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Bowen's disease and internal malignancy
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Bowen's disease and internal malignancy A matched case-control study Tsu-Yi Chuang, M.D., M.P.H., and George T. Reizner, M.D. Madison, WI Bowen's disease has been reported as a skin marker for internal malignancy. We conducted a matched case-control study to evaluate the significance of this link. Fifty white men with Bowen's disease diagnosed between 1977 and 1986 at a Veterans Administration Hospital were selected for study. These patients were matched by age, sex, race, and date of skin biopsy to 50 patients with basal cell carcinoma (control group 1) and another 50 patients with other dermatoses (control group 2). The original 50 patients with Bowen's disease include 12 (24%) with various internal malignancies. In comparison, nine patients (18%) in control group 1 and seven patients (14%) in control group 2 had internal malignancies. These numbers do not substantiate a statistically significant increase in the frequency of internal malignancies in Bowen's disease. We therefore conclude that Bowen's disease is not a skin marker for internal malignancy in elderly white men. (J AM ACADDERMATOL 1988;19:47-51 .)
B o w e n ' s disease was reported to be associated with internal malignancy by Graham and Helwig' in 1959. Several subsequent reports 2-7 have shared this view. However, these reports have been criticized for their lack of appropriate control groups. 8"9 A different study conducted by Andersen et al. m found no significant differences bet w e e n the observed and expected rates of internal m a l i g n a n c y in 207 consecutive patients with Bowe n ' s disease. These divergent conclusions are discussed at length in the book, Controversies in Dermatology, :~ yet the controversy remains unresolved. T h e present study is designed to determine if
From the Section of Dermatology, University of Wisconsin, and Dermatology Section, Medical Service, Win. S. Middleton Memorial Veterans Administration Hospital. Supported in 15art by Veterans Administration Merit Review Board Grant and the University of Wisconsin R & D Grant. Accepted for publication Nov. 12, 1987. Reprint requests to: Dr. Tsu-Yi Chuang, Section of Dermatology, University of Wisconsin Hospital and Clinics, 600 Highland Ave., J5/214 CSC, Madison, WI 53792.
the link between Bowen's disease and internal malignancy can be substantiated by following 50 patients with Bowen's disease and 100 matched control patients. SUBJECTS AND METHODS Sixty-eight veterans seen at the Wm. S. Middleton Memorial Veterans Administration Hospital, Madison, WI, between December 1977 and September 1986 had biopsy-proved Bowen's disease (squamous cell carcinoma in situ). Eighteen patients could not be followed because of their transfer to other Veterans Administration hospitals or the unavailability of their medical charts. The remaining 50 patients with Bowen's disease were white men with an average age Of 69 years at the time of diagnosis. One hundred patients were selected as controls from 2600 patients who had 3000 skin biopsies at the Veterans Administration hospital during the same period. Controls were matched with cases according to age, sex, race, and date of biopsy. These parameters were selected because the frequency of cancer, regardless of its location, is related to the patient's age, sex, and race. ~2 Furthermore, the timing of the biopsy or diagnosis may influence the length of follow-up and the 4'7
J o u r n a l of t h e American Academy of Dermatology
48 Chuang and Reizner
Table I. Comparability of case and
Table II. Occurrence of internal malignancy
control groups Case group
No. of patients Age at biopsy (yr) Mean SD Range Age at last follow-up (yr) Sex Race Observation period (yr)*
Control group 1
Control group 2
50
50
50
68.8 12.1 35-91 70.9
68.6 12.2 33-91 70.8
68.7 11.9 35-95 70.7
Male White 9.7
Male White 8.7
Male White 8.7
*Observation period is from first clinical visit to Veterans Administration Hospital to last visit or death.
