An unusual presentation of rare genodermatosis: Syringocystadenoma papilliferum with squamous cell carcinoma complicating hypertrophic Darier disease

INTRODUCTION

Darier’s disease (DD), or keratosis follicularis or Darier-White disease, is a rare autosomal dominant genodermatosis with abnormal keratinization and loss of epithelial adhesion.^[1,2] It is characterized by hyperkeratotic papules in seborrhoeic areas, with less frequent hypertrophic/vegetative lesions over flexures.^[2] We here report a case of hypertrophic DD with verruciform growth showing syringocystadenoma papilliferum (SCAP) with squamous cell carcinoma (SCC).

CASE REPORT

A 45-year-old unmarried manual laborer, born to non-consanguineous parents, presented with generalized progressive hyperkeratotic eruptions with a seborrhoeic predilection for 22 years. Lesions aggravated on sun exposure and occasionally malodorous. He had poor treatment compliance and was on carbamazepine and lorazepam for generalized tonic-clonic seizures since age 18. There were no similar illnesses in the family.

Examination revealed generalized hyperkeratotic and hyperpigmented verrucous papules, few coalesced plaques, punctate palmoplantar keratosis with pits, and distal longitudinal splitting of nails [Figures 1 and 2].

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Figure 1

(a): Hyperkeratotic papules predominantly over the intermammary area; (b and c): macerated plaque over the axilla and retroauricular area, respectively; and (d): hyperkeratotic papules over the scalp.

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Figure 2:

Punctuate keratosis over the (a): palms; (b): soles; (c): distal longitudinal splits of the right toenails; and (d) dorsum of left hand, respectively.

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The patient gradually developed painful proliferative warty growths of bilateral groins [Figure 3] over 4 years, without lymphadenopathy or systemic illnesses. His baseline investigations were within normal limits.

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Figure 3

(a): Vegetative growth over both groins; and (b): Close up image of vegetative growth on right side

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A skin biopsy from the forearm showed hyperkeratosis, irregular acanthosis, dyskeratosis, papillomatosis, and mild dermal perivascular lymphocytic infiltrate, consistent with DD [Figure 4].

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Figure 4:

Biopsy from forearm showing (a): hyperkeratosis, dyskeratosis, papillomatosis, and irregular acanthosis (H&E, 40×) and (b): mild perivascular infiltrates in the dermis (H&E, 100×). H&E: Hematoxylin and eosin.

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Wide excision of groin lesions revealed hyperkeratosis, papillomatosis, focal ulceration, and granulation tissue with a foreign body giant cell reaction. Sections showed cystic invaginations lined by keratinized stratified squamous epithelium, papillary projections with bilayered outer columnar and inner cuboidal cells, and stroma rich in plasma cells. Cords and strands of dysplastic cells extend into fibrocellular stroma and muscle bundles. Cells showed moderate eosinophilic cytoplasm with mild pleomorphism. Numerous keratin pearls were seen, suggestive of SCAP with SCC [Figure 5].

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Figure 5

(a): Hypertrophic growth of bilateral groin; (b): biopsy of growth showing papillomatous lesion with bilayered epithelium extending into the dermis (H&E, 40×); and (c): papillomatous area with dysplastic squamous cells and keratin pearls, black arrowkeratin pearls (H&E, 100×). H&E: Hematoxylin and eosin.

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The patient was treated with emollients containing urea and lactic acid and topical steroids with mild relief in symptoms. He was referred to a higher center for further management.

DISCUSSION

Prince Morrow first reported DD (1886) and later described by Darier and White (1889). It is caused by ATP2A2 gene mutation on chromosome 12q, which encodes for sarco/endoplasmic reticulum calcium ATPase pump. However, 47% of patients may lack a family history, possibly due to undiagnosed mild variants.^[1] None of the family members of our patient had features of DD. Epilepsy and mental retardation have been described in some families with DD.^[3] Our patient has been on epilepsy treatment for 22 years.

