A rare case of acrokeratosis paraneoplastica (Bazex syndrome) and a literature review

Abstract

Acrokeratosis paraneoplastica is a rare and obligate paraneoplastic dermatosis most commonly associated with squamous cell carcinoma of the upper aerodigestive tract and lung. It has also been linked to adenocarcinomas of the lung, colon, and stomach. However, reports of its association with esophageal adenocarcinoma are exceedingly rare, with only one documented case to date. This condition primarily affects middle-aged White men, with limited cases reported in women. Moreover, its occurrence in the Chinese population is uncommon. We herein present a case of acrokeratosis paraneoplastica in a Chinese woman with primary esophageal adenocarcinoma, along with a review of the relevant literature. To our knowledge, this is the first documented instance of paraneoplastic acrokeratosis associated with esophageal adenocarcinoma in a woman.

Introduction

Acrokeratosis paraneoplastica is a rare and obligatory paraneoplastic dermatosis that is characterized by acral psoriasiform plaques and most commonly associated with squamous cell carcinoma (SCC) of the upper gastrointestinal tract and airways.^1–3 The condition exhibits a male:female predominance of 4:1, with incidence peaking in the seventh decade of life and predominantly affecting White patients.^1,3,4 Skin lesions precede the diagnosis of the neoplasm in 63% of cases, occur concurrently in 21%, and develop subsequent to the diagnosis in 16%. A high index of suspicion for acrokeratosis paraneoplastica should prompt thorough investigation to rule out underlying malignancy.

Case report

A woman in her late seventies presented to the Department of Dermatology at West China Second University Hospital, Sichuan University, on 14 December 2023, with the chief complaint of a progressive rash, weight loss, and difficulty swallowing. The rash had first appeared approximately 8 months prior and was characterized by red, keratinized patches initially affecting the ears, fingers, and toes. She was diagnosed with psoriasis at multiple hospitals and underwent a 6-month treatment regimen involving oral methotrexate, topical calcipotriol, and ultraviolet A therapy; however, no significant improvement was noted. The rash rapidly spread to involve the face, hands, and feet before progressing to the forearms, calves, and buttocks. The patient denied experiencing itching or pain. Additionally, she reported symptoms of dysphagia, odynophagia, chest pain, and weight loss of 6 kg during the past 3 months. She had been previously healthy, with no relevant risk factors or family history of genetic conditions.

Upon physical examination, multiple erythematous scaly plaques and patches resembling psoriasis were symmetrically distributed across various areas of the body, including both ears (Figure 1(a), (b)), face (Figure 1(c)), hips (Figure 1(d)), dorsum of the hands and feet, legs (Figure 1(e)) and neck. Significant palmoplantar hyperkeratosis with sparing of the central regions were also noted (Figure 1(f), (g)). Additionally, roughening, thickening, and discoloration of both great toenails were observed (Figure 1(h)), while the fingernails remained unaffected. Histopathological examination of a specimen collected from the patient’s gluteal region revealed hyperkeratosis, parakeratosis, acanthosis, and perivascular lymphocyte infiltration in the superficial dermis (Figure 2(a)). Because of the persistence of skin manifestations and histopathological findings that did not definitively exclude conditions such as psoriasis, chronic eczema, tinea onychis, or diffuse palmoplantar hyperkeratosis, further diagnostic evaluations were undertaken.

Figure 1.

Symmetrical distribution of scaly erythema and plaques was observed on the (a, b) ears, (c) cheeks, (d) buttocks, and (e) legs. (f, g) Pronounced palmoplantar hyperkeratosis was present and (h) the dorsal surfaces of the hands and feet exhibited similar symptoms, along with toenail dystrophy and subungual hyperkeratosis.

Figure 2.

(a) Histopathological analysis of the skin biopsy revealed hyperkeratosis, parakeratosis, acanthosis, and perivascular lymphocyte infiltration in the superficial dermis. (b) Gastroscopy identified an irregular mass in the esophageal wall. (c) Further biopsy of the mass showed tumor cells arranged in adenoid and sheet-like structures. (d) The tumor cells exhibited increased volume, enlarged and hyperchromatic nuclei, prominent nucleoli, and evidence of localized nuclear division. Hematoxylin–eosin staining, magnification: (a) ×40, (c) ×100 and (d) ×200.

Mycological analysis of toenail samples ruled out the presence of fungal infection. Given the patient’s persistent dysphagia and weight loss, further diagnostic tests were conducted. Gastroendoscopy revealed a mass in the middle and lower segments of the esophageal wall (Figure 2(b)), raising suspicion for esophageal cancer. Biopsy results confirmed the diagnosis of esophageal adenocarcinoma (Figure 2(c), (d)). Positron emission tomography-computed tomography imaging further identified widespread metastatic involvement in the liver, left lung, and cervical lymph nodes.

The patient was ultimately diagnosed with synchronous esophageal adenocarcinoma with multiple metastases, accompanied by acrokeratosis paraneoplastica. Despite receiving treatment recommendations, the patient’s family opted to discontinue all medical interventions. Consequently, the patient succumbed to advanced multiorgan failure 3 months after the initial diagnosis.

This case report adheres to the relevant CARE guidelines for case reports. ⁶ Written informed consent for publication was obtained from the patient.

