Cutaneous Lymphadenoma Is a Distinct Trichoblastoma-like Lymphoepithelial Tumor With Diffuse Androgen Receptor Immunoreactivity, Notch1 Ligand in Reed-Sternberg–like Cells, and Common EGFR Somatic Mutations

Abstract

The term “cutaneous lymphadenoma” was coined in this journal for an unusual lymphoepithelial cutaneous adnexal neoplasm, possibly with immature pilosebaceous differentiation. Some authors further proposed that cutaneous lymphadenoma was an adamantinoid trichoblastoma. However, although a hair follicle differentiation is widely accepted, the fact that this is a lymphoepithelial tumor is not appropriately explained by the trichoblastoma hypothesis. Our goal was to further clarify the phenotypic and genotypic features of cutaneous lymphadenoma in a series of 11 cases. Histologically, a lobular architecture surrounded by a dense fibrous stroma was present in all cases. The lobules were composed of epithelial cells admixtured with small lymphocytes and isolated or clustered large Reed-Sternberg–like (RS-L) cells. The epithelial cells were diffusely positive for the hair follicle stem cell markers CK15, PHLDA1, and for androgen receptor. No immunostaining for markers of sebaceous differentiation was found. Intraepithelial lymphocytes were predominantly CD3 + , CD4 + , FoxP3 + T cells. RS-L cells showed both strong Jagged-1 and Notch1 cytoplasmic immunostaining. Androgen-regulated NKX3.1 nuclear immunostaining was present in a subset of large intralobular cells in all cases. Double immunostaining showed coexpression of NKX3.1 and CD30 in a subset of RS-L cells. No immunostaining for lymphocytic or epithelial markers was present in RS-L cells. EGFR, PIK3CA, and FGFR3 somatic mutations were found by next-generation sequencing in 56% of the cases. We consider that cutaneous lymphadenoma is a distinct benign lymphoepithelial tumor with androgen receptor and hair follicle bulge stem cell marker expression, RS-L cell-derived Notch1 ligand, and common EGFR gene mutations.

Cutaneous Lymphadenoma: A Case Report and Literature Review

“… 48 Another useful marker, AR, which usually showed focal immunoreactivity in BCC, was diffuses strong immunostaining in CL. 3 Trichoblastoma, many reports considered CL similar to trichoblastoma, CL was classified as an adamantoid variant of trichoblastoma in the latest WHO classification. 52 However, there are differences in many aspects: firstly, there are intraepithelial lymphocytes and RS-L cells in CL, but not in trichoblastoma; secondly, the latest research found that although both CL and trichoblastoma were positive for CK15, CL was also positive for AR while the latter was AR negative.…”

“…52 However, there are differences in many aspects: firstly, there are intraepithelial lymphocytes and RS-L cells in CL, but not in trichoblastoma; secondly, the latest research found that although both CL and trichoblastoma were positive for CK15, CL was also positive for AR while the latter was AR negative. 3 Trichoepithelioma, trichoepithelioma is a benign adnexal tumor of follicular germinative derivation. Although could be single, most are multiple and seen in patients with multiple familial trichoepithelioma or Brooke–Spiegler syndrome.…”

“…14 Recent studies showed that CL being a benign tumor with AR and hair follicle bulge stem cell marker (CK15) expression, RS-L cell-derived Notch 1 ligand, and common EGFR gene mutations. 3 It is now considered different with trichoblastoma. Furthermore, EGFR hotspot missense mutations in CL were considered pathogenic, and it was hypothesized that EGFR mutations may provoke a continuous hair follicle stem cell proliferation, and together with the Notch pathway stimulation, responsible for CL tumor growth.…”

“…A recent study showed that CL expressing hair follicle bulge stem cell CK15, PHLDA1 and androgen receptor (AR), considering that CL was a distinct benign lymphoepithelial tumor. 3 Although it exhibits benign biologic behavior, it could resemble closely to other non-melanoma skin cancers both clinically and histologically, there are also cases of recurrence after shave excision and metastasis to regional lymph nodes, so recognition of CL is of great importance. 4 , 5 Here we report a case of CL in an 80-year-old woman.…”

Odontogenic-like neoplasms of the rabbit cheek: pathological features and comparison to cutaneous trichoblastoma and jaw-associated ameloblastoma

“…In addition, other immunohistochemical studies indicate that adamantinoid trichoblastoma derives from stem cells of the hair follicle bulge, expressing CK15 and PHLDA1 . 12…”