Case Reports

Primary Cutaneous Apocrine Carcinoma Arising Within a Nevus Sebaceus

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References

Comment

Presentation
Nevus sebaceus is the most common adnexal tumor and is classified as a benign congenital hair follicle tumor that is located most commonly on the scalp but also occurs on the face and neck.1 The lesions usually are present at birth but also can develop during the first year of life.2 Diagnosis may be later, during adolescence, when patients seek medical attention during the lesion’s rapid growth phase.1 Nevus sebaceus also is known as an organoid nevus because it may contain all components of the skin. It was originally identified by Jadassohn in 1895.3 It presents as a yellowish, smooth, hairless patch or plaque in prepubertal patients. During adolescence, the lesion typically becomes more yellowish, as well as papillomatous, scaly, or warty. The reported incidence of NS is 0.05% to 1% in dermatology patients.2

Differential
Nevus sebaceus also is a component of several syndromes that should be kept in mind, including Schimmelpenning-Feuerstein-Mims syndrome, which presents with neurologic, skeletal, genitourinary, cardiovascular, and ophthalmic disorders, in addition to cutaneous features. Others include phacomatosis pigmentokeratotica, didmyosis aplasticosebacea, SCALP syndrome (sebaceus nevus, central nervous system malformations, aplasia cutis congenita, limbal dermoid, and pigmented nevus), and more.4,5

Etiology
The etiology of NS has not been completely determined. One study that evaluated 44 NS tissue samples suggested the presence of human papillomavirus (HPV) in NS formation, finding that 82% of NS lesions studied contained HPV DNA. From these results, Carlson et al6 suggested a possible maternal transmission of HPV and infection of ectodermal cells as a potential cause of NS; however, this hypothesis was soon challenged by a study that showed a complete absence of HPV in 16 samples via histological evaluation and polymerase chain reaction for a broad range of HPV types.7 There were investigations into a patched (PTCH) deletion as the cause of NS and thus explained the historically high rate of secondary BCC.8 Further studies showed no mutations at the PTCH locus in trichoblastomas or other tumors arising from NS.9,10

More recent studies have recognized HRAS and KRAS mutations as a causative factor in NS.11 Nevus sebaceus belongs to a group of syndromes resulting from lethal mutations that survive via mosaicism. Nevus sebaceus is caused by postzygotic HRAS or KRAS mutations and is known as a mosaic RASopathy.12 In fact, there is growing evidence to suggest that other nevoid proliferations including keratinocytic epidermal nevi and melanocytic nevi also fall into the spectrum of mosaic RASopathies.13

Staging
There are 3 clinical stages of NS, originally described by Mehregan and Pinkus.14 In stage I (historically known as the infantile stage), the lesion presents as a yellow to pink, smooth, hairless patch. Histologic features include immature hair follicles and hypoplastic sebaceous glands. In stage II (also known as the puberty stage), the lesion becomes more pronounced. Firmer plaques can develop with hyperkeratosis. Hormonal changes cause sebaceous glands to develop, accompanied by epidermal hyperplasia and maturation of apocrine glands. Stage III (the tumoral stage) is a period that various neoplasms have the highest likelihood of occurring. Nevus sebaceus in an adolescent or adult demonstrates mature adnexal structures and greater epidermal hyperplasia.2,4,15

Malignancy
By virtue of these stages of NS development, malignant transformation is expected most often during stage III. However, cases have been reported of malignant tumor development in NS in children before puberty. Two case reports described a 7-year-old boy and a 10-year-old boy diagnosed with a BCC arising from an NS.16,17 However, secondary BCC formation before 16 years of age is rare. Basal cell carcinoma arising from an NS has been commonly reported and is the most common malignant neoplasm in NS (1.1%).2,3 However, the most common neoplasm overall is trichoblastoma (7.4%). The second most common tumor was syringocystadenoma papilliferum, occurring in approximately 5.2% of NS cases. The neoplasm rate in NS was found to be proportional to the patient age.2,18 Multiple studies have shown the overall rate of secondary neoplasms in NS to be 13% to 21.4%, with malignant tumors composing 0.8% to 2.5%.2,15,19 Other neoplasms that have been reported include keratoacanthoma, trichilemmoma, sebaceoma, nevocellular nevus, squamous cell carcinoma, adnexal carcinoma, apocrine adenocarcinoma, and malignant melanoma.19-21

