A case of paraneoplastic bullous pemphigoid in association with squamous cell carcinoma of lung.

Bullous pemphigoid is a chronic, autoimmune, acquired subepidermal blistering disorder. It is idiopathic in origin, and mainly seen in elderly individuals. Association between bullous pemphigoid and internal malignancies is reported in the literature, but the exact causal relation is not established. Paraneoplastic bullous pemphigoid is rarely reported in lung cancers, especially in squamous cell variety. So their presence should raise the suspicion of various internal malignancies including lung cancer. It is presented mainly with tense, large blisters over the erythematous base or over normal skin. Subepidermal blisters with tissue eosinophilia are characteristic histopathological features of bullous pemphigoid. Direct immunofluorescence shows linear deposits of IgG - complement complex along the dermoepidermal junction. Conventional treatment of bullous pemphigoid along with treatment of lung cancer (surgery, chemotherapy, radiotherapy) may result in successful resolution of skin lesions. Here, we report a rare association of paraneoplastic bullous phemphigoid and squamous cell carcinoma of lung in a 76-year-old male to increase the awareness among the clinicians regarding this variety of cutaneous paraneoplastic manifestation of lung cancer.

Introduction

Paraneoplastic syndrome refers to non-metastatic metabolic or neuromuscular manifestations of certain malignancies and these paraneoplastic manifestations are not attributable to direct tumor invasion or compression as well as distant spread of tumor cells. It is most commonly associated with lung cancers, especially of small cell variety.[12] It can affect endocrine, neurologic, dermatologic, rheumatologic, and hematologic systems.[12] Paraneoplastic dermatologic syndromes include acanthosis nigricans, dermatomyositis, bullous pemphigoid, paraneoplastic phemphigus, and Sweet syndrome.[3] Incidence of paraneoplastic dermatologic manifestations in association with lung cancer is very low, and incidence of bullous pemphigoid is further rare. Paraneoplastic bullous pemphigoid is most commonly associated with B-cell lymphoproliferative disorders.[4] Management of paraneoplastic bullous pemphigoid consists of cancer-directed therapy plus standard treatment of its non-paraneoplastic counterpart. Here, we reported a rare case of paraneoplastic bullous pamphigoid with squamous cell carcinoma of lung in a 76-year-old male.

Case Report

A 76-year-old non-diabetic, smoker, male presented with cough, mucoid expectoration, and right-sided, dull aching chest pain for 3 months. There was history of recurrent episodes of streaky hemoptysis for 1 month and swelling of the face, neck, and upper half of the chest for 15 days. He also complained of itchy, painless, blistering skin lesions for 15 days over the outer aspect of the right arm, in both legs and over the front of chest.

On general survey, there were anemia, digital clubbing, and multiple, hard, non-tender cervical lymphadenopathy in the right supraclavicular area. Enlarged lymph nodes were fixed to underlying structure and overlying skin, but there was no discharging sinus. Progressively increasing swelling of the face, neck and upper half of the chest was associated with chemosis, corneal edema, and non-pulsatile engorged neck veins with negative abdomino-jugular reflux. The patient was hemodynamically stable.

Dermatological examination revealed large, tense vesicles and blisters over the erythematous base and multiple erosions of the whole skin, localized to the outer aspect of the right arm, the front of the chest, and over the extensor aspect of both legs. Nikolskiy's sign was negative.

Examination of the respiratory system revealed engorged, tortuous superficial veins over the chest with direction of blood flow from above downwards. The mediastinum was central. There was dull percussion note over the right clavicle, and over second to third intercostal spaces in right mid-clavicular line, and diminished vesicular breath sound with reduced vocal resonance over the right infra-clavicular and mammary areas without any adventitious sound — suggestive of a mass lesion in the right upper lobe.