It presents with characteristic skin-colored to yellow-brown, hyperkeratotic papules over seborrheic areas.^[4] Beerman et al. reported various DD lesions, including hypertrophic forms over flexures.^[5] The hypertrophic or vegetating variant is extremely rare, with few reports including Aliağaoğlu et al. (2006), Pezzini et al. (2015), widespread anogenital involvement by Ji et al. (2018), and a verruciform mass described by Cardoso et al. (2022).^[6-9] Typical nail features include fragility, painful longitudinal splits, red and white longitudinal bands, and V-shaped nicks. Palmoplantar pits or keratoses are common.^[3] Cobblestone-like oral lesions occur in 15–50% of cases.^[4] Ocular manifestations include chronic blepharitis, dry eyes, corneal erosions, and endophthalmitis.^[3] Our patient presented with classic cutaneous and nail changes with no oral or ocular lesions.

Key histologic characteristics of DD are aberrant epidermal keratinization and defective keratinocyte adhesion, followed by dyskeratosis, acantholysis, elongated papillae, focal parakeratosis, and hyperkeratosis.^[2] Corps ronds are basophilic dyskeratotic cells in the stratum granulosum, and grains are shrunken cells in the stratum corneum.^[3] A study by Manohar et al. revealed that follicular acantholysis was present in 13% of patients and not all dyskeratotic cells could be classified into corps ronds and grains.^[10] Histopathology in our patient was consistent with these findings.

Beerman (1949) described basal cell proliferation in DD as more noticeable in the vegetative type. In this variant, lacunae in the basal layer are absent, while features suggestive of epitheliomatous transformation are present. Basal cells form elongated, narrow, and tube-or-finger-like projections that extend deep into the dermis, with the thickened basal layer showing frequent mitotic activity.^[5] Hyperkeratosis and papillomatosis were observed in our patient, aligning with previous reports. A foreign body tissue reaction is also observed, possibly due to secondary infection. Along with this, SCAP features were present.

SCAP is associated with sebaceous nevus in 30–75% of head-and-neck cases^[11] and rarely is seen in the chest, limbs, breast, eyelids, axilla, scrotum, inguinal, and perineal areas.^[12] It presents in three clinical types: (i) Plaque type (often linked to sebaceous nevus), (ii) linear type (resembling molluscum contagiosum), and (iii) solitary nodular type (dome-shaped or pedunculated papules with a crusted or friable surface).^[13] SCAP is often described as arising from giant comedo and condyloma acuminata.^[14] In our patient, SCAP developed from hypertrophic lesions of both groins, which is rather a rare site with identical histopathological features in both groins, emphasizing the rarity of this presentation.

Malignant transformation in SCAP is rare, with basal cell carcinoma (BCC) reported in approximately 10% of cases. Nodular SCAP can occasionally mimic BCC clinically. Isolated cases of verrucous carcinoma have been reported with SCAP. Several theories exist regarding the dysplastic transformation of SCAP. SCAP is apocrine in origin rather than eccrine, and pluripotent stem cells may be the source of such tumors. The exact reason is still unclear.^[11] Few histologically confirmed cases of SCC developing in SCAP have been reported in the literature.^[14] A Swedish cohort study conducted in 2024 showed a non-significant tendency for SCC and a significantly elevated risk for BCC in DD. Although rare, SCC in DD might go undiagnosed due to overlapping skin changes. Carcinogenesis may be triggered by ATP2A2 gene mutations affecting calcium regulation and keratinocyte adhesion, as well as by immunosuppressive treatments, trauma, and chronic inflammation.^[15]

In our patient, the coexistence of SCAP and SCC in the context of DD represents a rare and diagnostically challenging presentation. The presence of dysplastic cells and keratin pearls underscores the malignant transformation and highlights the need for long-term monitoring in DD.

CONCLUSION

This case presents a rare form of hypertrophic DD in the groin, complicated by coexisting SCAP and SCC. To the best of our knowledge, this combination has not been previously reported. This case highlights the importance of monitoring chronic or atypical lesions, especially those with vegetative growth.