Darier's Disease in Gastric Malignancy: An Unusual Paraneoplastic Phenomenon.

Darier's disease is an autosomal dominant genodermatosis resulting from ATP2A2 gene mutation. A 62-year-old male presented at our outpatient (OPD) with sudden-onset numerous dirty, warty papules over the head, neck, and back since 2 months. Histopathology of the skin lesions revealed acantholytic dyskeratosis suggestive of Darier's disease. He was referred to the gastroenterology department for some gastrointestinal (GI) symptoms where he was diagnosed with adenocarcinoma of the stomach and was subsequently operated. On his next visit to our department for follow-up, we found a marked diminution of the skin lesions in the absence of any specific treatment. In view of the above finding, we concluded that paraneoplastic dermatosis in the form of Darier's disease occurred in this patient. Paraneoplastic Darier's disease with gastric adenocarcinoma is not yet described in dermatology literature and is hence reported here.

What was known?

Darier's disease is an autosomal dominant disorder. It is usually not associated with any underlying malignant condition. Again, gastric malignancy is associated with paraneoplastic skin manifestation like tripe palm.

Introduction

Darier's disease is an autosomal dominant disorder of keratinization affecting the skin, mucosa, and nails that typically manifests in the first and second decade of life.[1] Its association with underlying malignancy is extremely rare. We describe an elderly man with nonmetastatic gastric adenocarcinoma presenting with an acquired variant of Darier's disease presumably of paraneoplastic origin.

Case Report

A 62-year-old Muslim farmer was in otherwise good health until 2 months back when he suddenly started noticing some dark-colored, mildly itchy skin eruption. He also complained of nausea, vomiting, and loss of appetite and a single episode of passage of black, tarry stool.

On examination of his skin, numerous hyperpigmented, warty papules were seen over the face, neck, trunk, and scalp. The lesions were characteristically distributed in seborrheic areas like head–neck area, back, and front of chest [Figure 1]. There was punctate keratoderma of palms and soles with a few palmar pits as well [Figure 2]. The oral mucosa was normal. The nails showed a ‘V’-like notch at the free edge of the nail plate without longitudinal streaks. On the basis of these clinical features, our provisional diagnosis was Darier's disease. The complete hemogram was unremarkable except a hemoglobin level of 9 mg/dL. His blood sugar, liver, and renal function tests were within normal limits. Chest X-ray was unremarkable. There was neither a past history of similar lesions nor any family history of the same.

Figure 1

Dirty, warty papules over the back

Figure 2

Palms showing pits and keratoderma

Histopathology of the skin lesions revealed suprabasal acantholytic cleft and dyskeratotic cells like corps ronds and grains [Figure 3a and b]. Corroboration of clinical with histopathology findings suggested a diagnosis of Darier's disease.

Figure 3

Diminution of lesions following tumor resection (a) on back; (b) on chest and palm

He was referred to the gastroenterology department where after a series of investigations including endoscopic biopsy, he was diagnosed with gastric adenocarcinoma.

On his next follow-up in our outpatient department (OPD) 2 months later, we discovered that the skin lesions had remarkably diminished [Figure 4a and b]. By that time, the gastric tumor had already been excised by the surgical gastroenterologists. It was then that we retrospectively considered Darier's disease to be a paraneoplastic phenomenon.

Figure 4

Histopathology showing (a) prominent hyperkeratosis and suprabasal acantholytic cleft with villi (H and E, ×100); (b) dyskeratotic cells (H and E, ×400)

Discussion

Paraneoplastic dermatoses describes those benign skin changes in which there is a direct, often parallel course of a dermatosis with an underlying malignancy.[2] Their presence serves as an important marker of potentially associated neoplasm. Usually, these lesions subside following treatment of the cancer. There are several proposed hypotheses on the pathomechanism of paraneoplastic dermatoses, which highlight the role of various tumor-derived growth factors like transforming growth factor β (TGF-β), fibroblast growth factor, and so on.[3] TGF-β promotes the production of extracellular matrix proteins and inhibits their breakdown.[4] Regarding the pathogenesis of paraneoplastic Darier's disease, it can be speculated that the tumor product interferes with keratinocyte calcium homeostasis leading to disturbances in intracellular trafficking of desmosomal proteins. The autosomal dominant variety is due to mutations in the SERCA2 (sarco/endoplasmic reticulum calcium ATPase type 2), which regulates calcium homoestasis in the endoplasmic reticulum.[5] Our case involves an acquired form of Darier's disease whose diagnosis was supported both clinically and histopathologically. Although there are several variants of Darier's disease, the paraneoplastic variety is extremely rare. There is only a single case report on its association with metastatic papillary carcinoma of thyroid.[6] There are some sporadic reports on the occurrence of squamous cell carcinoma of skin, nail bed, esophagus, mouth, and vagina in patients with pre-existing Darier's disease but paraneoplastic association is very rare.[1] According to the criteria proposed by Helen Ollendorff Curth, a specific dermatosis occurs with a specific neoplasm, and a high percentage of association between two conditions is noted.[7] This does not hold true in our case. The paraneoplastic dermatoses that have been reportedly associated with gastric adenocarcinoma are acanthosis nigricans, tripe palms, and florid cutaneous papillomatoses.[8]

We consider this a paraneoplastic process due to its concurrent onset and almost parallel course with malignant neoplasm, which are also important requisites in the Curth criteria. Moreover, in this case, onset of Darier's disease was late, occurring in the seventh decade of life in contrast to its usual onset in the second decade of life. Also the skin changes resolved with treatment of the underlying cancer. This further served as an eye-opener for the clinical investigators of this case. Its paraneoplastic association with gastric adenocarcinoma is very unusual and not known to be mentioned in any dermatology literature so far and hence reported here.

What is new?

Darier's disease is an unusual paraneoplastic manifestation in gastric malignancy, not reported before.