Acrokeratosis paraneoplastica (Bazex syndrome): Report of a case associated with small cell lung carcinoma and review of the literature

Abstract

Acrokeratosis paraneoplastic (Bazex syndrome) is a rare, but distinctive paraneoplastic dermatosis characterized by erythematosquamous lesions located at the acral sites and is most commonly associated with carcinomas of the upper aerodigestive tract. We report a 58-year-old female with a history of a pigmented rash on her extremities, thick keratotic plaques on her hands, and brittle nails. Chest imaging revealed a right upper lobe mass that was proven to be small cell lung carcinoma. While Bazex syndrome has been described in the dermatology literature, it is also important for the radiologist to be aware of this entity and its common presentations.

CASE REPORT

A 58 year-old African-American female presented to a dermatology clinic with complaints of a hyperpigmented rash on her arms, legs, hands, and feet for the previous 2 years. She had been treated at an outside hospital for a presumed diagnosis of cutaneous lupus erythematosus with oral corticosteroids, hydrocortisone cream, and 8 months of hydroxychloroquine without any significant benefit. Additionally, she reported a 15-pound weight loss over the past year.

The patient has a past medical history significant for hypertension, possible lupus and smoking. She was up to date on health maintenance issues. She had no contributing family history and no known drug allergies. Complete lab work up revealed a positive ANA (homogeneous 1:1640 titer), but was otherwise normal.

Physical exam hyperkeratotic plaques on her hands most prominent over the joints. Her nails appeared brittle and atrophied (Figure 1). She had numerous hyperpigmented macules coalescing into patches in a reticulated pattern distributed over the dorsal arms and lower legs (Figure 2). There was a hyperpigmented, slightly scaly patch on her nose, and oral examination was normal.

Figure 1.

58 year old female with Bazex syndrome who presented with hyperkeratotic plaques on her hands (arrow) and brittle nails (thick arrow). Picture of hand demonstrates hyperkeratotic plaques most prominent over joints. The nails are brittle and atrophied.

Figure 2.

58 year old female with a 2 year history of a hyperpigmented rash over her forearms and legs. Photograph of the leg shows numerous hyperpigmented macules coalescing into patches in a reticulated pattern (arrow). Diagnosis of Bazex syndrome was eventually made after radiologic work up.

Three punch biopsies from the forearm, thigh, and finger were somewhat nonspecific but showed mild epidermal psoriasiform hyperplasia and a superficial perivascular lymphohistiocytic infiltrate with eosinophils and neutrophils (Figure 3). Her direct immunofluorescence was positive for a linear IgG and C3 deposition along the basement membrane. The indirect immunofluorescence was negative.

Figure 3.

58 year old female with Bazex syndrome had a 2 year history of a hyperpigmented rash and underwent punch biopsy of thigh. Biopsy from the right thigh showing mild epidermal acanthosis (arrow) and a superficial perivascular lymphohistiocytic infiltrate (thick arrow). (Hematoxylin and eosin, original magnification 200x)

A chest radiograph revealed an enlarged right hilum suggesting adenopathy (Figure 4). A subsequent contrast enhanced chest CT confirmed the presence a large perihilar soft tissue mass with narrowing of the right upper lobe bronchus and right paratracheal adenopathy with narrowing of the right upper lobe bronchus (Figures 5 and 6). No other discrete lung nodule was seen and only non-specific ground glass opacities were present in the right upper lobe. A CT of the abdomen and pelvis revealed a hypodense focal lesion in the liver consistent with metastatic disease (Figure 6).

Figure 4.

58 year old woman with Bazex syndrome presented with 2 year history of a hyperpigmented rash and a chest radiograph was obtained. Posteroanterior chest radiograph demonstrates enlarged right hilum due to adenopathy (arrow).

Figure 5.

58 year old female with Bazex syndrome had a 2 year history of a hyperpigmented rash and presented for CT after an abnormal chest radiograph. Contrast enhanced axial CT images of the chest confirms the presence of large right perihilar soft tissue mass. (protocol: 250 mAs, 120 kvp, 5mm slice thickness, venous phase, 100 cc isoview-300.)

Figure 6.

