Primary Cutaneous Apocrine Carcinoma and Syringocystadenoma Papilliferum Arising in Nevus Sebaceus: A Case Report and Review of the Literature

Abstract

Nevus sebaceus is a hamartomatous lesion characterized by epidermal, follicular, sebaceus, and apocrine gland abnormalities. Approximately 25% of affected individuals may develop benign or malignant secondary neoplasms within the preceding nevus sebaceus. Primary cutaneous apocrine carcinoma (PCAC) is a rare malignant skin tumor affecting elderly adults in their sixth decade of life. Histologically, PCAC appears as a dermal tumor displaying apocrine differentiation with decapitation secretion and malignant features. Secondary malignancy arising from nevus sebaceus is a rare complication, especially for apocrine carcinoma. To date, approximately 200 cases of PCAC have been reported in the literature, and only a few cases have developed PCAC on the scalp. Very few cases (approximately only 12) of PCACs developing in nevus sebaceus have been reported. Here, we report an extremely rare case of the coexistence of PCAC and syringocystadenoma papilliferum arising within nevus sebaceus of the scalp.

INTRODUCTION

Nevus sebaceus is a hamartomatous lesion characterized by epidermal, follicular, sebaceus, and apocrine gland abnormalities involving the scalp, neck, or face. Approximately 25% of affected individuals may develop benign or malignant secondary neoplasms within the preceding nevus sebaceus. Of those secondary neoplasms, trichoblastoma and basal cell carcinoma are the most common benign and malignant neoplasms, respectively¹.

Syringocystadenoma papilliferum (SCAP) is a rare, benign adnexal neoplasm of apocrine gland origin that usually manifests as a red-to-brown verrucous plaque typically on the scalp. Histopathology typically reveals invagination of the papillary projections covered by two layers: an inner layer of columnar to cuboidal cells with conspicuous decapitation secretion, and an outer layer composed of myoepithelial cells.

Primary cutaneous apocrine carcinoma (PCAC) is a rare malignant skin tumor (incidence, 0.005~0.017 per 100,000 patients per year)². It usually affects elderly adults in their sixth decade of life and most frequently involves the axilla, although cases involving the scalp and anogenital region have been reported³. Histologically, PCAC appears as a dermal tumor displaying apocrine differentiation with decapitation secretion and malignant features, including atypical architecture and cytological atypia. Various architectural patterns, including tubular, tubulopapillary, and solid growth, can be seen. The expression of cytokeratins, as well as gross cystic disease fluid protein (GCDFP-15), carcinoembryonic antigen, epithelial membrane antigen, estrogen receptor, progesterone receptor, and androgen receptor, as seen on immunohistochemical examination may aid in diagnosis.

Secondary malignancy arising from nevus sebaceus is a rare complication, especially for apocrine carcinoma⁴. To date, approximately 200 cases of PCAC have been reported in the literature, and only a few cases have developed PCAC on the scalp⁵,⁶. Very few cases (approximately only 12) of PCACs developing in nevus sebaceus have been reported. Here, we report an extremely rare case of the coexistence of PCAC and SCAP arising within nevus sebaceus of the scalp.

CASE REPORT

A 59-year-old male presented with a red to pink dome-shaped tumor on the scalp. The lesion appeared as an alopecic patch at birth and gradually increased in size over several years. The patient noticed a gradual increase in size and intermittent bleeding in the previous 1 year. Examination revealed a 3.3×2.1×1.5-cm ulcerative growth with a peripheral portion exhibiting a verrucous appearance (Fig. 1). Radiologic workup, including head to abdomen computed tomography, revealed no internal malignancies or evidence of metastasis. Wide local excision of the supragaleal plane was performed with primary skin closure. Histologic examination of the specimen revealed two distinct areas with clear demarcation: one with poorly circumscribed dermal tumors composed of moderately differentiated adenocarcinoma forming trabecular and cribriform structures, and other with invaginating papillations lined by an inner layer with decapitation secretion and an outer layer of myoepithelial cells (Fig. 2A, B). The main tumor showed glandular and ductal structures of variable size lined by a single or multilayered epithelium with prominent decapitation secretion (Fig. 2C). Most lumens contained eosinophilic materials that were positively stained with periodic acid-Schiff (Fig. 2D). Immunohistochemically, tumor cells were positively stained for GATA3, GCDFP-15, and androgen receptor, and negatively stained for cytokeratin 5/6 (Fig. 3). The peripheral margin of the specimen showed mild acanthosis and epithelial papillomatosis. Based on the clinical history, and histologic and immunohistochemical findings, the lesion was diagnosed as PCAC and SCAP arising from nevus sebaceus.

Fig. 1. (A) The 3.3×2.1×1.5-cm sized reddish to pinkish colored dome shaped nodule on the scalp. (B) Top view of the tumor after shaving with defined surgical margin. We received the patient’s consent form about publishing all photographic materials.