decision to investigate for a second malignancy. These features of case and control groups are presented in Table I, which shows the groups as quite compatible. The control patients were split into two groups. The first 50 patients (control group 1) had biopsy-proved basal cell carcinoma within 1 month of biopsy for Bowen's disease in its matched case. The second 50 patients (control group 2) had dermatoses other than skin cancer ranging from dermatitis to keratosis, all of which were proved by biopsy. Again, these were diagnosed within 1 month of the matched case's biopsy for Bowen's disease. The medical records of both cases and controls were reviewed and the following information was abstracted: date of birth, dates of onset and first diagnosis of Bowen's disease (or basal cell carcinoma and other dermatoses), date of first clinical visit, last follow-up examination, status at time of last follow-up examination, location and number of Bowen's disease (or basal cell carcinoma and other demmtoses) lesions, recurrence of Bowen's disease, and occurrence, nature, and onset of second malignancy. The observation period is defined as the time lapsing from the first clinic visit to the Veterans Administration hospital, for any reason, to the last clinic visit or death. In this study, squamous cell carcinoma in situ is considered synonymous with Bowen's disease. The McNemar test for matched-pair comparisons '3,14 was used to analyze statistically the significance of a second malignancy in case and control patients. About 30% of patients with Bowen's disease have internal
No. of patients with cancer (%) Cancer occurred before biopsyt Cancer occurred after biopsy'["
Case group
Control group 1
Control group 2
12 (24%)
9 (18%)
7 (14%)*
7
7
6
5
2
1
*If two patients with melanoma and one with mycosis fungoides are included, the figure is 10 (20%). tBiopsy for Bowen's disease, basal cell carcinoma, or other dermatoses.
malignancy. ~-7Based on incidence data in Connecticut, however, it is expected that only 10% of the normal population at age 60 years might have internal malignancy over a 10-year period, j2 With a statistical power of 0.83 to detect this difference in malignancy occurrence rates (30% versus 10% at the p = 0.05 level lone-sided]), we needed 50 patients for either case or control groups. ~s RESULTS The average observation periods for the original Bowen's disease group, control group I, a n d control group 2 are 9.7, 8.7, and 8.7 years, respectively (Table I). The average lengths of follow-up after the biopsy for skin disorder for these groups are 2.2, 2.2, and 2.0 years, respectively. There is only one patient with Bowen's disease whose age at biopsy is under 53 years. His disease was diagnosed at age 35 and he has been followed for 6 years. The occurrence of intemai malignancy during these periods is shown in Table II. Twelve patients with B o w e n ' s disease (24%) had internal malignancy. One patient had two B o w e n ' s disease lesions on the trunk. Each of the remaining 11 patients had only one lesion. The McNemar test for matched-pair comparison primarily looks at pairs of patients (one case and one control) in which either, but not both, develop a malignancy. These results are shown in Table HI. There is no statistically significant difference in the occurrence of internal malignancy b e t w e e n the groups.
Volume 19 N u m b e r 1, Part 1 July 1988
Bowen's disease and internal malignancy 49
Table III. Statistical comparison
Comparison
Case vs control group 1 Observation period Follow-up period Case vs control group 2 Observation period Exclude skin malignancy? Include skin malignancyt Follow-up period
No. of pairs in which ease had cancer but control did not
No. of pairs in which control had cancer
I I
p-value,
but case did not
two-sided*
9
6
5
2
0.608 0.453
11 10 5
6 8 1
0.238 0.814 0.219
The observation period is the period from the first clinical visit date to the last follow-up date; the follow-up period is the period from the biopsy date to the last follow-up date. *McNemar test for matched-pair comparison. ?There were three patients in control group 2 who had melanoma or mycosis fungoides.
Among the 12 patients with Bowen's disease and internal malignancy, in five the malignancy had developed during an average of 2.7 years after the diagnosis of Bowen's disease (range 0 to 4 years). One patient developed intramedullary B cell lymphoma 3 months after the diagnosis of Bowen's disease. Two patients had cancer 2 years later, one with lung cancer and the other with leukemia. The last two patients had cancer 4 years later, one with lung cancer and the other with renal cancer. In control group 1, two patients developed internal malignancy after diagnosis of their biopsyproved skin disorder, while in control group 2 only one patient developed an internal malignancy. These differences are not statistically significant (McNemar test, two-sided, p = 0.453 for case versus control group 1; p = 0.219 for case versus control group 2). As shown in Table IV, there is no single type of malignancy that occurred more frequently in the group with Bowen's disease when compared with the control groups. The data are also analyzed for both the group with Bowen's disease and control group 1 when tumors on sun-exposed and non-sun-exposed areas are considered. Thirty-nine patients developed Bowen's disease on sun-exposed areas such as the face, ear, neck, forearms, and hands. The 11 remaining patients developed Bowen's disease on non-sun-exposed areas in the upper and lower trunk. In the non-sun-exposed group, five (45%)