58 year old female with a 2 year history of a hyperpigmented rash who was found to have Bazex syndrome presented for CT after an abnormal chest radiograph. Contrast enhanced coronal reformatted CT images of the chest demonstrates the presence of large right perihilar soft tissue mass (thick white arrow), associated right paratracheal adenopathy (thin white arrow) and a focal right hepatic lobe metastatic lesion (black arrow). (protocol: 250 mAs, 120 kvp, 5mm slice thickness, venous phase, 100 cc isoview-300)

A diagnosis of acrokeratosis paraneoplastica was made based on the clinical presentation and evidence of metastatic carcinoma on imaging. The patient underwent bronchoscopy with biopsy of the right perihilar mass that revealed small cell carcinoma.

The patient underwent palliative chemotherapy, but unfortunately died 6 months after the diagnosis was made. Her cutaneous findings did not change during this period.

DISCUSSION

Multiple paraneoplastic syndromes exist and the majority will require radiological investigation for ultimate diagnosis of the underlying malignancy. Several paraneoplastic syndromes commonly associated with lung carcinoma include the syndrome of inappropriate antidiuretic hormone, limbic encephalitis, paraneoplastic cerebellar degeneration, and hypertrophic pulmonary osteoarthropathy. Central pontine myelinolysis can be a manifestation of the syndrome of inappropriate antidiuretic hormone secondary to small-cell lung carcinoma [1]. Limbic encephalitis can be paraneoplastic and is manifest by high T2 signal involving the limbic structures [1]. Paraneoplastic cerebellar degeneration is a diagnosis of exclusion but occurs most commonly in association with small-cell lung cancer [1]. Hypertrophic pulmonary osteoarthropathy (proliferative periostitis, arthropathy and digital clubbing) is most commonly associated with non-small-cell lung cancer [1].

Dermatologic signs and symptoms are also common paraneoplastic manifestations of underlying malignancy. Acanthosis nigricans is a well-known sign of insulin resistance, but it is also known to be associated with malignancy, most commonly gastrointestinal adenocarcinomas [2]. Necrolytic migratory erythema is most commonly associated with islet cell tumors [2]. Erythematous psoriasiform eruption involving the nose and helices, palmoplantar keratoderma and nail dystrophy is typical of Bazex syndrome, and the most common primary malignancy is squamous cell carcinoma of the upper areodigestive tract [2].

Bazex syndrome is an eponym used to describe two different clinical entities first reported in 1964 and 1965. The first described Bazex syndrome is an x-linked genetic disease also known as 'follicular atrophoderma-basal cell carcinoma' and is characterized by follicular atrophoderma, congenital hypotrichosis and hypohidrosis, and multiple basal cell carcinomas [3]. The second described Bazex syndrome is also known as 'acrokeratosis paraneoplastica' and is characterized by erythematous psoriasiform eruption typically involving the nose and helices, palmoplantar keratoderma and nail dystrophy that is most commonly associated with carcinomas of the upper aerodigestive tract [2,3,4,5].

Gougerot and Rupp first described paraneoplastic acrokeratosis in 1922 in a patient with squamous cell carcinoma of the tongue and with hyperkeratotic lesions of the nose, ears and palmo-plantar regions [4]. The eponymous of Bazex syndrome is ascribed to Andre Bazex who reported a case in 1965 of a squamous cell carcinoma of the piriform fossa associated with a psoriasis-like examthem [7].

Bazex syndrome is characterized by a hyperkeratotic, psoriasiform eruption that favors acral sites and parallels the evolution of a co-existing malignancy [2]. The cutaneous lesions precede the diagnosis of the tumor by an average of 11 months [2]. A review of the literature in 2005 found that 60% the associated neoplasms were squamous cell carcinoma of the head, neck and lungs [6]. Less commonly associated carcinomas are poorly differentiated carcinoma (16%), adenocarcioma of the prostate, lung, esophagus stomach, and colon (8%), and small cell carcinoma of the lung (2.5%) [7]. Even rarer associated carcinomas include transitional cell carcinoma of the bladder, Hodgkin's disease, T-cell lymphoma, carcinoid, thymoma, vulvar, liposarcoma, cholangiocarcinoma, uterine adenocarcinoma, and breast cancer [7,8,9,10]. Most described cases are white males older than 40 [2].

The cutaneous lesions are erythematous to violaceous in color with an associated scaling eruption and the most frequent sites of involvement are the ears, nose, hands, and feet (including the nails) [2]. They are typically non-pruritic, have ill-defined margins and are symmetric [8, 11].