Fig. 2. (A) Scan power view of the excised specimen (H&E, ×12). (B) Transitional zone within the tumor showing syringocystadenoma papilliferum (SCAP) on the left and primary cutaneous apocrine carcinoma (PCAC) on the right. PCAC showed multiple tumor nests within the dermis, which are composed of well-to-moderately differentiated adenocarcinoma forming ductal and glandular structures with apocrine differentiation (H&E, ×40). (C) A tumor nests of PCAC showing large cystic space lined by cuboidal cells with abundant eosinophilic cytoplasm, exhibiting decapitation secretion (H&E, ×400). (D) Glandular or ductal lumens containing eosinophilic material positively stained by periodic acid-Schiff (PAS, ×100). We received the patient’s consent form about publishing all photographic materials.

Fig. 3. Immunohistochemistry (IHC) profile of primary cutaneous apocrine carcinoma on the scalp. (A) Negative expression of cytokeratin 5/6 in tumor cells (IHC, ×100). (B) Membranous staining pattern of androgen receptor in tumor cells (IHC, ×100). (C) Weakly positive expression of GATA3 in tumor cells (IHC, ×100). (D) Expression of gross cystic disease fluid protein 15 in tumor nests (IHC, ×100).

DISCUSSION

Nevus sebaceus (nevus sebaceus of Jadassohn, organoid nevus) is a congenital cutaneous hamartoma characterized by epidermal hyperplasia, immature hair follicles, and sweat gland overgrowth. The lesion usually develops at birth, but it is rarely recognized due to its subtle initial manifestations. Nevus sebaceus is thought to undergo three clinical stages, originally described by Mehregan and Pinkus⁷. The lesion first presents as a smooth hairless patch in stage I (the infantile stage) and becomes pronounced with firm plaques and sebaceus gland proliferation under the hormonal influence of puberty in stage II (the pubertal stage). Stage III (the tumoral stage) is a period in which secondary neoplasms have the highest probability of occurrence. The most common benign neoplasm occurring in nevus sebaceus is trichoblastoma (7.4%)⁸, followed by SCAP (5%). Basal cell carcinoma has been reported to be the most common malignant neoplasm in nevus sebaceus (1.1%)¹. According to prior studies, the overall rate of secondary neoplasms in nevus sebaceus was calculated to be 13% to 21.4%. The rate of malignant transformation in nevus sebaceus is exceedingly rare (estimated 0.8%~2.5%)¹,⁹.

Apocrine carcinoma is a secondary malignant neoplasm known to arise within nevus sebaceus. More specifically, those arising within nevus sebaceus are classified as PCACs, which are distinguished from secondary apocrine carcinomas, which are thought to metastasize from other primary malignancies, including breast carcinoma. PCAC is a rare malignancy that typically develops in areas where apocrine glands are abundant, such as the axilla and anogenital region¹⁰. Due to its rare occurrence, its etiologic factors and pathogenesis are poorly understood. However, malignant transformation of nevus sebaceus commonly occurs during stage III, which may partially explain the pathogenesis of PCAC developing on the scalp¹¹. As anomalous apocrine glands begin to develop in stage II or III under the hormonal influence of puberty, some oncogenic events might occur around the apocrine gland, giving rise to PCAC¹¹. To date, 12 cases of PCAC arising from nevus sebaceus have been reported, and all lesions were located on the scalp, including that in our case (Table 1)³,¹¹,¹²,¹³,¹⁴,¹⁵. Compared to PCAC without a preceding lesion, there seems to be a difference in the site of predilection for PCAC arising from nevus sebaceus, which occurs exclusively on the scalp. However, according to one literature review, not all PCACs on the scalp were associated with nevus sebaceus. Only half of all reported cases (12 out of 24 cases) were identified to arise from nevus sebaceus¹⁶. Thus, the pathogenesis of PCAC of the scalp in association with nevus sebaceus is incompletely understood and requires further investigation to clarify the underlying oncopathogenic process.

Table 1. Clinical data of 8 case reports of primary cutaneous apocrine carcinoma arising from nevus sebaceus.

