British Journal of Dermatology (1990) 123, 439-445.
The association of bullous pemphigoid and malignant disease: a case control study V.A.VENNING AND F.WOJNAROWSKA Department of Dermatology, The Stade Hospital, Oxford Accepted for publication 21 May 1990
SUMMARY
In a case control study, the incidence of malignant disease in 84 patients with bullous pemphigoid (BP) was compared with 168 controls. The rate of malignant disease (past, concurrent or during follow-up) in BP patients was 179% compared to 5-3% in the controls. A number of the malignancies occurring in the BP group may be of doubtful significance, being either temporally very remote or partially attributable to treatment. The rate of concurrent BP and malignancy (within 8 weeks) was 60% suggesting that there is probably a slight excess of malignancy in BP, but insufficient to warrant extensive investigation in pursuit of cancer. Comparison of the BP patients with and without cancer identified no clinical or immunopathological subgroups in whom investigations would be indicated. Three patients with both BP and malignancy were HLA-DR 13 positive, which may point to an immunogenetic predisposition to both diseases.
Bullous pemphigoid (BP) has been reported in association with carcinoma at many different sites'"^* as well as with sarcoma,*^ melanoma,'* and lymphoproliferative disorders.^"'* The case for a genuine association is strengthened in a few of these reports by a parallel clinical course between the neoplasm and the blistering eruption,*'^ though there are also cases where this has not occurred.' In other reports the BP has had unusual clinical features, presenting as a figurate erythema*"'' and has led to the suggestion that atypical BP may be a marker for malignancy. Despite these numerous reports it remains controversial whether BP and malignant disease are truly associated, or whether their concurrence is merely a reflection of the fact that both diseases are most common in the elderly. There has been only one case control study,' and this concluded that there was no higher incidence of malignant disease in BP patients than in ageand sex-matched controls. In contrast, a higher than expected incidence of malignancy was found in BP patients in a study based on population malignancy rates.^° Of the other published series, some^'"^^ but not all^* have reported a higher incidence of malignant disease in BP Correspondence: Dr V.A.Venning, Department of Dermatology, The Slade Hospital, Headington, Oxford OX3 7JH, U.K.
439
44O
V. A. Venning and F. Wojnarowska
patients with negative indirect immunofiuorescence (IMF) findings compared to those with positive findings, suggesting that seronegative BP may be a marker for internal malignancy. In this study of 84 patients with bullous pemphigoid, the incidence of mahgnant disease was compared to that in 168 controls. The clinical and IMF findings and the HLA type in patients with and without malignant disease were analysed in order to identify any BP subgroups at increased risk of malignancy.
METHODS
Bullous pemphigoid patients
We reviewed all 84 bullous pemphigoid patients seen from 1975-89, and in all cases the diagnosis was confirmed by the presence of a linear band of IgG and/or C3 at the dermoepidermal junction on direct immunofiuorescence. The patients' details are shown in Table i. Special note was made of the indirect IMF findings, the presence of mucosal involvement, milia and any unusual clinical features of the BP. Thirty-seven patients had their HLA type determined using a lymphocyte microcytotoxicity assay.^' All neoplasms occurring in the BP patients were recorded with the date of their diagnosis. Apart from a history and clinical examination no routine investigations in pursuit of cancer were done other than those required for the management of the patients' treatments. Most patients had full blood counts, biochemistry and liver functions test, but no other tests unless indicated. Non-melanoma skin cancers were not included in the study because of the unreliability of patients' histories in respect of these tumours. Controls
Each patient was matched by age, sex and calendar year of diagnosis to two controls (168 controls). Controls were obtained from the venous leg ulcer clinics and from patients attending minor operating sessions for removal of skin lesions, including basal cell carcinoma but also a variety of benign skin lesions. Details of the medical histories of the controls were obtained by questionnaire if they were still attending the clinic, and otherwise from their hospital and general practitioner records and where relevant from post-mortem reports and death certificates. The controls were followed up from 3 months to 15 years (mean 3 years i month). The statistical analyses used were the Mantel-Haenzel estimate of the odds ratio and the chisquared test with Yates' correction.
