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, associate pathologist, Brigham and Women’s Hospital, Boston; and Amarpreet Bhalla, MD, assistant professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center.
Utility of claudin-4 versus MOC-31 and Ber-EP4 in the diagnosis of metastatic carcinoma
November 2023—Claudin-4 is a sensitive and specific marker for carcinoma in effusion cytology. The authors examined the diagnostic use of claudin-4 versus MOC-31 and Ber-EP4 by comparing their sensitivity, specificity, positive predictive value, and negative predictive value in differentiating carcinoma from mesothelioma and benign/mesothelial hyperplasia in effusion specimens. They conducted a retrospective study on a cohort of 229 cytology specimens, including 211 effusion fluid and 18 fine-needle aspiration specimens. The cytologic categories included 134 carcinoma, 28 mesothelioma, 46 indefinite (suspicious and atypical), and 21 benign. Cell block sections were stained for claudin-4 and compared with those previously stained for MOC-31 and Ber-EP4. Indefinite cases were further reclassified, based on clinical and pathologic findings, into benign (26 cases), mesothelioma (11 cases), and carcinoma (nine cases). None of the mesotheliomas (zero of 39) or benign effusions (zero of 47) were positive for claudin-4, whereas 134 of the 143 carcinoma specimens were positive. When compared with MOC-31 and Ber-EP4, claudin-4 had the highest specificity and positive predictive value (100 percent for each), followed by Ber-EP4. Claudin-4 showed high sensitivity (93.7 percent), albeit lower than MOC-31. MOC-31 had the lowest specificity and positive predictive value but the highest sensitivity and negative predictive value. Ber-EP4 had the lowest sensitivity (91.6 percent). The authors concluded that claudin-4 can be used as a single marker for carcinoma as a result of its high sensitivity and superior specificity compared with MOC-31 and Ber-EP4. Mesothelial lineage can be ruled out when claudin-4 is positive. In equivocal cytology samples with few scattered cells of interest, a panel of claudin-4 and Ber-EP4 results in the highest combined sensitivity and specificity.
Najjar S, Gan Q, Stewart J, et al. The utility of claudin-4 versus MOC-31 and Ber-EP4 in the diagnosis of metastatic carcinoma in cytology specimens. Cancer Cytopathol. 2023;131:245–253.
Correspondence: Dr. Nour Sneige at nsneige@mdanderson.org
Interobserver variability in assessment of depth of submucosal invasion in colonic endoscopic resections
Recent data support that patients with low-risk submucosally invasive (pT1) colonic adenocarcinomas—that is, completely resected tumors that lack high-grade morphology, tumor budding, and lymphovascular invasion—are considered cured via endoscopic resection provided that the submucosal invasion is less than 1,000 µm. Consequently, pathologists’ assessment of depth of submucosal invasion may guide further management—that is, use of surveillance versus colectomy. The authors conducted a study in which they assessed interobserver concordance among gastrointestinal pathologists in measuring submucosal depth of invasion in colonic endoscopic resections. Six gastrointestinal pathologists from five academic centers independently measured the greatest depth of submucosal invasion in micrometers using 52 H&E–stained slides from colonic endoscopic specimens with pT1 adenocarcinomas, per published guidelines (round one scoring). Following a consensus meeting, each pathologist then measured from the surface of the lesion to the greatest depth of submucosal invasion and from the muscularis mucosae to the greatest depth of submucosal invasion (round two scoring). Each pathologist subsequently chose the measurement they would report in clinical practice—that is, the best “real-life” measurement. Interobserver agreement was assessed by the intraclass correlation coefficient (ICC) and Cohen κ statistics. Round one had poor ICC (0.43; 95 percent confidence interval [CI], 0.31–0.56). Round two agreement was good (ICC = 0.83; 95 percent CI, 0.76–0.88) when measuring from the surface of the lesion but moderate (ICC = 0.59; 95 percent CI, 0.47–0.70) when measuring from the muscularis mucosae, and it became poor (ICC = 0.49; 95 percent CI, 0.36–0.61) for the best-assessment measurement. The authors concluded that clear and reproducible guidelines are needed if clinicians are to base important management decisions on pathologists’ estimates of the depth of submucosal invasion in colonic endoscopic resections.
