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Recurrent condyloma acuminatum in women over age 40: Association with immunosuppression and malignant disease
Recurrent condyloma acuminatum in women over age 40: Association with immunosuppression and malignant disease Paul B. Marshburn, MD, and Kenneth F. Trofatter, Jr., MD, PhD Durham, North Carolina Sixteen women aged ;;.40 years were studied within a total population of 77 women with recalcitrant condyloma acuminatum. Six of the 16 women (38%) were found to have coincident malignant disease (p < 0.001 ). Three of these had lymphoma (non-Hodgkin's), two had squamous cell cancer of the vulva or vagina, and one had breast carcinoma. Two of the three patients with lymphoma had recurrent genital condyloma diagnosed before the coexistent lymphoproliferative disorder was discovered. In all, 11 of 16 patients had dysplasia and neoplasia. Seven of the women had other medical conditions associated with immunosuppression. We conclude that the presence of recurrent condyloma acuminatum in women ;;.40 years of age should lead to examination for the presence of immunosuppression and its underlying cause. A high index of suspicion for concomitant genital squamous cell neoplasia and lymphoproliferative disorders should be realized. The factors relating age, recurrent condyloma, immunosuppression, and malignant disease are discussed. (AM J OBSTET GYNECOL 1988;159:429-33.)
Key words: Condyloma acuminatum, immunosuppression, lymphoma, malignant disease Recurrent viral infections of certain types can indicate underlying immunosuppression. The hematopoietic defenses against many viruses are mediated largely through T lymphocytes, and evidence suggests that tumor surveillance is also a function of certain T-lymphocyte subpopulations (cytotoxic and natural killer). In patients with depressed cell-mediated immunity, therefore, one might expect to find a higher incidence of neoplasia and opportunistic viral infection. Much attention has been focused on the relationship between certain types of human papillomaviruses (e.g., types 16, 18, 31, 33, and 35) and genital squamous cell dysplasia and carcinoma. 1-5 Some authors have proposed an immunity defect that predisposes individuals to recalcitrant genital warts, which thus enhances the risk of the development of dysplasia and malignant transformation. 1· B-s Interestingly, impaired immunity has been implicated in female genital condyloma infections associated with malignant disorders in case reports.9·10 Condyloma acuminatum is usually thought of as a disease affecting younger, sexually active women; however, a correlation between the presence of cervical intraepithelial neoplasia and viral cytologic lesions caused by human papilloma viruses is more common in women over the age of 30. 1· 6 • 11 In at least one study implicating immunosuppression and malignant disorFrom the Department of Obstetrics and Gynecology, Duke University Medical Center. Received for publication November 30, 1987; accepted April 20, 1988. Reprint requests: Kenneth F. Trofatter, Jr., MD, PhD, Departments of Obstetrics and Gynecology, University of Tennessee Medical Center at Knoxville, 1924 Alcoa Highway, Knoxville, TN 37920.
ders in condyloma infections, the older patients were found to have the most recalcitrant infections. 9 There is a need for more information concerning the relationship between age, human papillomavirus infections, and associated disease states. This study focused on 16 women ;;;<40 years of age who were initially seen for management of recalcitrant condyloma acuminatum. A high incidence of neoplasia, particularly lymphoma, and genital squamous cell dysplasia and carcinoma was found. The factors relating condyloma in women ;;;<40 years to malignant disorders and immunosuppression are discussed.
Methods Patients included in this study were referred from throughout the southeastern United States to Duke University Medical Center between November 1982 and July 1984 with recurrent condyloma acuminatum. Recurrent status was designated in patients in whom at least 6 months of topical therapy had failed with > 10 attempts at therapy with podophyllum resin, trichloroacetic acid, or ablative surgical therapy. A complete history, physical examination, and baseline laboratory studies were obtained. Histologic confirmation of condyloma acuminatum was required. From a total of 77 women, 16 were aged ;;;<40. Examination of epidemiologic factors in a control population was obtained by randomly choosing 77 subjects matched by age and race being seen for gynecologic problems other than condyloma acuminatum. Comparison of data obtained from groups of patients aged ;;;<40 and those aged <40 and from normal control subjects by X2 statistical analysis.