TABLE I. Details of bullous pemphigoid patients studied Total number Sex Age
Follow-up
84 M39 F45
Range 45-94 years Mean 73 9 years Range 2 weeks-15 years i month Mean 3 years 1 month
BP and malignant disease
441
RESULTS
Overall frequency of neoplasia
Neoplasms recorded among the BP patients were carcinomas of bronchus, breast, bladder, prostate and colon, two lymphomas (one Hodgkin's disease, one cutaneous T-cell lymphoma), a melanoma and a case of monoclonal gammopathy, which though neoplastic, has so far behaved in a benign fashion over 3 years 2 months of follow-up. Sixteen neoplasms were recorded in 15 BP patients (179%), compared to nine in the control group (54%; odds ratio = 3 63; P < 001) (Table 2). As the smoking history of patients and controls was unknown, the analysis was also done excluding carcinoma of the bronchus. The frequency of non-bronchus neoplasms was 11/ 84 (13%) in the BP patients, compared to 8/168 (3-5%) in the controls (P smgle patient
I
I
I
0
I
2
0
I
0
I
2
t6 (in 15 patients) 17-9%
9
5-4%
V.A.Venning and F.Wojnarowska
442
TABLE 3. Cancers preceding the onset of BP Interval to diagnosis ofBP*
Cancer 1 2 3 4 5 6 7 8 9 10 11 12 t3 14 15
Ca breast Ca colon Ca breast Ca breast Transitional cell Ca bladder Ca prostate Ca breast Melanoma Monoclonal gammaopathy Ca bronchus Hodgkin's disease Ca breast Cutaneous T-cell lymphoma Ca bronchus Ca bronchus Ca bronchus
— 29 years — 22 years - 1 1 years — 3 years 6 months — I year 11 months o o o o +1 month + 7 months + I year 8 months + : year 11 months + 2 years + 3 years 4 months + 4 years
Comment
Metastatic relapse 9 months prior to A of BP On tamoxifen 2nd malignancy (prostate) A at time of onset of BP Neoplasm detected at time of A of BP
On prednisolone and azathioprine On prednisolone On prednisolone and azathioprine On azathioprine On prednisolone and sulphapyridine On prednisolone and azathioprine
* A minus sign indicates date of A of tumour preceded the onset of BP.
a higher dose (2-5 mg/kg) of azathioprine combined with 7 5-15 mg/day of prednisolone until he presented with cutaneous T-cell lymphoma after i year 11 months. In view of the effect of treatment we repeated the analysis excluding the three possibly treatment-related malignancies, giving an incidence of 12/84 (i4'2%). Controls. All the neoplasms in the controls preceded the reference time point (i.e. their first presentation to the skin clinic) by 3 years-17 years 11 months (mean 10 years i month). None developed concurrently with their presentation or during follow-up. Comparison of BP with and without malignant disease
To look for an identifiable subgroup with an increased risk of cancer, we compared the 15 patients with a history of malignant disease with the 69 patients without malignancy (Table 4). The only difference was in the sex ratio with a slight excess of males in the cancer group compared to a female preponderance in the non-cancer group. The prevalence of mucosal TABLE 4. Comparison of BP patients with and without cancer
No. of patients Mean age at onset BP Sex ratio F: M No. (%) with mucosal lesions No. (%) with circulating Ab
Neoplasia-associated BP
BP without neoplasia
15
69 73 years
75 5 years 079:1
1-5:1
7/15 (44%) 8/10(80%)
28/69(40-5%) 31/46 (67%)
BP and malignant disease
443
TABLE
5. HLA-DR types in seven patients with BP and neoplasia
DR DR DR DR DR DR DR
2 II
3 —
4 4 3
13 13 13
2
4 7
4
involvement, and the presence of a circulating antibody were looked at but the differences between the groups did not reach statistical significance. There were no differences between the neoplasm and non-neoplasm BP patients in respect of any other clinical feature, notably the duration of prodromal itching, the presence of milia and the morphology and distribution of lesions. HLA typing Thirty-seven patients were HLA typed for the A, B, C and D loci, and they did not differ from 151 unrelated controls drawn from our local population. Seven of these patients had both BP and a tumour; the HLA type for the A, B and C loci in these patients did not differ significantly from that in BP patients without a tumour. The HLA-DR types in the patients with both BP and a tumour are shown in Table 5. HLA-DR 13 occurred in three of the seven patients with both BP and neoplasia, compared to only 2/28 of the BP patients without neoplasia.