developed malignancies, two of which developed subsequent to the diagnosis of Bowen's disease. In comparison, six patients in control group 1 had basal cell carcinoma on non-sun-exposed areas and two of these (33%) developed internal malignancies (one of the malignancies developed after the diagnosis of basal cell carcinoma). The occurrence of malignancy among patients who had either Bowen's disease or basal cell carcinoma on non-sun-exposed skin does not differ significantly (McNemar test, p = 0.453, two-sided). Control group 2 is not selected for this comparison because it contains a variety of dermatoses in which either sun-exposed or non-sun-exposed area carries no notable meaning. DISCUSSION
The present study shows there is no increase in internal malignancy among patients with Bowen's disease when compared with matched controls. Data indicate that most malignancies occur before the diagnosis of Bowen's disease, and that no particular malignancy developed more frequently in the patients with Bowen's disease than in the controis. Furthermore, patients with Bowen's disease on non-sun-exposed skin did not carry a higher risk of developing internal malignancy when compared with the controls with basal cell carcinoma on non-sun-exposed skin. These observations may draw criticism in three areas: (1) the "biased" selection of patients, (2) a
50
Journal of the American Academy of Dermatology
Chuang and Reizner
Table IV. Types of internal malignancy in case and control groups Control group
Control group
Type
Case
1
2
Lung Lcukemia/lymphoma Prostate Renal Gastroenterologic Other
3 3 2 1 0 3
3 1 0 0 2 3
0 3* 3* 1 1 0
*One patient had lymphoma and prostate cancer.
small sample size, and (3) the low frequency of internal malignancy. These Veterans Administration Hospital patients were all male, white, and elderly. However, we feel this "biased" selection is unlikely to alter the conclusion we reached. Bowen's disease more commonly presents in elderly persons, as noted in many Bowen's disease-related articles. ~-7'~~Previous reports also show that sex does not play a significant role in determining whether patients develop an internal malignancy. 4'6 Finally, the reports by Graham and Helwig are composed primarily of white patients. ~.2Regardless, bias in the present series was controlled by selecting matched cases and controls with compatible age, sex, and race from one source. Unfortunately, we do not have information regarding young patients, female patients, or patients with other ethnic backgrounds. Our small patient number (50) could be why we detected no statistically significant difference in observed internal malignancy between case and control patients. However, this sample size is presumably adequate to detect the difference in malignancy occurrence rates among case and control groups at the level o f p = 0.05. It is in fact more than the number of patients (35) collected by Graham and Helwig in their first report, ~ which indicated a significant difference in malignancy occurrence rates. Subsequent reports range from only I1 to 72 patients) 7 Ironically, the largest series of patients (207 cases) is the one that fails to support any link between Bowen's disease and internal malignancy.l~ We report a "low" frequency of internal malig-
nancy (24%) among patients with Bowen's disease. Graham and Helwig t observed 69% of patients with Bowen's disease and internal malignancy (excluding skin cancer), while others cited 16% to 36%. 2-7 Our numbers are well within this range and in fact very close to the rate (25%) calculated from the follow-up article by Graham and Helwig in 1961.2 In addition, Andersen et al. ~0 reported an 11% frequency of malignancy subsequent to the diagnosis of Bowen's disease; we observed 10%. Arbesman and Ransohoff9 addressed well the problems that detracted from prior articles supporting a link between Bowen's disease and internal malignancy. First, there were no comparison or control groups at all, which flawed four reports) ,3'5'7 Second was the inclusion of internal malignancies that occurred before the development of Bowen's disease. Bowen's disease should not be called a skin marker for an internal malignancy that has already been diagnosed for quite some time. This flaw occurred in two reports. 