429
430
Marshburn and Trofatter
August 1988 Am J Obstet Gynecol
Table I. Clinical data of patients aged Genital squamous dysplasia I neoplasia
Case
with recalcitrant condyloma acuminatum
~40
Hysterectomy (reason)
Other neoplasia
Immunosuppression therapy
+
Carcinoma in situ of arm
40
CIN 2
2
40
3
41
VIN 3, vulvar carcinoma (stage I)
4
41
5
42
6
46
CIN + VIN 3
7
47
CIN 3
8
48
9
48
10
49
11
49
12
53
13
55
14
57
15
59
16
63
Azathioprine + prednisone
Chronic glomerulonephritis, renal transplant, general atopy
Prednisone
Cushing's disease, PCOD, hirsutism, hypothyroidism, hypertension
+ Carcinoid of appendix, pituitary adenoma (ACTH-proclueing)
+
(DUB)
+
Irregular menses, chronic bronchitis, cutaneous warts, general atopy
+
Obesity, hypertension
+
(DUB)
+
(DUB/CIN)
+
Hirsutism
(DUB/CIN)
+
CIN 3, VIN
(Pelvic relaxation)
Idiopathic colitis Pneumocystis carinii pneu-
(CIN)
monia
+
(Unknown)
+
(DUB)
Breast carcinoma CIN 2: vaginal carcmoma (stage I)
+
+
Non- Hodgkin's lymphoma Non-Hodgkin's lymphoma
+
+
+
+
+
+
(Pelvic relaxation) (Unknown) (CIN)
+
Non-Hodgkin's lymphoma
Prednisone
Diabetes, obesity, hypertension Diabetes, general atopy Peptic ulcers, verruca vulgaris
Prednisone
(Pelvic relaxation)
+
Endometrial
Concurrent medical problems
H ypogammaglobulinemia, chronic active hepatitis Hypertension, obesity
CIN = Cervical intraepithelial neoplasia; VIN = vulvar intraepithelial neoplasia; ACTH = adrenocorticotropic hormone; DUB = dysfunctional uterine bleeding; PCOD = polycystic ovarian disease.
Table II. Comparison of women (aged
~40
versus aged <40) with recurrent condyloma acuminatum
Group
Race
Smoker
Dysfunctional uterine bleeding
Age 2:40 (n = 16)
Black:3/l6 (19%) White: 13/16 (81%) Black: 13/61 (21%) White: 48/81 (79%) NS
9116 (56%)
10116 (63%)
6/16 (38%)
4116 (25%)
2116 (13%)
6/16 (38%)
37/61 (69%)
24/61 (41%)
24/61 (41%)
3/61 (5%)
9/61 (15%)
3/61 (5%)
NS
NS
NS
NS
NS
Age <40 (n = 61) Significance
Abnormal Papanicolaou tests
Immunosuppressive therapy
Diabetes mellitus
Malignant disorder
p<
0.001
NS = No significant difference.
Results
A summary of the data for women aged ;;.:40 is presented in Table I. Included are the results of evaluation for (1) presence of genital squamous cell dysplasia and
neoplasia, (2) presence of other neoplasia, (3) history of hysterectomy and reason, (4) smoking history, (5) immunosuppressive therapy, and (6) concurrent medical problems.
Condyloma acuminatum in women over age 40
Volume 159 Number 2
10080·
D
31/31 4/4 ;..;.;_;; Abnormal Pap Smears
~
~ Genital Squamous Cell
MaHgnancy
23/31
3/4
r-
%
of Tota I (n=77)
431
60· ~
2/4
40· 20·
n
0-20
21-30
31,...40 Age (years)
41-50
>51
Fig. I. Cumulative frequency distribution of abnormal Papanicolaou test results and genital squamous cell carcinoma in women with recurrent condyloma. Numbers above bars represent actual patient numbers.