Karamchandani DM, Westerhoff M, Arnold CA, et al. Interobserver variability in assessment of depth of submucosal invasion for colonic endoscopic resections among subspecialized gastrointestinal pathologists. Arch Pathol Lab Med. 2023;147:534–545.
Correspondence: Dr. Dipti M. Karamchandani at dipti.karamchandani@utsouthwestern.edu
Assessment of microcribriform adenocarcinoma of salivary glands: a unique tumor entity
The landscape of salivary gland carcinoma is ever-changing, with the list of new tumors and newly elucidated variants of well-known tumor entities growing. The routine use of next-generation sequencing has been instrumental in identifying novel fusions and tumor entities and has led to a more objective and evidence-based model for classification. However, morphology remains critical in assessing the validity of novel molecular findings and, more importantly, in assessing which of these findings will influence patient prognosis and treatment decisions. The recognition of microsecretory adenocarcinoma as a distinct low-grade malignancy of salivary glands, underpinned by MEF2C::SS18, and a single possibly related case of SS18::ZBTB7A have expanded the growing list of distinctive tumors. The morphology of the latter case was determined to be unique and reproducible. The authors reviewed four cases of SS18::ZBTB7A, which showed a combination of distinctive oncocytic cells forming compact glandular growth and amphophilic cells forming tubular growth, and they suggested the appellation microcribriform adenocarcinoma. The tumors appeared to preferentially occur in non-oral sites—two parotid, one submandibular gland, and one bronchial seromucous gland. By IHC, they expressed S100 and SOX-10 with focal outer myoepithelial cells marked by circumferential p63, p40, and smooth muscle actin staining around some of the nests and tubules. The tumors showed infiltrative growth within a hyalinized and myxoid stroma. Cytologically, they appeared generally low grade, similar to microsecretory adenocarcinomas. The authors concluded that the morphologic and molecular uniformity of these four microcribriform adenocarcinoma tumors warrants their recognition. While related to microsecretory adenocarcinoma, the tumors differ sufficiently enough to be classified as a distinct tumor entity. In limited follow-up, the tumors appeared to be relatively indolent.
Weinreb I, Hahn E, Dickson BC, et al. Microcribriform adenocarcinoma of salivary glands: a unique tumor entity characterized by an SS18::ZBTB7A fusion. Am J Surg Pathol. 2023;47(2):194–201.
Correspondence: Dr. Ilan Weinreb at weinrebi@yahoo.ca
Nephrogenic adenoma intermixed with urothelial carcinoma: a potential mimic of glandular differentiation and invasive cancer
Nephrogenic adenoma is a common urinary tract lesion typically associated with urothelial disruption, leading to implantation of shed renal tubular cells. It may demonstrate a spectrum of architectural and cytologic features that mimic urothelial carcinoma (UC); adenocarcinoma, including clear cell adenocarcinoma and prostatic adenocarcinoma; and invasion. However, admixed UC and nephrogenic adenoma (NA) has not been described. The authors conducted a study in which they assessed cases in which NA was intimately intermixed with UC, potentially mimicking variant differentiation or invasion. They identified specimens from three health care systems in which NA and UC were intimately intermixed to the extent that they could mimic a spectrum of one lesion. The authors analyzed patterns of NA and clinical implications of misdiagnosing NA as glandular differentiation of UC. The study involved four women and 29 men (median age, 72 years; range, 31–89 years). Twenty-four patients had transurethral resections, three had biopsies, and six had major resections. Fourteen patients had noninvasive high-grade papillary UC, six had carcinoma in situ, and 11 had invasive high-grade UC. NA developed in a papillary urothelial neoplasm with extensive denudation in two patients. Three patients had fibromyxoid NA infiltrated by invasive UC. Classical NA (n = 30) had tubulopapillary (n = 18), pure tubular (n = 7), or pure papillary (n = 5) architecture. NA was present in the muscularis propria in one patient, and two lesions involved adventitia. NA could have been misdiagnosed as invasion in 17 of 22 (77 percent) noninvasive tumors or a higher stage of disease in 19 of 33 (58 percent). The authors concluded that nephrogenic adenoma can be intermingled with high-grade urothelial carcinoma, expanding the spectrum of entities that must be considered in the differential diagnosis, and it may mimic glandular or tubular differentiation, invasion, or a higher stage of disease. Misinterpretation of nephrogenic adenoma in such a setting may incorrectly convey to clinicians a more aggressive biological potential of cancer.