4'6 Third is the selection of a biased group of patients with Bowen's disease as in the first report by Graham and Helwig.~ They selected a group of patients who died from a variety of disorders including malignancy. Such a selection may erroneously gather a higher number of patients with internal malignancy. By reviewing Table VI of their article, we find that 76% of 29 deceased patients with Bowen's disease had internal malignancy and 63 % of 35 deceased patients with senile keratoses had malignancy. Although both groups of patients had exceedingly high rates of internal malignancy, the rate difference cited is not statistically significant (p = 0.30). Similar and additional shortcomings have also been identified by Andersen et aF ~ and Chuang and Ilstrup) In addition to these problems, misclassification should also be considered. Different authors may categorize Bowen's disease by different criteria. The spectrum of non-sun-exposed areas includes upper and lower extremities in the article by Peterka et al., ~ but only lower extremities in the article by Callen and Headington. 6 In our series non-sun-exposed areas are limited to the trunk. Arsenic exposure could be a possible common cause for both Bowen's disease and internal ma-
Volume 19 Number I, Part 1 July 1988
l i g n a n c y . However, such exposure has been rep o r t e d only rarely. 6,1~In our study there is no reco r d o f arsenic e x p o s u r e in our case and control g r o u p s . Nonetheless, this information is better obt a i n e d through a comprehensive medical history a n d tests, which we did not pursue. I n conclusion, we do not find enough evidence to substantiate a link between B o w e n ' s disease and i n t e r n a l malignancy. W e therefore believe extens i v e investigation for internal malignancy in patients with B o w e n ' s disease is unwarranted. REFERENCES I. Graham JH, Helwig ED. Bowen's disease and its relationship to systemic cancer. Arch Dermatol 1959;80:13359. 2. Graham JH, Helwig EB. Bowen's disease and its relationship to systemic cancer. Arch Dermatol 1961;83:73858. 3. Epstein E. Association of Bowen's disease with visceral cancer. Arch Dermatol 1960;80:349-51. 4. Peterka ES, Lynch FW, Goltz RW. An association between Bowen's disease and internal cancer. Arch Dermatol 1961;84:623-9. 5. Hugo NE, Conway H. Bowen's disease. Its malignant potential and relationship to systemic cancer. Plast Reconstr Surg 1967;39:190-4.
Bowen's disease and internal malignancy 51
6. Callen JP, Headington J. Bowen's and non-Bowen's squamous intraepidennal neoplasia of the skin: relationship to internal malignancy. Arch Dermatol 1980;116: 422-6. 7. Miki Y, Kawatsu T, Matsuda K, Machino H, Kubo K. Cutaneous and pulmonary cancers associated with Bowen's disease. J AM ACADDERMATOL1982;6:26-31. 8. Chuang T-Y, Ilstrup DM. Relationship of Bowen's and non-Bowen's squamous intraepidermal neoplasia to internal malignant neoplasms. Arch Dermatol 1981;117: 317-8. 9. Arbesman H, Ransohoff DF. Is Bowen's disease a predictor for the development of internal malignancy? A methodological critique of the literature. JAMA 1987; 257:516-8. 10. Andersen SLC, Nielsen A, Reymann F. Relationship between Bowen disease and internal malignant tumors. Arch Dermatol 1973;108:367-70. 11. Epstein E, ed. Controversies in dermatology. Philadelphia: WB Saunders, 1984:86-95. 12, Heston JF. Forty-five years of cancer incidence in Connecticut, 1935-1979. Nail Cancer Inst Monogr 1986; 70:1-111. 13. Conover WL Practical nonparametric statistics. New York: John Wiley & Sons, 1971. 14. Fless JL. Statistical methods for rates and proportions. New York: John Wiley & Sons, 1973. 15. Schlesselman JI, Stolley PD. Case-control studies, design, conduct, analysis. New York: Oxford University Press, 1982.
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II
ill
III
Bowen's disease and internal malignancy A matched case-control study Tsu-Yi Chuang, M.D., M.P.H., and George T. Reizner, M.D. Madison, WI Bowen's disease has been reported as a skin marker for internal malignancy. We conducted a matched case-control study to evaluate the significance of this link. Fifty white men with Bowen's disease diagnosed between 1977 and 1986 at a Veterans Administration Hospital were selected for study. These patients were matched by age, sex, race, and date of skin biopsy to 50 patients with basal cell carcinoma (control group 1) and another 50 patients with other dermatoses (control group 2). The original 50 patients with Bowen's disease include 12 (24%) with various internal malignancies. In comparison, nine patients (18%) in control group 1 and seven patients (14%) in control group 2 had internal malignancies. These numbers do not substantiate a statistically significant increase in the frequency of internal malignancies in Bowen's disease. We therefore conclude that Bowen's disease is not a skin marker for internal malignancy in elderly white men. (J AM ACADDERMATOL 1988;19:47-51 .)