It is argued that the reported rate of BCC formation is overestimated, as prior studies incorrectly labeled trichoblastomas as BCCs. In fact, the largest studies of NS from the 1990s revealed lower rates of malignant secondary tumors than previously determined.4

The identification of apocrine adenocarcinoma tumors arising from NS is exceedingly rare. A study performed by Cribier et al19 in 2000 retrospectively analyzed 596 cases of excised NS from 1932 to 1998. No apocrine carcinomas were reported in this study.19 Approximately 12 cases have been previously reported throughout the literature.20-26 Apocrine carcinomas occur most frequently in apocrine-rich areas such as the axillae, external ears, eyelids, and anogenital area. However, in the cases with apocrine carcinomas that developed from NS, the carcinomas have been located almost exclusively on the scalp.23

Histopathology
Histopathologic examination reveals considerable variation in morphology, and an underlying pattern has been difficult to recognize. Unfortunately, some authors have concluded that the diagnosis of apocrine carcinoma is relatively subjective.26 Robson et al26 identified 3 general architectural patterns: tubular, tubulopapillary, and solid. Tubular structures consisted of glands and ducts lined by a single or multilayered epithelium. Tubulopapillary architecture was characterized by epithelium forming papillary folds without a fibrovascular core. The solid morphology showed sheets of cells with limited ductal or tubular formation.26 The most specific criteria of these apocrine carcinomas are identification of decapitation secretion, periodic acid–Schiff–positive diastase-resistant material present in the cells or lumen, and positive immunostaining for gross cystic disease fluid protein-15.27

Robson et al26 reported estrogen receptor positivity and androgen receptor positivity in 62% and 64% of 24 primary apocrine carcinoma cases, respectively. However, whether these markers are as common in NS-related apocrine carcinomas has yet to be noted in the literature. One study reports a case of apocrine carcinoma from NS with positive staining for human epidermal growth factor-2, a cell membrane receptor tyrosine kinase commonly investigated in breast cancers and extramammary Paget disease.22

These apocrine carcinomas do have the potential for lymphatic metastasis, as seen with multiple studies. Domingo and Helwig21 identified regional lymph node metastasis in 2 of its 4 apocrine carcinoma patients. Robson et al26 reported lymphovascular invasion in 4 cases and perineural invasion in 2 of 24 patients studied. However, even in the context of recurrence and regional metastasis, the prognosis was good and seldom fatal.26

Treatment
The most effective treatment of NS is excision of dermal and epidermal components. Excision should be completed with a minimum of 2- to 3-mm margins and full thickness down to the underlying supporting fat.28 Historically, the practice of prophylactic excision of NS was supported by the potential for malignant transformation; however, early excision of NS may be less reasonable in light of these more recent studies showing lower incidence of BCC (0.8%), replaced by benign trichoblastomas.19 In the case of apocrine carcinoma development, excision is undoubtedly recommended, with unclear recommendations regarding further evaluation for metastasis.

Excision also may be favored for cosmetic purposes, given the visible regions where NS tends to develop. Chepla and Gosain29 argued that surgical intervention should be based on other factors such as location on the scalp, alopecia, and other issues affecting appearance and monitoring rather than incidence of malignant transformation. Close monitoring and biopsy of suspicious areas is a more conservative option.

Other therapies include CO2 laser, as demonstrated by Kiedrowicz et al,30 on linear NS in a patient with Schimmelpenning-Feuerstein-Mims syndrome.31 However, this approach is palliative and not effective in removing the entire lesion. Electrodesiccation and curettage and dermabrasion also are not good options for the same reason.4

Occurrence in Children
Nevus sebaceus in children, accompanied by other findings suggestive of epidermal nevus syndromes, should prompt further investigation. Schimmelpenning-Feuerstein-Mims syndrome includes major neurological abnormalities including hemimegalencephaly and seizures.32

Conclusion

Apocrine carcinomas are malignant neoplasms that may rarely arise within an NS. Their clinical identification is difficult and requires histopathologic evaluation. Upon recognition, prompt excision with tumor-free margins is recommended. As a rare entity, little data is available regarding its metastatic potential or overall survival rates. Further investigation is clearly necessary as new cases arise.

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