Discussion

Acrokeratosis paraneoplastica was first documented by Gougerot and Rupp ⁷ in 1922 and later attributed to Andre Bazex, ⁸ who identified a correlation between psoriasiform cutaneous manifestations and SCC originating from the piriform fossa. This condition is a rare paraneoplastic dermatosis, with fewer than 200 cases reported in the literature. The majority of affected individuals are White and over the age of 40 years.^3,9 Notably, only two cases have been reported in the Chinese population.^10,11 Acrokeratosis paraneoplastica also exhibits a marked male predominance, with approximately 86% of cases occurring in males; reports in female patients remain relatively scarce.^4,12,13 This sex disparity is likely linked to higher rates of alcohol and tobacco consumption among men, both of which are significant risk factors for the condition. ³

The precise etiology and its correlation with malignancy remain poorly understood. Proposed mechanisms include potential cross-reactivity between tumor antibodies and basement membrane antigens, a cytotoxic cellular immune response, tumor-derived growth factors (such as transforming growth factor α, epidermal growth factor, or insulin-like growth factor 1) inducing hyperkeratosis, and deficiencies in zinc and vitamin A due to tumor growth.^1,2,14

Acrokeratosis paraneoplastica is closely associated with various internal malignancies, particularly SCC of the upper aerodigestive tract, including the pharynx, larynx, and esophagus.^1–3 It is also linked to SCC of the lung and adenocarcinomas of the gastrointestinal tract.^2,4,9,15 Other cancers associated with acrokeratosis paraneoplastica include metastatic breast carcinoma, ¹⁴ lymphoma,^10,16,17 tonsillar adenocarcinoma, ¹⁸ pancreatic adenocarcinoma, ¹³ and cervical SCC. ¹⁹ To date, only one documented case has linked acrokeratosis paraneoplastica with esophageal adenocarcinoma. ²⁰ Skin lesions frequently, although not always, precede the diagnosis of an associated malignancy, typically appearing approximately 11 months prior. ² As a result, acrokeratosis paraneoplastica has been proposed as a significant cutaneous marker of underlying neoplasms, highlighting the importance of early recognition to facilitate timely and effective therapeutic intervention.^1,2,4,12

Acrokeratosis paraneoplastica is characterized by symmetrical scaly plaques and/or patches, ranging in color from red to violaceous and resembling psoriatic eruptions. In the early stages, lesions typically appear on acral sites such as the helix of the ears, nose, fingers, and toes. ¹⁵ Concurrently, nonspecific nail changes, including thickening of the nail plate, subungual hyperkeratosis, longitudinal ridging, onycholysis, and discoloration, often accompany the cutaneous manifestations. ²¹ As the disease progresses, lesions may extend to the palms, soles, and cheeks and, if left untreated, may ultimately affect the extremities and torso. ³ The appearance of rashes often signals the development and spread of underlying malignancies. Thickening of the soles, accompanied by keratotic papules, is a primary diagnostic indicator.^4,12 In some cases, these changes may resemble arsenic keratosis. Additionally, atypical rashes, including bullae, vesicles, and Raynaud’s-like symptoms, have been reported.^12,17,22 The rash is typically asymptomatic; however, in rare cases, patients have experienced pruritus, pain, or a burning sensation, although these symptoms are not believed to be directly related to the underlying tumor.^2,12,23 In our documented case, despite the extensive rash, the patient did not report any pain or pruritus. Differential diagnoses include psoriasis, palmoplantar keratoderma, pityriasis rubra pilaris, and chronic eczema.

While histopathological findings—such as hyperkeratosis, hypokeratosis, acanthosis, dyskeratotic keratinocytes, and vacuolar degeneration—may lack specificity, they play a crucial role in ruling out other diseases with distinct histopathological changes.^1,2,4 Immunofluorescence studies of skin eruptions typically yield negative results; however, some cases have exhibited nonspecific deposits of immunoglobulin A, immunoglobulin G, and complement component 3 along the epidermal basement membrane.^15,24

Active treatment of a patient’s primary malignancy remains the only effective approach to curing acrokeratosis paraneoplastica.^1,3 Skin eruptions generally respond well to oncologic therapy but show limited improvement with traditional dermatological treatments. Nail involvement, however, often persists after tumor treatment.^21,25 The occasional recurrence of skin lesions may serve as an early indicator of tumor relapse. Various treatments—including topical and systemic steroids, oral retinoids, topical vitamin D analogs, salicylic acid, and oral psoralen-UVA phototherapy—have been reported with varying degrees of success in managing the condition.^21,26

Conclusion

The inherent association between acrokeratosis paraneoplastica and underlying malignancies offers valuable insights into the diagnosis of intrinsic tumors. The possibility of acrokeratosis paraneoplastica should be considered in patients with psoriasiform cutaneous lesions appearing at atypical sites, particularly on the ears and nasal tips, and exhibiting resistance to conventional therapies. Prompt management of the associated tumor may lead to complete or partial remission of the dermatological manifestations. Therefore, it is crucial for healthcare professionals to have a thorough understanding of this rare syndrome to facilitate timely recognition and diagnosis of the corresponding neoplastic disorder.

This case is distinguished by several significant factors. First, it represents only the third documented instance of acrokeratosis paraneoplastica in China reported in the English-language literature. Second, esophageal adenocarcinoma as the underlying malignancy in association with acrokeratosis paraneoplastica has been documented in only one previous case. Furthermore, the rarity of this condition in women makes this case particularly noteworthy. To the best of our knowledge, this is the first documented instance of paraneoplastic acrokeratosis associated with esophageal adenocarcinoma in a female patient.