B o w e n ' s disease was reported to be associated with internal malignancy by Graham and Helwig' in 1959. Several subsequent reports 2-7 have shared this view. However, these reports have been criticized for their lack of appropriate control groups. 8"9 A different study conducted by Andersen et al. m found no significant differences bet w e e n the observed and expected rates of internal m a l i g n a n c y in 207 consecutive patients with Bowe n ' s disease. These divergent conclusions are discussed at length in the book, Controversies in Dermatology, :~ yet the controversy remains unresolved. T h e present study is designed to determine if
From the Section of Dermatology, University of Wisconsin, and Dermatology Section, Medical Service, Win. S. Middleton Memorial Veterans Administration Hospital. Supported in 15art by Veterans Administration Merit Review Board Grant and the University of Wisconsin R & D Grant. Accepted for publication Nov. 12, 1987. Reprint requests to: Dr. Tsu-Yi Chuang, Section of Dermatology, University of Wisconsin Hospital and Clinics, 600 Highland Ave., J5/214 CSC, Madison, WI 53792.
the link between Bowen's disease and internal malignancy can be substantiated by following 50 patients with Bowen's disease and 100 matched control patients. SUBJECTS AND METHODS Sixty-eight veterans seen at the Wm. S. Middleton Memorial Veterans Administration Hospital, Madison, WI, between December 1977 and September 1986 had biopsy-proved Bowen's disease (squamous cell carcinoma in situ). Eighteen patients could not be followed because of their transfer to other Veterans Administration hospitals or the unavailability of their medical charts. The remaining 50 patients with Bowen's disease were white men with an average age Of 69 years at the time of diagnosis. One hundred patients were selected as controls from 2600 patients who had 3000 skin biopsies at the Veterans Administration hospital during the same period. Controls were matched with cases according to age, sex, race, and date of biopsy. These parameters were selected because the frequency of cancer, regardless of its location, is related to the patient's age, sex, and race. ~2 Furthermore, the timing of the biopsy or diagnosis may influence the length of follow-up and the 4'7
J o u r n a l of t h e American Academy of Dermatology
48 Chuang and Reizner
Table I. Comparability of case and
Table II. Occurrence of internal malignancy
control groups Case group
No. of patients Age at biopsy (yr) Mean SD Range Age at last follow-up (yr) Sex Race Observation period (yr)*
Control group 1
Control group 2
50
50
50
68.8 12.1 35-91 70.9
68.6 12.2 33-91 70.8
68.7 11.9 35-95 70.7
Male White 9.7
Male White 8.7
Male White 8.7
*Observation period is from first clinical visit to Veterans Administration Hospital to last visit or death.
decision to investigate for a second malignancy. These features of case and control groups are presented in Table I, which shows the groups as quite compatible. The control patients were split into two groups. The first 50 patients (control group 1) had biopsy-proved basal cell carcinoma within 1 month of biopsy for Bowen's disease in its matched case. The second 50 patients (control group 2) had dermatoses other than skin cancer ranging from dermatitis to keratosis, all of which were proved by biopsy. Again, these were diagnosed within 1 month of the matched case's biopsy for Bowen's disease. The medical records of both cases and controls were reviewed and the following information was abstracted: date of birth, dates of onset and first diagnosis of Bowen's disease (or basal cell carcinoma and other dermatoses), date of first clinical visit, last follow-up examination, status at time of last follow-up examination, location and number of Bowen's disease (or basal cell carcinoma and other demmtoses) lesions, recurrence of Bowen's disease, and occurrence, nature, and onset of second malignancy. The observation period is defined as the time lapsing from the first clinic visit to the Veterans Administration hospital, for any reason, to the last clinic visit or death. In this study, squamous cell carcinoma in situ is considered synonymous with Bowen's disease. The McNemar test for matched-pair comparisons '3,14 was used to analyze statistically the significance of a second malignancy in case and control patients. About 30% of patients with Bowen's disease have internal
No. of patients with cancer (%) Cancer occurred before biopsyt Cancer occurred after biopsy'["
Case group
Control group 1
Control group 2
12 (24%)
9 (18%)
7 (14%)*
7
7
6
5
2
1
*If two patients with melanoma and one with mycosis fungoides are included, the figure is 10 (20%). tBiopsy for Bowen's disease, basal cell carcinoma, or other dermatoses.
