The ever-changing world of nevus sebaceus

By Warren R. Heymann, MD, FAAD
Sept. 14, 2022
Vol. 4, No. 37

The aphorism in medical education that half of what you learn in medical school will prove to be wrong could use the nevus sebaceus (sebaceous) of Jadassohn as its poster child.

First described by Jadassohn in 1895, nevus sebaceus (NS) is a common lesion, affecting 0.3% of newborns. It is a benign congenital hamartoma related to abnormalities of the epidermis, sebaceous glands, sweat glands, and hair follicles. Lesions characteristically present at birth as a well-demarcated hairless, yellowish patch or plaque. NS become more prominent during puberty, reflecting sebaceous growth, often becoming verrucous. NS appear mostly on the scalp and the face. Secondary neoplasms — mostly benign and occasionally malignant — can develop within NS, usually in adulthood. (1,2) Larger lesions in a Blaschkoid distribution are observed in the epidermal nevus syndrome known as the Schimmelpenning-Feuerstein-Mims syndrome (SFM), associated with extracutaneous abnormalities of the eyes (strabismus, colobomas, lipodermoids), central nervous system (structural brain abnormalities, seizures), and skeleton (craniofacial, limb deformities). (3,4)

NS is not an inherited disorder — it is due to post-zygotic mutations in the RAS/MAP kinase pathway (a mosaic “RASopathy”) responsible for transmitting extracellular growth factor signals to the nuclear transcription cascade, affecting cellular growth, apoptosis, and differentiation. (5) HRAS and KRAS mutations are typically reported in NS and SFM. (3,5) Theiler et al reported specific post-zygotic mutations in the transmembrane domain of FGFR2 in 6 of 8 children with a cerebriform NS (with 4 of the 8 patients demonstrating a papillomatous and pedunculated appearance). No cases in this series displayed features of SFM syndrome. One patient had an attendant syringocystadenoma papilliferum (SCP). Post-zygotic mutations in FGFR2 have also been identified in mosaic forms of acne, keratinocytic epidermal nevi, nevoid acanthosis nigricans/rounded and velvety epidermal nevus (RAVEN). (6)

An area of ongoing controversy revolves around the risk of secondary neoplasms within a NS. As a dermatology resident in the early 1980s, the risk of developing a basal cell carcinoma (BCC) was considered considerable (I vaguely recall learning that it was in the 30% range). In 1998, Karnbach et al reported a case of a trichoblastoma appearing in a NS along with a syringocystadenoma papilliferum (SCP) in a 43-year-old man. (7) It is likely that many tumors called BCCs were probably benign trichoblastomas. Additional benign neoplasms such as trichoepithelioma (8), tubular apocrine adenomas (9), sebaceomas (1), and others have been reported within NS. Rarely, other malignancies such as sebaceous carcinoma, microcystic adnexal carcinoma, and melanoma may complicate NS. (2)

Idriss and Elston retrospectively reviewed 706 patients (707 specimens) with NS. Trichoblastoma was the most frequent benign tumor (n = 52, 7.4%) followed by SCP (n = 33, 5.2%). Malignant tumors were present in 2.5% of the specimens with BCC being the most common (n = 8, 1.1%) followed by squamous cell carcinoma (n = 4, 0.57%). The incidence of secondary neoplasms was statistically related to age and anatomic site (P < .05). Almost all malignant tumors were seen in adults. The authors concluded: “Our study confirms that most of the secondary neoplasms arising in association with nevus sebaceus are benign. As no malignant tumors were seen in children, we believe it is reasonable to delay surgical management until adolescence.” (9) In their retrospective review of 450 cases of NS from Taiwan, Hsu et al reported 38 secondary neoplasms, accounting for 8.5% of all cases. Benign tumors represented more than 80% of all tumors. SCP (2.7%) was the most common benign tumor, followed by trichoblastoma (1.6%) and trichilemmoma (1.6%) whereas BCC (0.9%) was the most frequent malignant tumor on NS and its clinical features were not typical. All the malignant tumors on NS were noted only in adulthood and the mean age of those with BCC was significantly older than that of trichoblastoma (P = 0.028). The authors concluded that malignant transformation is rare in NS, occurring uniquely in adulthood. They suggest that prophylactic excision of NS can be elective during childhood but is strongly advocated at puberty due to the increased risk of malignant transformation with time. (10)

The cornerstone of managing patients with NS is education about the natural history of the lesion, with the understanding that changes during childhood are highly unlikely. If changes appear within lesions (aside from the expected pubertal thickening), biopsies can be performed. Should the family decide to have the lesion excised prophylactically, this can be delayed until after puberty or during adulthood, when the lesion can be excised with local anesthesia. Superficial procedures such as shave removal, dermabrasion, or laser resurfacing are not recommended because the entire lesion is not removed. (2) In an intriguing development worthy of more study, Zhou and Antaya demonstrated that topical 1% sirolimus cream flattened lesions in 4 of 5 patients with NS and epidermal nevi. (11). For patients with extensive NS, a multidisciplinary assessment for the SFM syndrome is warranted.

In conclusion, compared to my residency days, dermatologists may now be even more reassuring to patients and their families about long-term outcomes, presenting a rational approach for managing NS. Understanding the molecular biology of NS allows medical management to be on the horizon to potentially prevent secondary neoplasms within these lesions.