A hysterectomy had been performed in 13 of 16 women: five for dysfunctional uterine bleeding, three for carcinoma iri situ of the cervix, one for endometrial hyperplasia with atypia, and five for benign or unknown reasons. An additional four women among the eight having had hysterectomy for carcinoma in situ or benign reasons gave a history of heavy and irregular menstrual periods. In all, nine of 16 women (56%) gave a history of abnormal uterine bleeding. Six of 16 women in the age group ;;340 had a history of malignant disorders (p < 0.001) (Tables I and II): Two had invasive stage I squamous cell carcinoma of the vulva or vagina and another three had a previous diagnosis of carcinoma in situ of the cervix or vulva. In addition, of the four women aged 35 to 40 (not included in Table I), two had a stage I vulvar carcinoma and another had vulvar carcinoma in situ. Three of the four women with invasive squamous cell carcinoma had had condyloma acuminatum for at least 5 years. Wom,en with in situ disease or no dysplasia showed a similar period of exposure. Fig. 1 illustrates the cumulative frequency of the incidence of abnormal Papanicolaou test results in genital squamous cell carcinoma. Statistical analysis within the age group ;;340 showed no difference in the incidence of genital squamous cell carcinoma, but did reveal a higher incidence of other malignant disorders (p < 0.001) (Table Ill). A notable finding was the presence of lymphoma in three of the women in the group aged ;;340. Two of these women had condyloma acuminatum diagnosed before the coexistent lymphoma was discovered. AdditionaJly, two of these patients with lymphoma had concomitant long-standing undefined immunodeficiency syndromes. Both of them had progressively deteriorating clinical courses, with death following within 1 year. Four patients with recurrent condyloma had received
Table III. Genital dysplasia and malignant disease in women with and without recurrent condyloma
Group
Recurrent condyloma Age <40 Age :2:40 Age-matched controls Age <40 Age :2:40
Genital dysplasia
Genital squamous carcznoma
Nongenital malignant disease
25/61 (41%) 6116 (38%)
2/61 (5%) 2/16 (13%)
1161 (5%) 5116* (31%)
0161 0116
1116 (6%)
3/61 (5%) 3/16 (19%)
l/61 (2%)
*P
oral corticosteroid therapy for various medical conditions including severe atopy, renal transplantation, and adrenal insufficiency. In all but the recipient of renal transplant, who also required azathioprine (lmuran), adjustment of corticosteroid therapy to the lowest therapeutic dose resulted in improvement of severe genital infection (our observation). Comparison of data in the groups of patients aged .;;40 and those ;;340 with recurrent disease is presented in Tables II and III. A significant difference was found in the higher incidence of total and nongenital malignant disorders in the group ;;340. In the group <40, two women had microinvasive squamous cell carcinoma of the vulva and another had chronic myelogenous leukemia. Also, two among the patients in the younger group with recurrent disease had severe hematologic disorders ( Fanconi's aplastic anemia) and were receiving androgenic steroids for these. Data present in Table IV show that women with recalcitrant condyloma acuminatum had a higher association of smoking (p < 0.001), dysfunctional uterine bleeding (p < 0.01), abnormal Papanicolaou test re-
432
Marshburn and Trofatter
August 1988 Am J Obstet Gynecol
Table IV. Comparison of women with and without recurrent condyloma Race
Group
Recurrent condyloma (n = 77) Age-matched controls (n = 77) Significance
Black: White: Black: White:
15/77 (20%) 62/77 (80%) 15/77 (20%) 62/77 (80%) NS
Smoker
Dysfunctional uterine bleeding
Abnormal Papanicolaou tests
1177 (1%)
50177 (65%)
35/77 (45%)
31/77 (40%)
32/27 (42%)
1177 (1%)
13/77 (17%)
18177 (23%)
6177 (8%)
NS
NS
p < 0.001
p < O.Dl
p < 0.001
Multiparity
Ectopic pregtuJrtcy
30177 (39%)
suits (p < 0.001), insulin-dependent diabetes mellitus (p < 0.001), and malignant disorders (p < 0.05). No difference was found between these women and the control population when analyzed for parity or history of ectopic pregnancy. Although patients in the study group (11177) had a higher use of immunosuppressive therapy than control patients (4/77), this did not achieve statistical significance (p = 0.1). Comment