DISCUSSION
Despite the frequently reported occurrence of BP in patients with malignant tumours,'"'^ it remains controversial whether there is a genuine association^" or just coincidence.''^''" Only Chorzelski et al. found an excess incidence of malignancy amongst BP patients,^" though other groups have suggested that there may be subgroups of BP, with a increased risk of malignancy, such as seronegative^'"^^ or clinically atypical BP.^'^ In this case control study, malignancy, whether past, concurrent or developing during followup occurred more commonly in BP patients (17-9%) than in controls (54%). However, there are important difficulties in interpreting these data, particularly in determining which cases of cancer have a valid relationship to BP. Previous authors have varied in their inclusion criteria, some including only tumours strictly concurrent with BP (i.e. within 6 months),^^ and others allowing more relaxed criteria, such as 5 years before or after the onset of BP.' Ahmed et al. included those tumours developing during follow up of 5-43 months,^""^ but in Chorzelski's series the criteria are not specified.^" Neither of these reports refer to the possible effects of treatment for BP. In view of the increased incidence of neoplasia in immunosuppressed renal transplant recipients,'^* we excluded the three BP patients who developed neoplasms while receiving prednisolone and azathioprine. This reduced the incidence of BP to 12/84 (i4%) which is still significantly higher than in the controls.
444 V.A. Venning and F. Wojnarowska Like other authors we also excluded temporally remote tumours from the analysis, though the validity of this is less certain and rests oh the assumption that the supposed link between BP and neoplasia operates contemporaneously in both diseases. The most commonly proposed model for a causal link between BP and cancer, that of antigenic cross reactivity between tumour and skin,* implies concurrence of onset. In our study, exclusion of three tumours preceding the BP by a long period of time reduced the incidence of BP and cancer to 9/84 (10-7%), and exclusion of all tumours not strictly concurrent (i.e. within 8 weeks) further reduced this figure to 5/84 (60%), a result similar to the 8% incidence reported for tumours developing 6 months either side of the onset of BP.^^ This pick-up rate for tumours at the time of presentation of BP is likely to be similar in other dermatology departments as the patients in the present study were not routinely investigated for cancer. In the control group, all of the cancers preceded the reference time point by a number of years, and none presented within the 8 week-period on either side of their first clinic attendance. Hence, although there appears to be a difference between BP and controls, refiecting an excess incidence of cancer at or around the time of the development of BP, the true magnitude of this difference is unknown. The incidence of cancer in the control group may be an underestimate, as patients experiencing other problems with their health are less likely to present for management of benign skin lesions. We also considered the possibility of an alternative model for a link between BP and cancer, that of an underlying genetic predisposition to both diseases, a hypothesis consistent with their non-concurrent onset. No HLA differences in respect of the A, B or C loci were detected between cancer-BP patients, non-cancer-BP patients and controls. Though the numbers are small it is of interest that three of the seven patients with both BP and cancer were HLA-DR 13 positive compared to only 9% of our local population. If confirmed, a link between this antigen and cancer-proneness in BP patients would not readily be explicable in terms of the theory that a breakdown in immunosurveillance predisposes to cancer. The DR-13 antigen contributes to the DR-6 phenotype, which in renal transplant recipients has been associated with heightened rather than impaired immune responsiveness.^''^* However, if this association with DR 13 is borne out and confirmed as a marker for cancer-associated cases of BP when larger number of cases are studied, then reappraisal of our figures with inclusion of temporally remote tumours would be valid, making the excess incidence of tumours in the BP group more highly significant. Previous authors have cited a parallel course between the two diseases as further evidence in support of a causal link;*'" none of the patients in this study had a parallel clinical course. Despite previous reports that cancer-associated BP is commoner in patients with seronegative gp2i-23 Qj. occurs with morphologically atypical BP*''^ we have been unable to confirm these findings. Comparison of cancer-associated BP with non-cancer-associated BP patients in respect of the lesion morphology and distribution, mucous membrane involvement and immunopathological findings identified no subgroup at increased risk of cancer. We conclude that the rate of malignant disease (past, concurrent or during follow-up) in BP patients is higher than in controls, though a proportion of these cases may be of doubtful significance. Disallowing doubtful cases reduces the incidence to 60%, similar to the overall incidence in controls. There is probably an excess of cancers clustering around the time of onset of BP though the exact magnitude of this increased risk is difficult to estimate. This level of risk does not support the case for extensive investigations in patients presenting with BP as the detection of cancer at presentation is likely to be low. There also does not appear to be any identifiable subgroup of BP for whom extensive investigations would be indicated. Further studies are needed to determine whether cancer-associated BP is linked to HLA-DR phenotype.
