Anatomic pathology selected abstracts

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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