Evidence of genital infection with human papillomavirus can be found in approximately 10% of sexually active women of reproductive age. A vast majority of patients in whom condyloma acuminatum develops will undergo remission spontaneously or with conventional therapy (e.g. podophyllum resin, trichloroacetic acid, or surgical ablation). The patients in whom treatment failed are the subjects of our study. The data presented herein focus on the population of women with recurrent genital condyloma who are :;=:40 years of age. An association between this age group and both malignant disease (squamous cell carcinoma of the genital tract and lymphoma) and immunosuppression was found. A wealth of evidence has linked human papillomavirus infection of the female genital tract with the development of dysplasia and even invasive carcinoma of the cervix and the vulva. 1· 5 Cofactors such as impaired immunity may allow persistence of human papillomavirus infection, which may possibly favor the development of intraepithelial neoplasia and cancer. 1• 6 Studies on age-related frequency in patients with viral lesions caused by human papillomavirus show that whereas viral lesions were more common in women in the late teens and early 20s, there was a significantly higher incidence of cervical intraepithelial neoplasia associated with viral lesions in women aged :;=:30.6 Clinical observation suggests thai earlier exposure to human papillomavirus may push this risk for carcinoma to an even younger age group. Our data support these findings. All four cases of invasive squamous cell carcinoma (three vulvar and one vaginal) occurred in women aged >32 years with two cases in the age group :;=:40. In addition, five of seven women receiving long-term immunosuppressive therapy or with a condition predisposing to an immuno-
deficient status had biopsy-proved intraepithelial neoplasia of the vulva or cervix. These findings support those of Schneider et al. 12 who found condyloma and cervical neoplasia to be more common in immunosuppressed renal transplant recipients. The average age of the four womeh with stage I vulvar carcinoma was 41, below the commonly accepted 65 to 70 years of age for peak incidence. We report, however, too few cases to assess whether this represents a significantly earlier onset of disease in women with condyloma. A striking finding is the incidence of lymphoma in three of the 16 women with recurrent condyloma acuminatum and an age :;=:40. The association of immunosuppression with lymphoma is recognized, although the issue of whether lymphoma is the cause or the result of an immunity defect is not settled. A high incidence of lymphoma in human allograft recipients who require immunosuppressive therapy has been reported.'· 13 Anderson et al. 14 demonstrated an impairment of skin test reactivity, a sensitive test of T cell function, in patients with malignant lymphoma, especially of the diffuse histiocytic and poorly differentiated types. These authors assessed immunologic status before radiation or chemotherapy, thus adjusting for an intrinsic and not an iatrogenically induced immunodeficiency in these patients. 14 Interestingly, women with recurrent condyloma also appear to have a defect in cell-mediated immunity as shown by abnormally low lymphocyte transformation responses to the mitogens phytohemagglutinin A, concanavalin A, and pokeweed mitogen. 15 In our study, two of the three patients with lymphoma had a long history of genital condyloma acuminatum before the diagnosis of the malignant disease. This suggests that recurrent condyloma in the older population may be a first indication of immunosuppression and a presenting sign associated with occult lymphoma. All three of our patients were over age 45. Two of the three patients died soon after presentation for treatment of condyloma. Interestingly, one had diffuse histiocytic lymphoma and the others a diffuse, poorly differentiated type, the classes of lymphoma cited previously as having a broader spectrum of T -cell malfunction. 14 Comparison of our total population of women and recurrent condyloma and matched controls showed a
Condyloma acuminatum in women over age 40
Volume 159 Number 2
Immunosuppressive therapy
Diabetes mellitus
Malignant disease
11/77 (14%)
12/77 (16%)
11/77 (14%)
4/77 (5%)
1177 (1%)
2177 (3%)
NS
p < 0.001
p < 0.05
significantly higher incidence of smoking, abnormal Papanicolaou test results, dysfunctional bleeding, and malignant disease. Only malignant disease was more common in the group aged ~40 when these factors were examined within the entire population of patients with recurrent condyloma. In summary, women over age 40 with recurrent condyloma acuminatum should be examined for the presence of immunosuppression and i~s underlying cause. A high index of suspicion for concomitant genital squamous cell and lymphoproliferative carcinoma should be realized. The search for coexistent diabetes mellitus or medications that may predispose to immunosuppression is important for optimal control of infection. We wish to thank john Soper, MD,Joe Lanman, PhD, and the staff at Duke University Medical Center for their comments and assistance in this study. REFERENCES 1. Meisels A, Morin C, Casas-Cordero M, Rabreau M. Human papillomavirus (HPV) venereal infections and gynecologic cancer. Pathol Annu 1983;18:277.