BP and malignant disease
445
ACKNOWLEDGMENTS
We gratefully acknowledgefinancialsupport for the HLA typing from the Oxfordshire District Cancer Research Fund, and statistical advice from Dr Michael Goldacre. REFERENCES 1 Stone SP, Schroeter AL. Bullous pemphigoid and associated malignant neoplasms. Arch Dermatol 1975; 111:991-4. 2 Tanaka T, Ogino A, Ogura K, Nakagawa K. A case of bullous pemphigoid and transitional cell carcinoma of the bladder. Arch Dermatol 1983; 119: 704-5. 3 Amer MH, Akthar M, Mackey DM, Butler PG. Bullous pemphigoid after chemotherapy for choriocarcinoma. IntJ Dermatol 1982; 21: 32-5. 4 Binet O, Brunetiere RA, Rabary G et al. Immunologic studies of bulious pemphigoid associated with carcinoma of the colon. New Engl J Med 1983; 308: 460-1. 5 Abadir R, Emery EW, Hare PJ. Pemphigoid, bronchial neoplasm and radiotherapy. Proc R Sec Med 1967; 60:12712.
6 Rook AJ. A pemphigoid eruption associated with carcinoma of the bronchus. Trans Rep St John's Hosp Derm Soc Lond 1968; 54: 152-4. 7 Furukawa F, Osaki M, Imamura S, Hirose S. Bullous pemphigoid associated with radiotherapy for esophageal carcinoma. Dermatologica 1981; 162: 451-9. 8 Graham-Brown RAC. Bullous pemphigoid with figurate erythema associated with carcinoma of the bronchus. BrJ Dermatol 1987; 117: 385-8. 9 Parsons RL, Savin JA. Pemphigoid and malignancy. Br J Cancer 1968; 2z: 669-72. to Paslin DA. Bullous pemphigoid and hypernephroma: a critical review of bullous pemphigoid and malignancy. Cutis 1973; 12: 554-511 Van Poppel H, Aswarie H, Baert L. Bullous pemphigoid associated with renal carcinoma. BrJ Urol 1988; 61: 361. 12 Dahl MV, Ristow S. Bullous pemphigoid and ovarian cystadenocarcinoma: immunologic studies. Arch Dermatol 1978; 114:903-5. 13 Forman L. Pemphigoid occurring with carcinoma of the rectum. Proc R Soc Med i960; 53: 563-4. 14 Boyd RV. Pemphigoid and carcinoma of the pancreas. Br Med J 1964; i: 1092. 15 Tye MJ. Bullous pemphigoid and Kaposi's sarcoma. Arch Dermatol 1970; ioi: 690-1. 16 Marks JM, Gold SC. Pemphigoid with maiignant melanoma. Proc R Soc Med 1961; 54: 225-6. 17 Cuni LJ, Griinwald H, Rosner F. Bullous pemphigoid: in chronic lymphocytic leukemia with the demonstration of antibasement membrane zone antibodies. Am J Med 1974; 57: 987-92. 18 Goodnough LT, Muir A. Bulious pemphigoid as a manifestation of chronic lymphocytic leukaemia. Arch Intern Med 1980; 140; 1526-27. 19 Saikia NK, MacKie RM, McQueen A. A case of bullous pemphigoid and figurate erythema in association with metastatic spread of carcinoma. Br J Dermatol, 1973; 88: 331-4. 20 Chorzeiski TP, Jablonska S, Maciejowska E et al. Coexistence of malignancies with bullous pemphigoid. Arch Dermatol 197S; 114: 964-6. 21 Person JR, Rogers RS. Bullous and cicatriciai pemphigoid. Clinical, histopathologic and immunopathologic correlations. Mayo Clin Proc 1977; 52: 54-66. 22 Hodge L, Marsden RA, Black MM et al. Bullous pemphigoid: the frequency of mucosal involvement and concurrent malignancy. Br. J Dermatol 1981; 105: 65-9. 23 Venencie PY, Rogers RS, Schroeter AL. Bulious pemphigoid and malignancy: Relationship to indirect immunofluorescence findings. Acta Derm Venereol (Stockh) 1984; 64: 316-19. 