid change (39 percent), peliosis (46 percent), and sinusoidal dilatation (46 percent). Molecular studies confirmed somatic inactivation of HNF1A in three cases and absence of TERT promotor and exon 3 CTNNB1 mutations in five cases.
Putra J, Ferrell LD, Gouw ASH, et al. Malignant transformation of liver fatty acid binding protein-deficient hepatocellular adenomas: histopathologic spectrum of a rare phenomenon. Mod Pathol. 2020;33(4):665–675.
Correspondence: Dr. J. Putra at juan.putra@sickkids.ca
Evaluation of HPV-positive squamous cell carcinoma of the larynx, oral cavity, and hypopharynx
Human papillomavirus is a principal driver for most oropharyngeal squamous cell carcinomas (OPSCC), for which it is strongly associated with improved survival. Human papillomavirus (HPV) is much less frequently detected in squamous cell carcinomas arising in nonoropharyngeal sites (non-OPSCC), and its pathogenic role and prognostic value in these tumors is unclear. The authors evaluated the clinicopathologic features of 52 non-OPSCCs considered HPV positive based on p16 IHC and direct HPV detection using RNA in situ hybridization (ISH), DNA ISH, or real-time DNA polymerase chain reaction. The HPV-positive non-OPSCCs were from the larynx (n = 27), oral cavity (n = 21), and hypopharynx (n = 4). While most cases (n = 34, 65 percent) showed classic histologic features of HPV-positive OPSCC, including endophytic growth, minimal keratinization, and hyperchromatic nuclei without koilocytic changes, a subset (n = 13, 25 percent) were characterized by exophytic growth, exuberant surface hyperkeratosis and parakeratosis, marked nuclear pleomorphism, and prominent koilocytic atypia. These antithetical features were highly reminiscent of the warty variant of HPV-positive squamous cell carcinoma described in anogenital sites. Compared with tumors without warty features, the warty tumors presented at lower stage and were not associated with lymph node metastasis, local recurrence, or distant spread (four-year disease-free survival of 100 percent versus 66 percent, P = .069). The presence of transcriptionally active HPV detected by RNA ISH suggests a pathogenic role for HPV in these nonoropharyngeal sites. The authors concluded that while most HPV-positive non-OPSCCs are morphologically similar to their tonsillar counterparts, this study highlights a previously unrecognized warty variant that may be associated with a highly favorable clinical outcome.
Rooper LM, Windon MJ, Hernandez T, et al. HPV-positive squamous cell carcinoma of the larynx, oral cavity, and hypopharynx: clinicopathologic characterization with recognition of a novel warty variant. Am J Surg Pathol. 2020;44(5):691–702.
Correspondence: Dr. William H. Westra at william.westra@mountsinai.org
Link between differentiated exophytic vulvar intraepithelial lesion and verrucous carcinoma of the vulva
Verruciform proliferations of the vulva unrelated to human papillomavirus infection are rare. The term differentiated exophytic vulvar intraepithelial lesion (DEVIL) was recently proposed for these entities that harbor recurrent PIK3CA mutations. It is unclear whether DEVIL is related to verrucous carcinoma, a neoplasm characterized by persistence and local recurrence but no risk of distant spread. The authors conducted a study to document the clinical, histopathologic, and molecular alterations involved in DEVIL and verrucous carcinoma to identify features that could explain their potential relationship and the histogenesis of verrucous carcinoma. They reviewed specimens identified using the words “verruciform” and “verrucous.” The diagnosis of DEVIL required verruciform acanthosis; hyperkeratosis or parakeratosis, or both; hypogranulosis; cytoplasmic pallor; and bland nuclei. Verrucous carcinoma also required discontinuous, bulbous, puzzle-like nests in the stroma. Targeted next-generation sequencing using a custom 11-gene panel was performed. Eighteen specimens corresponding to 10 patients with DEVIL or verrucous carcinoma, or both, were included. The median age at presentation was 66 years for DEVIL and 70 years for verrucous carcinoma. A similar spectrum of prevalent mutations was found in both lesions, involving HRAS, PIK3CA, and BRAF. DEVIL preceded verrucous carcinoma or was diagnosed concurrently or in subsequent follow-up in five patients. In four of these cases, the same mutation was identified in DEVIL and synchronous or metachronous carcinoma. All cases showed wild-type p53 staining and lacked pathogenic TP53 mutations. DEVIL is a rare form of squamous proliferation characterized by prevalent PIK3CA and HRAS mutations. Its temporal relationship with verrucous carcinoma and their shared mutational profile in some patients suggest that DEVIL is a precursor of verrucous carcinoma. Moreover, given their morphologic and molecular overlap and that verrucous carcinoma has no risk for distant spread, it is conceivable that DEVIL and verrucous carcinoma represent a spectrum of the same entity.
Akbari A, Pinto A, Amemiya Y, et al. Differentiated exophytic vulvar intraepithelial lesion: Clinicopathologic and molecular analysis documenting its relationship with verrucous carcinoma of the vulva [published online ahead of print May 19, 2020]. Mod Pathol. doi:10.1038/s41379-020-0573-5
Correspondence: Dr. Carlos Parra-Herran at carlos.parraherran@sunnybrook.ca