Reference	Age (yr)	Sex	Size (cm)	Time evolved, growth	Location	Coexistent tumor	Recurrence or Metastases	Outcome (follow-up)	Immunohistochemistry profile
Domingo and Helwig (1979)12	77	M	2×1.2	1.5 mon	Scalp	-	LN cervical (6 mon) LR (1.5 yr)	AWD (1.5 yr)	-
Domingo and Helwig (1979)12	63	F	1.5	Birth	Scalp	-	NED	NED (6 yr)	-
Domingo and Helwig (1979)2	68	F	0.7	Unknown	Scalp	-	NR	LTF	-
Domingo and Helwig (1979)12	65	M	7	Birth, 1 mon growth	Scalp	-	LN post-auricular, cervical, and supraclavicular (6 mon) Metastasis, bone (9 mon)	DWD (2 yr)	-
Jacyk et al. (1998)13	53	F	4×1	Since childhood, few months growth	Scalp	Syringocystadenoma papilliferum	NED	NED (1 yr)	MNF-116 (+)/luminal border: EMA(+), CEA(+), GCDFP-15(+)
Dalle et al. (2003)14	66	M	0.8	Birth, 6 mon growth	Scalp	-	NR	NR	CEA(+), EMA(+), CK7(+), CD15 (Leu-M1)(+)
Robson et al. (2008)3	NR	NR	NR	NR	Scalp	NR	NR	NR	-
Tanese et al. (2010)11	70	M	2	2 mon	Scalp	-	NR	NR	p53(+), HER-2(+), ER(–), PR(–), AR(–)
Paudel et al. (2012)4	45	M	2×2	Since childhood, 4 mon growth	Scalp	-	NR	NR	-
Edgar et al. (2018)15	76	F	2.5	2 mon	Scalp	Trichoblastoma	NED	NED (10 mon)	CEA(+), EMA(+), CK7(+)
Kim et al. current report	59	M	3.3×2.1×1.5	Unknown, 1 yr growth	Scalp	Syringocystadenoma papilliferum	NED	NED (6 mon)	GATA3(+), GCDFP-15(+), AR(+), CK5/6(–)

M: male, F: female, LN: lymph node, LR: local recurrence, AWD: alive with disease, NED: no evidence of disease, LTF: lost to follow-up, DWD: died with disease, NR: not reported, EMA: epithelial membrane antigen, CEA: carcinoembryonic antigen, GCDFP-15: gross cystic disease fluid protein 15, HER-2: human epidermal growth factor receptor 2. Editing of the table that was done by Brown et al. (Glob Dermatol 2016;3:356-360)² with original copyright holder's permission.

In terms of diagnosis, histopathologic features of PCAC exhibit considerable variations in morphology. Although Robson et al. defined three general architectural patterns (tubular, tubulo-papillary, and solid), the diagnostic value of histopathologic examination is limited. To date, the most specific criteria for diagnosing PCAC include decapitation secretion, periodic acid-Schiff-positive diastase-resistant material present in the cells or lumen, and positive immunostaining for GCDFP-15¹⁷.

There have been several attempts to identify pathognomonic immunohistochemical markers that are highly correlated with PCAC³. Although some markers have been suggested to be useful tools for differentiating PCAC from other apocrine neoplasms, they were not as powerful as GCDFP-15 in diagnosis. GATA3, typically expressed in adnexal tumors of sebaceus and apocrine differentiation, has been suggested as a useful marker for differentiating primary cutaneous apocrine cribriform carcinoma from metastatic breast carcinoma¹⁸. Our case had positive staining for GATA3, but no internal malignancies, including breast cancer, were identified, which is inconsistent with previous results. However, the diagnostic value of GATA3 for differentiating PCAC remains uncertain.

Robson et al.³ reported the usefulness of hormone receptors for diagnosing PCAC, finding that estrogen and androgen receptors were expressed in 62% and 64% of 24 cases, respectively. However, hormone receptor staining in PCAC associated with nevus sebaceus has yet to be explored in the literature. Only one out of 12 nevus sebaceus-related PCAC cases revealed negative staining for all three hormone receptors (estrogen, progesterone, and androgen)¹¹, while the remaining cases did not undergo staining for hormone receptors. Our case had positive staining for the androgen receptor.

Our case presented with the coexistence of SCAP and PCAC within the nevus sebaceus. As the patient reported an alopecic patch since birth and histological examination revealed diffuse papillomatosis, it is highly likely that nevus sebaceus existed as a primary skin lesion. SCAP and PCAC may have independently developed from nevus sebaceus. In other words, PCAC arising from SCAP is highly unlikely for the following reasons. First, there has been no report of apocrine carcinoma secondarily developed from SCAP. Very rare cases of syringocystadenocarcinomas are reported to arise from SCAP through malignant transformation¹⁹. Second, SCAP is the second most common benign tumor arising from the nevus sebaceus (5%), and one third of SCAP is known to be associated with nevus sebaceus²⁰.

In the prior literature, there were two reports of PCAC accompanying another coexisting tumor within the nevus sebaceus, one including SCAP and the other including trichoblastoma (Table 1). The cases accompanying another secondary neoplasm within nevus sebaceus were at the age of 65 and 76 years respectively. Multiple tumors in addition to PCAC may develop in nevus sebaceus in older age, as the neoplasm rate in nevus sebaceus was proportional to the patient age¹,⁸.

In conclusion, we report an exceedingly rare case of PCAC arising from nevus sebaceus. This is the second case report of PCAC accompanying SCAP arising from nevus sebaceus in the literature. This case supports one mechanism of pathogenesis for PCAC on the scalp where almost 50% of cases PCAC on the scalp develop due secondary malignant transformation from a preceding nevus sebaceus, which occurs under the influence of anomalous sweat gland transformation and hormonal change during puberty.