24 Ahmed AR, Amerian ML. Correlation of serum anti-basement zone antibody and malignancy in bullous pemphigoid. Dermatologica 1985; 171: 82-5. 25 Terasaki PI, McClelland JD. Microdroplet assay of human serum microcytotoxins. Nature 1964; 204: 998-1000. 26 Sheil AGR. Cancer in organ transplant recipients: part of an induced immune deficiency syndrome. Br MedJ 1984; 288: 659-60. 27 Hendriks GFJ, Schreuder GM Th, D'Amaro J, Van Rood JJ. The regulatory role of HLA-DR6 in renal transplantation. Tissue Antigens 1986; 27: 121-30. 28 Tsakiris T, Watson MA, Degiannis D et al. Association between blood transfusion, HLA DRw6 and response to dinitrochlorobenzene skin test. Transplant Proc 1987; 19: 705-7.
The association of bullous pemphigoid and malignant disease: a case control study V.A.VENNING AND F.WOJNAROWSKA Department of Dermatology, The Stade Hospital, Oxford Accepted for publication 21 May 1990
SUMMARY
In a case control study, the incidence of malignant disease in 84 patients with bullous pemphigoid (BP) was compared with 168 controls. The rate of malignant disease (past, concurrent or during follow-up) in BP patients was 179% compared to 5-3% in the controls. A number of the malignancies occurring in the BP group may be of doubtful significance, being either temporally very remote or partially attributable to treatment. The rate of concurrent BP and malignancy (within 8 weeks) was 60% suggesting that there is probably a slight excess of malignancy in BP, but insufficient to warrant extensive investigation in pursuit of cancer. Comparison of the BP patients with and without cancer identified no clinical or immunopathological subgroups in whom investigations would be indicated. Three patients with both BP and malignancy were HLA-DR 13 positive, which may point to an immunogenetic predisposition to both diseases.
Bullous pemphigoid (BP) has been reported in association with carcinoma at many different sites'"^* as well as with sarcoma,*^ melanoma,'* and lymphoproliferative disorders.^"'* The case for a genuine association is strengthened in a few of these reports by a parallel clinical course between the neoplasm and the blistering eruption,*'^ though there are also cases where this has not occurred.' In other reports the BP has had unusual clinical features, presenting as a figurate erythema*"'' and has led to the suggestion that atypical BP may be a marker for malignancy. Despite these numerous reports it remains controversial whether BP and malignant disease are truly associated, or whether their concurrence is merely a reflection of the fact that both diseases are most common in the elderly. There has been only one case control study,' and this concluded that there was no higher incidence of malignant disease in BP patients than in ageand sex-matched controls. In contrast, a higher than expected incidence of malignancy was found in BP patients in a study based on population malignancy rates.^° Of the other published series, some^'"^^ but not all^* have reported a higher incidence of malignant disease in BP Correspondence: Dr V.A.Venning, Department of Dermatology, The Slade Hospital, Headington, Oxford OX3 7JH, U.K.