On the basis of clinical observation, acrokeratosis paraneoplastica has been divided into 3 stages, which reflect the growth and dissemination of the underlying malignancy [8,11]. The psoriasiform dermatitis begins in the fingers, toes, nose, and helix of the ears which progresses to involve the palms, soles, and cheeks to finally extends centripetally to the arms, legs, scalp, and trunk [5,6].

Typically, the histologic examination of the biopsy specimen and direct immunofluorescence is nonspecific, but is useful in ruling out other major dermatoses [9]. Interestingly, the direct immunofluorescence findings in this case paralleled that of a bullous eruption, such as bullous pemphigoid or even paraneoplastic pemphigus which may be characterized by linear deposition of IgG and C3 along the basement membrane however, but no bullae were seen clinically.

Several mechanisms for development of this paraneoplastic syndrome have been proposed. One theory proposes that antibodies against the tumor cross react with the keratinocyte or basement membrane leading to damage of the basal layer of the skin [2]. Alternatively, an immune reaction directed against tumor like antigens in the epidermis could be responsible for the cutaneous eruptions [11]. Yet another proposed mechanism is tumor production of autocrine growth factors for keratinocytes, transforming growth factor-, and insulin like growth factor-1 leading to epidermal hyperplasia [2,11].

The cutaneous eruptions are typically resistant to topical treatments [2]. Treatment of the underlying neoplasm often improves the cutaneous symptoms significantly and reappearance of the lesions may signal recurrence of the tumor or development of metastatic disease [2,11].

TEACHING POINT

Acrokeratosis paraneoplastica (Bazex syndrome) is a rare, but distinctive paraneoplastic dermatosis characterized by erythematosquamous lesions located at the acral sites and is most commonly associated with carcinomas of the upper aerodigestive tract. When given particular clinical histories, the appropriate radiographic investigations should be initiated and the radiologist's suspicion for an underlying malignancy should heighten leading to prompt diagnosis and ultimately a better prognosis.

Table 1.

Summary table for Bazex syndrome (acrokeratosis paraneoplastica)

Etiology	Paraneoplastic syndrome
Incidence	120 reported cases
Gender ratio	More common in males
Age predilection	Most common over age 40
Treatment	Treatment of underlying neoplasm often improves cutaneous symptoms
Prognosis	Depends on extent of cancer
Imaging findings	Neoplastic process most commonly involving the upper aerodigestive tract

Table 2.

Summary of paraneoplastic processes and their radiographic manifestations.

Paraneoplastic Syndrome	Clinical presentation	Radiological findings	Underlying Malignancy
Syndrome of inappropriate antidiuretic hormone secretion	Hyponatremia	Central pontine myelinolysis on MRI	Small cell lung cancer (most common), head and neck tumors, gastrointestinal tumors, and gynecological malignancy
Limbic encephalitis	Short term memory loss, seizure, irritability, thalamic dysfunction, and psychiatric imbalances.	On MRI, high T2 signal in the limbic structures	Small cell lung cancer (most common), testicular carcinoma, breast carcinoma, Hodgkin’s lymphoma, teratoma and thymoma
Paraneoplastic cerebellar degeneration	Ataxia and nystagmus	In acute phase, high T2 signal in the cerebellum on MRI In chronic phase, cerebellar atrophy on MRI and CT	Lung carcinoma (most common), gynecological malignancies, Hodgkin’s lymphoma, and breast carcinoma
Hypertrophic pulmonary osteoarthropathy	Pain and swelling in the ankles and wrists	On radiographs, digital clubbing and lamellar periosteal reaction in the diametaphyseal regions Bone scintigraphy shows increased uptake along the cortical margin of long bones	Non small cell lung cancer or metastatic disease to the lungs
Acanthosis nigricans	Hyperpigmentation in intertriginous regions	On CT, a mass arising from the gastrointestinal tract; most commonly, the stomach	Adenocarcinoma arising from the gastrointestinal tract (stomach, most common), lungs or uterus
Necrolytic migratory erythema	Hyperglucagonemia and weight loss	On CT, an arterial hyperenhancing pancreatic mass	Glucagonoma
Bazex syndrome	Hyperkeratotic, psoriasiform eruption located at the acral sites	On CT, a mass arising from the upper aerodigestive tract	Squamous cell carcinoma of the head, neck or lungs

ABBREVIATIONS

CT

computed tomography

IgG

immunoglobulin G