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DERMATOLOGY DEBATE
Year : 2014  |  Volume : 59  |  Issue : 4  |  Page : 390-393
Association of bullous pemphigoid with malignancy: A myth or reality?


Department of Dermatology, Venereology and Leprology, Goa Medical College, Bambolim, Goa, India

Date of Web Publication27-Jun-2014

Correspondence Address:
Dr. Joycelin Fernandes
Department of Dermatology, Venereology and Leprology, Goa Medical College, Bambolim, Goa
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.135493

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   Abstract 

Bullous pemphigoid (BP) is an autoimmune sub-epidermal blistering disorder of the skin. The association of BP with internal malignancy has always been a matter of debate with no consensus reached despite many published case reports and clinical trials. However, we report a hitherto unreported association of BP with squamous cell carcinoma of the tongue, wherein the patient had a recalcitrant downhill course despite adequate treatment measures with control of skin lesions being achieved only following excision of the tumor, and relapse coinciding with detection of metastasis. Hence, given the clinical behavior, it is reasonable to speculate that the association of malignancy was more than co-incidental.


Keywords: Bullous pemphigoid, squamous cell carcinoma, association


How to cite this article:
Fernandes J, Barad P, Shukla P. Association of bullous pemphigoid with malignancy: A myth or reality?. Indian J Dermatol 2014;59:390-3

How to cite this URL:
Fernandes J, Barad P, Shukla P. Association of bullous pemphigoid with malignancy: A myth or reality?. Indian J Dermatol [serial online] 2014 [cited 2019 Dec 7];59:390-3. Available from: http://www.e-ijd.org/text.asp?2014/59/4/390/135493

What was known?
Controversial role of bullous pemphigoid (BP) with malignancy.



   Introduction Top


Bullous pemphigoid (BP), an autoimmune sub-epidermal blistering disorder, was recognized as a distinct disorder from pemphigus by Lever in 1953. [1] A decade later, Jordan et al. [2] demonstrated the presence of antibodies against basement membrane zone. Its association with malignancy is debatable. However, we report a case whose clinical course closely followed that of malignancy.


   Case Report Top


A 64-year-old male presented with an abrupt onset of pruritic targetoid lesions and erythematous plaques predominantly in a flexural distribution for 2 weeks. Subsequently, a crop of tense vesicles and bullae appeared over these lesions [Figure 1]. Oral and genital mucosae revealed multiple vesicles and erosions covered with pseudomembranes. Nikolsky sign and bulla spread sign were negative.
Figure 1: Presence of targetoid lesions with centers showing bullae filled with hemorrhagic fluid

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Considering a differential diagnosis of bullous erythema multiforme, BP, epidermolysis bullosa acquisita, and pemphigus, the patient was investigated.

Hematological investigations revealed leukocytosis and eosinophilia. Renal and liver parameters were normal. An extensive search for malignancy with thorough clinical examination coupled with radiological investigations proved futile.

A tzanck smear from the vesicle revealed abundant neutrophils with few eosinophils and no acantholytic cells. Histopathological examination revealed a sub-epidermal blister with abundant fibrin, neutrophils, and eosinophils in the blister cavity suggestive of BP [Figure 2]. Direct immunofluorescence revealed linear deposits of IgG and C 3 along the basement membrane zone without intercellular deposits [Figure 3]. Salt split skin technique by direct immunofluorescence, showed immunoreactants on both, epidermal and dermal sides of the split [Figure 4] confirming BP as the diagnosis.
Figure 2: A sub-epidermal bulla containing abundant fibrin, neutrophils, and eosinophils (H and E, original magnification ×50)

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Figure 3: Direct immunofluorescence revealed linear deposits of IgG and C3 along the basement membrane zone

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Figure 4: Immunoreactants on the epidermal and dermal sides of the salt split skin (1 M NaCl) as seen on direct immunofluorescence

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The patient was given antibiotics based on skin swab culture sensitivity and dapsone for 2 weeks. With no significant response to dapsone, therapy was changed to oral prednisolone 1 mg/kg and azathioprine as an immunosuppressant. The lesions began to heal with post-inflammatory hyperpigmentation without milia formation or scarring. The patient followed up at a fortnightly basis with regular monitoring of hematological parameters. Despite being on adequate dose of steroids, new lesions were noticed each time on tapering.

During a follow-up visit, 4 months after the diagnosis, a break through was seen where the patient presented with numerous vesicles in a generalized distribution [Figure 5]. Consequently, the steroid dose was increased. Oral cavity examination revealed a white, raised, necrotic plaque, 2 × 2 cm on the left lateral aspect of the tongue [Figure 6]. On clinical suspicion of malignancy, the patient was biopsied and diagnosed with squamous cell carcinoma of tongue. Computed tomography scan of the neck did not reveal metastasis at this stage and an in toto surgical excision of the tumor mass with free margins was followed, which confirmed a grade II squamous cell carcinoma of the tongue on histopathology [Figure 7] with a TNM staging of T 2 N 0 M 0 . The excision of the malignancy and marginal increase in steroids were followed by marked improvement.
Figure 5: Eruption of multiple tense vesicles and bullae on an erythematous base

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Figure 6: Eroded necrotic plaque on the left lateral aspect of tongue

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Figure 7: Fibrocollagenous tissue and muscle bundles diffusely infiltrated by nests of malignant squamous cells exhibiting foci of keratinization (H and E, ×400)

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During the next 5 months of follow-up, the patient was free of symptoms, with all previous lesions having healed and prednisolone tapered to 5 mg/day.