Kryvenko ON, Wasco MJ, Williamson SR. Nephrogenic adenoma intermixed with urothelial carcinoma: A potential mimic of divergent glandular differentiation, variant morphology, or invasion. Arch Pathol Lab Med. 2023;147:552–558.
Correspondence: Dr. Oleksandr Kryvenko at o.kryvenko@med.miami.edu
Alterations in signaling pathways in sinonasal tract melanoma: a molecular genetics and IHC study
Sinonasal mucosal melanoma is a rare tumor arising in the nasal cavity, paranasal sinuses, and nasopharynx (sinonasal tract). The authors conducted a study in which they evaluated 90 cases of the disease diagnosed in 29 males and 61 females who were a median age of 68 years. Most tumors involved the nasal cavity and had an epithelioid morphology. The research techniques used in this analysis included targeted-DNA and -RNA next-generation sequencing, Sanger sequencing, FISH, and IHC. Sinonasal melanomas were commonly driven by RAS (38 of 90, 42 percent), particularly NRAS (n=36), mutations and rarely displayed BRAF pathogenic variants (four of 90, four percent). BRAF/RAS mutants were identified in 71 percent (10 of 14) of primary paranasal sinus melanomas but in only 41 percent (26 of 64) of nasal cavity tumors. BRAF/RAS-wild type tumors occasionally harbored alterations of the key components and regulators of the Ras-MAPK signaling pathway: NF1 mutations (one of 17, six percent) or NF1 locus deletions (one of 25, four percent), and SPRED1 (three of 25, 12 percent), PIK3CA (three of 50, six percent), PTEN (four of 50, eight percent), and mTOR (one of 50, two percent) mutations. These mutations often occurred in a mutually exclusive manner. In several tumors, some of which were NRAS mutants, TP53 was deleted (six of 48, 13 percent) or mutated (five of 90, six percent), or both. Variable nuclear accumulation of TP53, mirrored by elevated nuclear MDM2 expression, was seen in more than half of cases. Furthermore, sinonasal melanomas (n=7), including RAS/BRAF-wild type tumors (n=5), harbored alterations of the key components and regulators of the canonical Wnt signaling pathway: APC (four of 90, four percent), CTNNB1 (three of 90, three percent), and AMER1 (one of 90, one percent). TERT promoter mutations (five of 53, nine percent) and fusions (two of 40, five percent) were identified. The latter occurred in BRAF/RAS-wild type tumors. No oncogenic fusion gene transcripts previously reported in cutaneous melanomas were detected. Eight tumors, including seven BRAF/RAS-wild type cases, expressed ADCK4::NUMBL cis-fusion transcripts. In summary, this study documented mutational activation of NRAS and other key components and regulators of the Ras-MAPK signaling pathway in a majority of sinonasal melanomas.
Chłopek M, Lasota J, Thompson LDR, et al. Alterations in key signaling pathways in sinonasal tract melanoma. A molecular genetics and immunohistochemical study of 90 cases and comprehensive review of the literature. Mod Pathol. 2022;35(11):1609–1617.
Correspondence: Dr. Jerzy Lasota at jurek.p.lasota@gmail.com