Beyond the "3 Ps": A critical appraisal of the non-endocrine manifestations of multiple endocrine neoplasia type 1

Abstract

Multiple endocrine neoplasia type 1 (MEN1), an autosomal-dominantly inherited tumor syndrome, is classically defined by tumors arising from the "3 Ps": Parathyroids, Pituitary, and the endocrine Pancreas. From its earliest descriptions, MEN1 has been associated with other endocrine and non-endocrine neoplastic manifestations. High quality evidence supports a direct association between pathogenic MEN1 variants and neoplasms of the skin (angiofibromas and collagenomas), adipose tissue (lipomas and hibernomas), and smooth muscle (leiomyomas). Although CNS tumors, melanoma, and, most recently, breast cancer have been reported as MEN1 clinical manifestations, the published evidence to date is not yet sufficient to establish causality. Well-designed, multicenter prospective studies will help us to understand better the relationship of these tumors to MEN1, in addition to verifying the true prevalence and penetrance of the well-documented neoplastic associations. Nevertheless, patients affected by MEN1 should be aware of these non-endocrine manifestations, and providers should be encouraged always to think beyond the "3 Ps" when treating an MEN1 patient.

Keywords: MEN1; angiofibroma; breast cancer; collagenoma; ependymoma; leiomyoma; lipoma; meningioma.

Figure 1

Facial angiofibromas as seen in a 39-year-old woman (A), 14-year-old girl (B), 48-year-old man (C), and 43-year-old man (D) with multiple endocrine neoplasia type 1. Angiofibromas are telangiectatic, skin colored to pink to red-brown, dome-shaped papules that are histologically characterized by fibrous tissue and vascular proliferation. They are distributed primarily on the central part of the face, especially the nose.

Figure 2

Multiple endocrine neoplasia type 1-associated collagenomas, which are benign connective tissue nevi with a dominant collagen component. They are hypopigmented or skin-colored and usually found on the neck, shoulder, and trunk. (A) 46-year-old woman with multiple collagenomas in addition to pigmented nevi on the arm. (B) 46-year-old man with innumerable collagenomas on the back. (C) 33-year-old man with multiple peri-umbilical collagenomas. (D) 46-year-old man with truncal collagenomas.

Figure 3

Lipomas in patients with multiple endocrine neoplasia type 1. Lipomas are benign tumors made of mature adipocytes that can arise from anywhere that fat is located. (A) 62-year-old man with a subcutaneous lipoma located over the spine in the mid back. Also seen is an adjacent surgical scar related to the prior resection of a large lipoma and scattered collagenomas. (B) 49-year-old woman with multifocal intramuscular lipomas, including a large posterior thigh lipoma as seen on axial T1-weighted pre- (left panel) and post-contrast (right) magnetic resonance imaging. (C) 16-year-old boy with a mobile soft tissue mass arising over the lower anterior chest. Ultrasound showed a 3.7 cm lesion consistent with lipoma. (D) 25-year-old man with a 3.6 cm lipoma (arrows) in the right scalene muscle, adjacent to the right thyroid lobe, as seen on contrast-enhanced computed tomography.

Figure 4

Leiomyoma (LMA). A 41-year-old man with MEN1 presented with an enlarging, painless perineal swelling. Magnetic resonance imaging (Left panel: contrast–enhanced sagittal T1-weighted fat suppressed image; right panel: axial T2-weighted fat suppressed image) identified a 5.8 x 2.6 x 3.8 cm mass in the perineum abutting the crus of the penis and the bulbous urethra. The mass was completely excised and histologic evaluation confirmed a leiomyoma. Somatic testing of the leiomyoma revealed the known germline pathogenic MEN1 variant and evidence for biallelic loss (loss of heterozygosity) at chromosome 11q (next-generation sequencing performed by Foundation Medicine; Cambridge, Massachusetts, USA).