439
44O
V. A. Venning and F. Wojnarowska
patients with negative indirect immunofiuorescence (IMF) findings compared to those with positive findings, suggesting that seronegative BP may be a marker for internal malignancy. In this study of 84 patients with bullous pemphigoid, the incidence of mahgnant disease was compared to that in 168 controls. The clinical and IMF findings and the HLA type in patients with and without malignant disease were analysed in order to identify any BP subgroups at increased risk of malignancy.
METHODS
Bullous pemphigoid patients
We reviewed all 84 bullous pemphigoid patients seen from 1975-89, and in all cases the diagnosis was confirmed by the presence of a linear band of IgG and/or C3 at the dermoepidermal junction on direct immunofiuorescence. The patients' details are shown in Table i. Special note was made of the indirect IMF findings, the presence of mucosal involvement, milia and any unusual clinical features of the BP. Thirty-seven patients had their HLA type determined using a lymphocyte microcytotoxicity assay.^' All neoplasms occurring in the BP patients were recorded with the date of their diagnosis. Apart from a history and clinical examination no routine investigations in pursuit of cancer were done other than those required for the management of the patients' treatments. Most patients had full blood counts, biochemistry and liver functions test, but no other tests unless indicated. Non-melanoma skin cancers were not included in the study because of the unreliability of patients' histories in respect of these tumours. Controls
Each patient was matched by age, sex and calendar year of diagnosis to two controls (168 controls). Controls were obtained from the venous leg ulcer clinics and from patients attending minor operating sessions for removal of skin lesions, including basal cell carcinoma but also a variety of benign skin lesions. Details of the medical histories of the controls were obtained by questionnaire if they were still attending the clinic, and otherwise from their hospital and general practitioner records and where relevant from post-mortem reports and death certificates. The controls were followed up from 3 months to 15 years (mean 3 years i month). The statistical analyses used were the Mantel-Haenzel estimate of the odds ratio and the chisquared test with Yates' correction.
TABLE I. Details of bullous pemphigoid patients studied Total number Sex Age
Follow-up
84 M39 F45
Range 45-94 years Mean 73 9 years Range 2 weeks-15 years i month Mean 3 years 1 month
BP and malignant disease
441
RESULTS
Overall frequency of neoplasia
Neoplasms recorded among the BP patients were carcinomas of bronchus, breast, bladder, prostate and colon, two lymphomas (one Hodgkin's disease, one cutaneous T-cell lymphoma), a melanoma and a case of monoclonal gammopathy, which though neoplastic, has so far behaved in a benign fashion over 3 years 2 months of follow-up. Sixteen neoplasms were recorded in 15 BP patients (179%), compared to nine in the control group (54%; odds ratio = 3 63; P < 001) (Table 2). As the smoking history of patients and controls was unknown, the analysis was also done excluding carcinoma of the bronchus. The frequency of non-bronchus neoplasms was 11/ 84 (13%) in the BP patients, compared to 8/168 (3-5%) in the controls (P smgle patient
I
I
I
0
I
2
0
I
0
I
2
t6 (in 15 patients) 17-9%
9
5-4%
V.A.Venning and F.Wojnarowska
442
TABLE 3. Cancers preceding the onset of BP Interval to diagnosis ofBP*
Cancer 1 2 3 4 5 6 7 8 9 10 11 12 t3 14 15
Ca breast Ca colon Ca breast Ca breast Transitional cell Ca bladder Ca prostate Ca breast Melanoma Monoclonal gammaopathy Ca bronchus Hodgkin's disease Ca breast Cutaneous T-cell lymphoma Ca bronchus Ca bronchus Ca bronchus
— 29 years — 22 years - 1 1 years — 3 years 6 months — I year 11 months o o o o +1 month + 7 months + I year 8 months + : year 11 months + 2 years + 3 years 4 months + 4 years
Comment
Metastatic relapse 9 months prior to A of BP On tamoxifen 2nd malignancy (prostate) A at time of onset of BP Neoplasm detected at time of A of BP
On prednisolone and azathioprine On prednisolone On prednisolone and azathioprine On azathioprine On prednisolone and sulphapyridine On prednisolone and azathioprine
* A minus sign indicates date of A of tumour preceded the onset of BP.