malignancy. ~-7Based on incidence data in Connecticut, however, it is expected that only 10% of the normal population at age 60 years might have internal malignancy over a 10-year period, j2 With a statistical power of 0.83 to detect this difference in malignancy occurrence rates (30% versus 10% at the p = 0.05 level lone-sided]), we needed 50 patients for either case or control groups. ~s RESULTS The average observation periods for the original Bowen's disease group, control group I, a n d control group 2 are 9.7, 8.7, and 8.7 years, respectively (Table I). The average lengths of follow-up after the biopsy for skin disorder for these groups are 2.2, 2.2, and 2.0 years, respectively. There is only one patient with Bowen's disease whose age at biopsy is under 53 years. His disease was diagnosed at age 35 and he has been followed for 6 years. The occurrence of intemai malignancy during these periods is shown in Table II. Twelve patients with B o w e n ' s disease (24%) had internal malignancy. One patient had two B o w e n ' s disease lesions on the trunk. Each of the remaining 11 patients had only one lesion. The McNemar test for matched-pair comparison primarily looks at pairs of patients (one case and one control) in which either, but not both, develop a malignancy. These results are shown in Table HI. There is no statistically significant difference in the occurrence of internal malignancy b e t w e e n the groups.
Volume 19 N u m b e r 1, Part 1 July 1988
Bowen's disease and internal malignancy 49
Table III. Statistical comparison
Comparison
Case vs control group 1 Observation period Follow-up period Case vs control group 2 Observation period Exclude skin malignancy? Include skin malignancyt Follow-up period
No. of pairs in which ease had cancer but control did not
No. of pairs in which control had cancer
I I
p-value,
but case did not
two-sided*
9
6
5
2
0.608 0.453
11 10 5
6 8 1
0.238 0.814 0.219
The observation period is the period from the first clinical visit date to the last follow-up date; the follow-up period is the period from the biopsy date to the last follow-up date. *McNemar test for matched-pair comparison. ?There were three patients in control group 2 who had melanoma or mycosis fungoides.
Among the 12 patients with Bowen's disease and internal malignancy, in five the malignancy had developed during an average of 2.7 years after the diagnosis of Bowen's disease (range 0 to 4 years). One patient developed intramedullary B cell lymphoma 3 months after the diagnosis of Bowen's disease. Two patients had cancer 2 years later, one with lung cancer and the other with leukemia. The last two patients had cancer 4 years later, one with lung cancer and the other with renal cancer. In control group 1, two patients developed internal malignancy after diagnosis of their biopsyproved skin disorder, while in control group 2 only one patient developed an internal malignancy. These differences are not statistically significant (McNemar test, two-sided, p = 0.453 for case versus control group 1; p = 0.219 for case versus control group 2). As shown in Table IV, there is no single type of malignancy that occurred more frequently in the group with Bowen's disease when compared with the control groups. The data are also analyzed for both the group with Bowen's disease and control group 1 when tumors on sun-exposed and non-sun-exposed areas are considered. Thirty-nine patients developed Bowen's disease on sun-exposed areas such as the face, ear, neck, forearms, and hands. The 11 remaining patients developed Bowen's disease on non-sun-exposed areas in the upper and lower trunk. In the non-sun-exposed group, five (45%)
developed malignancies, two of which developed subsequent to the diagnosis of Bowen's disease. In comparison, six patients in control group 1 had basal cell carcinoma on non-sun-exposed areas and two of these (33%) developed internal malignancies (one of the malignancies developed after the diagnosis of basal cell carcinoma). The occurrence of malignancy among patients who had either Bowen's disease or basal cell carcinoma on non-sun-exposed skin does not differ significantly (McNemar test, p = 0.453, two-sided). Control group 2 is not selected for this comparison because it contains a variety of dermatoses in which either sun-exposed or non-sun-exposed area carries no notable meaning. DISCUSSION
The present study shows there is no increase in internal malignancy among patients with Bowen's disease when compared with matched controls. Data indicate that most malignancies occur before the diagnosis of Bowen's disease, and that no particular malignancy developed more frequently in the patients with Bowen's disease than in the controis. Furthermore, patients with Bowen's disease on non-sun-exposed skin did not carry a higher risk of developing internal malignancy when compared with the controls with basal cell carcinoma on non-sun-exposed skin. These observations may draw criticism in three areas: (1) the "biased" selection of patients, (2) a
50
Journal of the American Academy of Dermatology
Chuang and Reizner
Table IV. Types of internal malignancy in case and control groups Control group
Control group
Type
Case
1
2
Lung Lcukemia/lymphoma Prostate Renal Gastroenterologic Other
3 3 2 1 0 3
3 1 0 0 2 3
0 3* 3* 1 1 0
*One patient had lymphoma and prostate cancer.