Point to Remember: Nevus sebaceus is a common lesion with a small risk of developing secondary malignancies, with basal cell carcinomas being most likely. This complication is almost exclusively seen in adults, allowing patients (and parents) to take their time before deciding when (or if) prophylactic surgery is warranted. Understanding the molecular pathogenesis of NS has allowed topical agents such as sirolimus to be utilized thereby improving the appearance of NS. More study is warranted to determine if development of secondary neoplasms can be obviated.

Our expert’s viewpoint

Richard J. Antaya, MD, FAAD
Professor, Dermatology, Pediatrics, and Nursing
Yale University School of Medicine

All birthmarks, including nevus sebaceus, are caused by somatic mutations during embryonic or fetal development. Our understanding of the genetic basis of many diseases, including birthmarks and malformations, has exploded over the past several decades, translating into significant benefits for our patients. During my career, I have witnessed a nearly complete reversal in the treatment of facial angiofibromas (AF) associated with tuberous sclerosis complex (TSC). In the 1990s, AFs were treated primarily with laser destruction; with vascular lasers for early lesions and ablative lasers as the angiofibromas became more fibrotic. TSC results from activating mutations in hamartin or tuberin. These molecules form the TSC protein complex, which acts as an inhibitor of the target of rapamycin (mTOR) signaling pathway. Topical application of sirolimus, an mTOR inhibitor, results in significant reductions in and prevention of AF formation and has supplanted destructive modalities for TSC associated-facial angiofibromas. Topical sirolimus cream has also been useful in the control of superficial microcystic lymphatic malformations.

While not likely the best choice for nevus sebaceus, application of sirolimus cream, an mTOR inhibitor, may exert some effect on the activated RAS/MAP kinase pathway in these lesions. As our understanding of the mutations and the affected pathways responsible for birthmarks increases, our ability to identify targets and inhibitors will also. We are now taking our first “baby” steps on this exciting journey to discover new therapeutics for birthmarks and malformations.

1. Fathaddin A, Almukhadeb E. A Rare Occurrence of Sebaceous Carcinoma, Sebaceoma, Syringocystadenoma Papilliferum, and Trichoblastoma in a Single Nevus Sebaceous Lesion. Case Rep Dermatol. 2021 Jun 8;13(2):271-277. doi: 10.1159/000516351. PMID: 34177517; PMCID: PMC8215995.

2. Baigrie D, Troxell T, Cook C. Nevus Sebaceus. 2020 Nov 20. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 29494100.

3. Luo Q, Zhang Q, Shen J, Guan W, Li M, Zhang J, Tan Z. Expanding mutational spectrum of HRAS by a patient with Schimmelpenning-Feuerstein-Mims syndrome. J Dermatol. 2021 Aug;48(8):1273-1276. doi: 10.1111/1346-8138.15922. Epub 2021 Jun 9. PMID: 34109654.

4. Nicholson CL, Daveluy S. Epidermal Nevus Syndromes. 2021 Jun 20. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 32644429.

5. Kapoor S, Scanga HL, Reyes-Múgica M, Nischal KK. Somatic KRAS mutation affecting codon 146 in linear sebaceous nevus syndrome. Am J Med Genet A. 2021 Jul 13. doi: 10.1002/ajmg.a.62422. Epub ahead of print. PMID: 34254724.

6. Theiler M, Weibel L, Christen-Zaech S, Carmignac V, Sorlin A, Neuhaus K, Chevarin M, Thauvin-Robinet C, Philippe C, Faivre L, Vabres P, Kuentz P. Cerebriform sebaceous nevus: a subtype of organoid nevus due to specific postzygotic FGFR2 mutations. J Eur Acad Dermatol Venereol. 2021 Oct;35(10):2085-2090. doi: 10.1111/jdv.17319. Epub 2021 May 22. PMID: 33930231.

7. Karnbach C, Neuber K, Diaz-Cascajo C, Steinkraus V. Syringocystadenoma papilliferum und Trichoblastom innerhalb eines Naevus sebaceus [Syringocystadenoma papilliferum and trichoblastoma within a sebaceous nevus]. Hautarzt. 1998 Aug;49(8):654-6. German. doi: 10.1007/s001050050804. PMID: 9759568.

8. Chahboun F, Eljazouly M, Elomari M, Abbad F, Chiheb S. Trichoblastoma Arising From the Nevus Sebaceus of Jadassohn. Cureus. 2021 May 29;13(5):e15325. doi: 10.7759/cureus.15325. PMID: 34235008; PMCID: PMC8240673.

9. Idriss MH, Elston DM. Secondary neoplasms associated with nevus sebaceus of Jadassohn: a study of 707 cases. J Am Acad Dermatol. 2014 Feb;70(2):332-7. doi: 10.1016/j.jaad.2013.10.004. Epub 2013 Nov 20. PMID: 24268309.

10. Hsu MC, Liau JY, Hong JL, Cheng Y, Liao YH, Chen JS, Sheen YS, Hong JB. Secondary neoplasms arising from nevus sebaceus: A retrospective study of 450 cases in Taiwan. J Dermatol. 2016 Feb;43(2):175-80. doi: 10.1111/1346-8138.13070. Epub 2015 Sep 12. PMID: 26361884.

11. Zhou AG, Antaya RJ. Topical sirolimus therapy for nevus sebaceus and epidermal nevus: A case series. J Am Acad Dermatol. 2021 Aug 21:S0190-9622(21)02365-3. doi: 10.1016/j.jaad.2021.08.029. Epub ahead of print. PMID: 34428533.

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