a higher dose (2-5 mg/kg) of azathioprine combined with 7 5-15 mg/day of prednisolone until he presented with cutaneous T-cell lymphoma after i year 11 months. In view of the effect of treatment we repeated the analysis excluding the three possibly treatment-related malignancies, giving an incidence of 12/84 (i4'2%). Controls. All the neoplasms in the controls preceded the reference time point (i.e. their first presentation to the skin clinic) by 3 years-17 years 11 months (mean 10 years i month). None developed concurrently with their presentation or during follow-up. Comparison of BP with and without malignant disease
To look for an identifiable subgroup with an increased risk of cancer, we compared the 15 patients with a history of malignant disease with the 69 patients without malignancy (Table 4). The only difference was in the sex ratio with a slight excess of males in the cancer group compared to a female preponderance in the non-cancer group. The prevalence of mucosal TABLE 4. Comparison of BP patients with and without cancer
No. of patients Mean age at onset BP Sex ratio F: M No. (%) with mucosal lesions No. (%) with circulating Ab
Neoplasia-associated BP
BP without neoplasia
15
69 73 years
75 5 years 079:1
1-5:1
7/15 (44%) 8/10(80%)
28/69(40-5%) 31/46 (67%)
BP and malignant disease
443
TABLE
5. HLA-DR types in seven patients with BP and neoplasia
DR DR DR DR DR DR DR
2 II
3 —
4 4 3
13 13 13
2
4 7
4
involvement, and the presence of a circulating antibody were looked at but the differences between the groups did not reach statistical significance. There were no differences between the neoplasm and non-neoplasm BP patients in respect of any other clinical feature, notably the duration of prodromal itching, the presence of milia and the morphology and distribution of lesions. HLA typing Thirty-seven patients were HLA typed for the A, B, C and D loci, and they did not differ from 151 unrelated controls drawn from our local population. Seven of these patients had both BP and a tumour; the HLA type for the A, B and C loci in these patients did not differ significantly from that in BP patients without a tumour. The HLA-DR types in the patients with both BP and a tumour are shown in Table 5. HLA-DR 13 occurred in three of the seven patients with both BP and neoplasia, compared to only 2/28 of the BP patients without neoplasia.
DISCUSSION
Despite the frequently reported occurrence of BP in patients with malignant tumours,'"'^ it remains controversial whether there is a genuine association^" or just coincidence.''^''" Only Chorzelski et al. found an excess incidence of malignancy amongst BP patients,^" though other groups have suggested that there may be subgroups of BP, with a increased risk of malignancy, such as seronegative^'"^^ or clinically atypical BP.^'^ In this case control study, malignancy, whether past, concurrent or developing during followup occurred more commonly in BP patients (17-9%) than in controls (54%). However, there are important difficulties in interpreting these data, particularly in determining which cases of cancer have a valid relationship to BP. Previous authors have varied in their inclusion criteria, some including only tumours strictly concurrent with BP (i.e. within 6 months),^^ and others allowing more relaxed criteria, such as 5 years before or after the onset of BP.' Ahmed et al. included those tumours developing during follow up of 5-43 months,^""^ but in Chorzelski's series the criteria are not specified.^" Neither of these reports refer to the possible effects of treatment for BP. In view of the increased incidence of neoplasia in immunosuppressed renal transplant recipients,'^* we excluded the three BP patients who developed neoplasms while receiving prednisolone and azathioprine. This reduced the incidence of BP to 12/84 (i4%) which is still significantly higher than in the controls.