Complete hemogram and blood biochemistry was normal, except hemoglobin concentration being 6.7 g/dL. Sputum was negative for acid fast bacilli and malignant cell. Fine-needle aspiration cytology (FNAC) of right-sided cervical lymph nodes showed metastatic squamous cell carcinoma. On chest X-ray, the postero-anterior view showed a mass lesion occupying right upper and mid zones, adjacent to the mediastinum. Contrast-enhanced computed tomography (CECT) scan of thorax showed a mass lesion in the right upper lobe [Figure 1]. CT-guided FNAC of the mass lesion in the right lung showed non-small cell carcinoma. A CT-guided tru-cut biopsy revealed squamous cell carcinoma of the right lung [Figure 2]. Histopathology of a skin biopsy tissue showed a subepidermal blister with mixed inflammatory infiltrates with predominance of eosinophils, within the dermis — compatible with bullous pemphigoid [Figure 3]. No malignant deposit in the skin tissue was noted. A linear band of C3 deposits was seen along the dermoepidermal junction on direct immunofluorescence examination [Figure 4]. Hence, the diagnosis was right-sided squamous cell carcinoma of lung with superior vena caval obstruction, complicated by paraneoplastic bullous pemphigoid.

Figure 1

CECT thorax showing a mass lesion in the right upper lobe, compressing superior vena cava

Figure 2

Microphotograph of histopathology of CT-guided tru-cut biopsy tissue of the right lung mass showing squamous cell carcinoma. (H and E stain, 10×)

Figure 3

Microphotograph of histopathology of a skin biopsy tissue taken from bullous lesion showing a subepidermal blister with mixed inflammatory infiltrates, predominantly eosinophils, within the dermis. (H and E stain, 10×)

Figure 4

Microphotograph of direct immunofluorescence study showing a linear band of C3 deposits

Skin lesions were initially treated with oral prednisolone (40 mg/day) and cyclophosphamide (100 mg/day) for 3 weeks. Topical application of beclomethasone and mupirocin ointment was given. Intravenous antibiotic was also given. But the number of blisters was gradually increasing. After the tissue diagnosis of lung cancer, cisplatin (75 mg/m2 on day 1) and gemcitabine (1250 mg/m2 on days 1 and 8) were given. After first cycle of chemotherapy, the number of skin lesions gradually decreased, and complete resolution of them was noted after third cycle of chemotherapy of the same regimen.

Discussion

Bullous pemphigoid is a chronic, autoimmune, subepidermal, blistering skin disease that does not involve mucous membranes usually in contrast to pemphigus vulgaris. It is mainly seen in elderly individuals. But, it may be associated with diabetes, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, multiple sclerosis, myasthenia gravis, etc.[5]

Iwashita et al. reported 10.4% cases of bullous pemphigoid are associated with internal malignancies.[6] However, it is reported to occur in association with parotid carcinoma, breast cancer, lung cancer, colo-rectal cancer, endometrial cancer, B-cell lymphoma, renal cell carcinoma, cholangiocarcinoma, esophageal carcinoma, endometrial cancer, bladder cancer, etc., as paraneoplastic syndrome.[78910]

Bullous pemphigoid is caused by immunoglobulin G (IgG) autoantibodies against the hemidesmosomal bullous pemphigoid antigens BP230 (BPAg1) and BP180 (BPAg2).[10] Bullous pemphigoid has diverse presentations, like classic tense bullous pattern or nodular, erythrodermic, eczematous, acral patterns, etc.

Bullous pemphigoid is very rarely reported in association with lung cancers, especially with the squamous cell carcinoma of the lung.

Paraneoplastic bullous pemphigoid presents with large tense bullae on erythematous bases or on normal skin. Histopathologically, the disease is characterized by subepidermal blisters, tissue eosinophilia, and IgG — complement complex deposition along the dermoepidermal junction.

Standard therapy with steroids and other immunosuppressants fails to resolve the paraneoplastic bullous pemphigoid. In such cases, treatment of lung cancer results in successful resolution of the skin lesions. In our case, skin lesions developed following the onset of the lung malignancy, and despite of adequate treatment with steroids and cyclophosphamide, the number of blisters of bullous pemphigoid was gradually increasing. The blisters disappeared after giving chemotherapy. So why these two facts probably suggest the paraneoplastic nature of these skin lesions.

Conclusion

In conclusion, definite relationship between bullous pemphigoid and lung cancer is not revealed, but their concurrent presentation is unexplained. As bullous pemphigoid develops prior to development of internal malignancies, the patients with bullous phemphigoid should be checked for internal malignancies including lung cancers.