small sample size, and (3) the low frequency of internal malignancy. These Veterans Administration Hospital patients were all male, white, and elderly. However, we feel this "biased" selection is unlikely to alter the conclusion we reached. Bowen's disease more commonly presents in elderly persons, as noted in many Bowen's disease-related articles. ~-7'~~Previous reports also show that sex does not play a significant role in determining whether patients develop an internal malignancy. 4'6 Finally, the reports by Graham and Helwig are composed primarily of white patients. ~.2Regardless, bias in the present series was controlled by selecting matched cases and controls with compatible age, sex, and race from one source. Unfortunately, we do not have information regarding young patients, female patients, or patients with other ethnic backgrounds. Our small patient number (50) could be why we detected no statistically significant difference in observed internal malignancy between case and control patients. However, this sample size is presumably adequate to detect the difference in malignancy occurrence rates among case and control groups at the level o f p = 0.05. It is in fact more than the number of patients (35) collected by Graham and Helwig in their first report, ~ which indicated a significant difference in malignancy occurrence rates. Subsequent reports range from only I1 to 72 patients) 7 Ironically, the largest series of patients (207 cases) is the one that fails to support any link between Bowen's disease and internal malignancy.l~ We report a "low" frequency of internal malig-
nancy (24%) among patients with Bowen's disease. Graham and Helwig t observed 69% of patients with Bowen's disease and internal malignancy (excluding skin cancer), while others cited 16% to 36%. 2-7 Our numbers are well within this range and in fact very close to the rate (25%) calculated from the follow-up article by Graham and Helwig in 1961.2 In addition, Andersen et al. ~0 reported an 11% frequency of malignancy subsequent to the diagnosis of Bowen's disease; we observed 10%. Arbesman and Ransohoff9 addressed well the problems that detracted from prior articles supporting a link between Bowen's disease and internal malignancy. First, there were no comparison or control groups at all, which flawed four reports) ,3'5'7 Second was the inclusion of internal malignancies that occurred before the development of Bowen's disease. Bowen's disease should not be called a skin marker for an internal malignancy that has already been diagnosed for quite some time. This flaw occurred in two reports. 4'6 Third is the selection of a biased group of patients with Bowen's disease as in the first report by Graham and Helwig.~ They selected a group of patients who died from a variety of disorders including malignancy. Such a selection may erroneously gather a higher number of patients with internal malignancy. By reviewing Table VI of their article, we find that 76% of 29 deceased patients with Bowen's disease had internal malignancy and 63 % of 35 deceased patients with senile keratoses had malignancy. Although both groups of patients had exceedingly high rates of internal malignancy, the rate difference cited is not statistically significant (p = 0.30). Similar and additional shortcomings have also been identified by Andersen et aF ~ and Chuang and Ilstrup) In addition to these problems, misclassification should also be considered. Different authors may categorize Bowen's disease by different criteria. The spectrum of non-sun-exposed areas includes upper and lower extremities in the article by Peterka et al., ~ but only lower extremities in the article by Callen and Headington. 6 In our series non-sun-exposed areas are limited to the trunk. Arsenic exposure could be a possible common cause for both Bowen's disease and internal ma-
Volume 19 Number I, Part 1 July 1988
l i g n a n c y . However, such exposure has been rep o r t e d only rarely. 6,1~In our study there is no reco r d o f arsenic e x p o s u r e in our case and control g r o u p s . Nonetheless, this information is better obt a i n e d through a comprehensive medical history a n d tests, which we did not pursue. I n conclusion, we do not find enough evidence to substantiate a link between B o w e n ' s disease and i n t e r n a l malignancy. W e therefore believe extens i v e investigation for internal malignancy in patients with B o w e n ' s disease is unwarranted. REFERENCES I. Graham JH, Helwig ED. Bowen's disease and its relationship to systemic cancer. Arch Dermatol 1959;80:13359. 2. Graham JH, Helwig EB. Bowen's disease and its relationship to systemic cancer. Arch Dermatol 1961;83:73858. 3. Epstein E. Association of Bowen's disease with visceral cancer. Arch Dermatol 1960;80:349-51. 4. Peterka ES, Lynch FW, Goltz RW. An association between Bowen's disease and internal cancer. Arch Dermatol 1961;84:623-9. 5. Hugo NE, Conway H. Bowen's disease. Its malignant potential and relationship to systemic cancer. Plast Reconstr Surg 1967;39:190-4.
Bowen's disease and internal malignancy 51
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