Subsequently, he developed another exacerbation of lesions. Around this time, follow-up in oncology revealed a metastasis to the lymph node, which was proven on excisional biopsy. The steroid dose was again increased and the patient underwent 6 weeks of concurrent radiotherapy and six cycles of weekly injection Cisplatin as chemotherapy. This was followed by dramatic improvement of the skin condition with steroids being tapered and omitted. Unfortunately, the patient went downhill with the development of cachexia and succumbed 8 months later.


   Discussion Top


The association of BP with internal malignancy has always been a matter of debate with no consensus reached. Despite many published case reports and trials, a definite association is lacking. Ogava et al., in their study involving over 1,000 Japanese patients, found a significantly higher incidence of malignancy in BP (5.8%) than that of controls aged over 70 years (0.6%). [3] Similar associations are cited in Asia. [4] However, studies conducted in Sweden [5] and the USA [6] failed to prove any statistically significant association.

Since BP and malignancy are confined to the geriatric population, many consider the association to be co-incidental. However, we beg to differ, as in our patient, the clinical course of the disease closely followed that of malignancy. The disease which usually runs a benign and self-limiting course had a very recalcitrant nature in our patient. A significant control of the disease was not achieved despite being on adequate dose of oral steroids (1 mg/kg) and immunosuppressant, with new lesions erupting when steroids were tapered. The first major relapse coincided with the detection of malignancy, settled completely with excision of the tumor, and marginal increase of systemic steroids. The patient remained free of symptoms for a long period (5 months) on low dose of steroids. Unfortunately, the patient developed metastasis to lymph nodes and recurrence of BP. Hence, given the clinical behavior, it is reasonable to speculate that the association with malignancy was more than co-incidental.

The time of presentation of malignancy can be variable, with malignancy presenting either before, concurrently or after the appearance of BP. A Swedish study found that, patients who develop malignancy after BP, the mean lag time to uncovering the malignancy was 2 years and 8 months. [5] In our patient, the time lag was 4 months.

The simultaneous presence of malignancy may not morphologically alter the clinical appearance of BP lesions. However, some authors have suggested that bullae on gyrate erythema are more commonly associated with internal malignancy. [7]

BP has been reported with various malignancies especially of the gastrointestinal tract. To the best of our knowledge, this is the first report of BP associated with squamous cell carcinoma of the tongue.

After extensive review of literature, we found two case reports of squamous cell carcinoma of the skin associated with BP. [8],[9] Both these patients had an outcome similar to our case, with no response to therapy and resolution with resection of the malignancy.

Wong and Ho have reported squamous cell carcinoma of the tongue with atypical paraneoplastic pemphigus. [10] Their patient had clinical and histopathological features of BP but direct immunofluorescence showed intercellular deposits of IgG and C 3 throughout the epidermis. In our patient however, clinical, histopathological, and direct immunofluorescence findings were that of BP.

In conclusion, a thorough and extensive search for malignancy is warranted in BP, particularly in those patients who are refractory to the standard line of management. Moreover, a high index of suspicion is necessary in early diagnosis as the clinical pattern of disease may be altered.

 
   References Top

1.Lever WF. Pemphigus. Medicine (Baltimore) 1953;32:1-123.  Back to cited text no. 1
    
2.Jordon RE, Beutner EH, Witebsky E, Blumental G, Hale WL, Lever WF. Basement zone antibodies in bullous pemphigoid. JAMA 1967;200:751-6.  Back to cited text no. 2
    
3.Ogawa H, Sakuma M, Morioka S, Kitamura K, Sasai Y, Imamura S, et al. The incidence of internal malignancies in pemphigus and bullous pemphigoid in Japan. J Dermatol Sci 1995;9:136-41.  Back to cited text no. 3
    
4.Chang YT, Liu HN, Wong CK. Bullous pemphigoid-A report of 86 cases from Taiwan. Clin Exp Dermatol 1996;21:20-2.  Back to cited text no. 4
    
5.Lindelöf B, Islam N, Eklund G, Arfors L. Pemphigoid and cancer. Arch Dermatol 1990;126:66-8.  Back to cited text no. 5
    
6.Stone SP, Schroeter AL. Bullous pemphigoid and associated malignant neoplasms. Arch Dermatol 1975;111:991-4.  Back to cited text no. 6
    
7.Gilmour E, Bhushan M, Griffiths CE. Figurate erythema with bullous pemphigoid: A true paraneoplastic phenomenon? Clin Exp Dermatol 1999;24:446-8.  Back to cited text no. 7
    
8.Deguchi M, Tsunoda T, Tagami H. Resolution of bullous pemphigoid and improvement of vitiligo after successful treatment of squamous cell carcinoma of the skin. Clin Exp Dermatol 1999;24:14-5.  Back to cited text no. 8
    
9.Levin DL, Sadhwani A. Blistering on a squamous cell carcinoma graft site in a patient with bullous pemphigoid. Cutis 1994;54:40.  Back to cited text no. 9
    
10.Wong KC, Ho KK. Pemphigus with pemphigoid-like presentation, associated with squamous cell carcinoma of the tongue. Australas J Dermatol 2000;41:178-80.  Back to cited text no. 10
    

What is new?
A positive association between bullous pemphigoid (BP) and malignancy, .probably causal.


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]



 

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