444 V.A. Venning and F. Wojnarowska Like other authors we also excluded temporally remote tumours from the analysis, though the validity of this is less certain and rests oh the assumption that the supposed link between BP and neoplasia operates contemporaneously in both diseases. The most commonly proposed model for a causal link between BP and cancer, that of antigenic cross reactivity between tumour and skin,* implies concurrence of onset. In our study, exclusion of three tumours preceding the BP by a long period of time reduced the incidence of BP and cancer to 9/84 (10-7%), and exclusion of all tumours not strictly concurrent (i.e. within 8 weeks) further reduced this figure to 5/84 (60%), a result similar to the 8% incidence reported for tumours developing 6 months either side of the onset of BP.^^ This pick-up rate for tumours at the time of presentation of BP is likely to be similar in other dermatology departments as the patients in the present study were not routinely investigated for cancer. In the control group, all of the cancers preceded the reference time point by a number of years, and none presented within the 8 week-period on either side of their first clinic attendance. Hence, although there appears to be a difference between BP and controls, refiecting an excess incidence of cancer at or around the time of the development of BP, the true magnitude of this difference is unknown. The incidence of cancer in the control group may be an underestimate, as patients experiencing other problems with their health are less likely to present for management of benign skin lesions. We also considered the possibility of an alternative model for a link between BP and cancer, that of an underlying genetic predisposition to both diseases, a hypothesis consistent with their non-concurrent onset. No HLA differences in respect of the A, B or C loci were detected between cancer-BP patients, non-cancer-BP patients and controls. Though the numbers are small it is of interest that three of the seven patients with both BP and cancer were HLA-DR 13 positive compared to only 9% of our local population. If confirmed, a link between this antigen and cancer-proneness in BP patients would not readily be explicable in terms of the theory that a breakdown in immunosurveillance predisposes to cancer. The DR-13 antigen contributes to the DR-6 phenotype, which in renal transplant recipients has been associated with heightened rather than impaired immune responsiveness.^''^* However, if this association with DR 13 is borne out and confirmed as a marker for cancer-associated cases of BP when larger number of cases are studied, then reappraisal of our figures with inclusion of temporally remote tumours would be valid, making the excess incidence of tumours in the BP group more highly significant. Previous authors have cited a parallel course between the two diseases as further evidence in support of a causal link;*'" none of the patients in this study had a parallel clinical course. Despite previous reports that cancer-associated BP is commoner in patients with seronegative gp2i-23 Qj. occurs with morphologically atypical BP*''^ we have been unable to confirm these findings. Comparison of cancer-associated BP with non-cancer-associated BP patients in respect of the lesion morphology and distribution, mucous membrane involvement and immunopathological findings identified no subgroup at increased risk of cancer. We conclude that the rate of malignant disease (past, concurrent or during follow-up) in BP patients is higher than in controls, though a proportion of these cases may be of doubtful significance. Disallowing doubtful cases reduces the incidence to 60%, similar to the overall incidence in controls. There is probably an excess of cancers clustering around the time of onset of BP though the exact magnitude of this increased risk is difficult to estimate. This level of risk does not support the case for extensive investigations in patients presenting with BP as the detection of cancer at presentation is likely to be low. There also does not appear to be any identifiable subgroup of BP for whom extensive investigations would be indicated. Further studies are needed to determine whether cancer-associated BP is linked to HLA-DR phenotype.
BP and malignant disease
445
ACKNOWLEDGMENTS
We gratefully acknowledgefinancialsupport for the HLA typing from the Oxfordshire District Cancer Research Fund, and statistical advice from Dr Michael Goldacre. REFERENCES 1 Stone SP, Schroeter AL. Bullous pemphigoid and associated malignant neoplasms. Arch Dermatol 1975; 111:991-4. 2 Tanaka T, Ogino A, Ogura K, Nakagawa K. A case of bullous pemphigoid and transitional cell carcinoma of the bladder. Arch Dermatol 1983; 119: 704-5. 3 Amer MH, Akthar M, Mackey DM, Butler PG. Bullous pemphigoid after chemotherapy for choriocarcinoma. IntJ Dermatol 1982; 21: 32-5. 4 Binet O, Brunetiere RA, Rabary G et al. Immunologic studies of bulious pemphigoid associated with carcinoma of the colon. New Engl J Med 1983; 308: 460-1. 5 Abadir R, Emery EW, Hare PJ. Pemphigoid, bronchial neoplasm and radiotherapy. Proc R Sec Med 1967; 60:12712.
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