433
2. Crum CP, Levine RV. Human papillomavirus infection and cervical neoplasia: new perspectives. Int 1 Gynecol Pathol 1984;3:376. 3. Steffen C. Concurrence of condylomata acuminata and bowenoid papulosis. Am1 Dermatopathol1982;4:5. 4. Ejeckam GC, Idikio HA, Nayak V, Gardiner 1P. Malignant transformation in an anal condyloma acumi'natum. Can 1 Surg 1983;26: 170. 5. Chuang T-Y, Perry HO, Kurland LT, Ilstrup DM. Condyloma acuminatum in Rochester, Minnesota, 1950-1978. Arch Dermatol 1984;120:476. 6. Virgiliis G, Mauri L, Masserini M, et al. Age-related frequency of viral lesions and their association with uterine cervical intraepithelial neoplasia. Tumori 1982;68:465. 7. Hoover R, Fraumeni 1F. Risk of cancer in renal transplant recipients. Lancet 1973;2:55. 8. Ferenczy A, Masaru M, Nagai N, Silverstein S, Crum C. Latent papillomavirus and recurring genital warts. N Engl 1 Med 1985;313:784. 9. Lowell DM, LiVolsi VA, Ludwig ME. Genital condyloma virus infection following pelvic radiation therapy: report of seven cases. Int 1 Gynecol Pathol 1983;2:294. 10. Shokri-Tabibzadeh S, Koss LG, Molnar 1. Romney S. Association of human papillomavirus with neoplastic processes in the genital tract of four women with impaired immunity. Gynecol Oncol 1981;12:5129. 11. Schmauz R, Owor R. Condylomatous tumors of vulva, vagina and penis. 1 Clin Pathol 1980;33:1039. 12. Schneider V, Kay S, Huyung ML. Immunosuppression as a high risk factor in the development of condyloma acuminatum and squamous neoplasia of the cervix. Acta Cytol 1983;27:220. 13. Penn I. Tumor incidence in human allograft recipients. Transplant Proc 1979;11:1047. 14. Anderson TC,1ones SE, Soehnlen B1, Moon TE, Griffith K, Stanley P. Immunocompetence and malignant lymphoma: immunologic status before therapy. Cancer 1981; 12:2702. 15. Seski 1C, Reinhalter ER, Silva J. Abnormalities of lymphocyte transformations in women with condylomata acuniinata. Obstet Gyriecol 1978;51: 188.
Key words: Condyloma acuminatum, immunosuppression, lymphoma, malignant disease Recurrent viral infections of certain types can indicate underlying immunosuppression. The hematopoietic defenses against many viruses are mediated largely through T lymphocytes, and evidence suggests that tumor surveillance is also a function of certain T-lymphocyte subpopulations (cytotoxic and natural killer). In patients with depressed cell-mediated immunity, therefore, one might expect to find a higher incidence of neoplasia and opportunistic viral infection. Much attention has been focused on the relationship between certain types of human papillomaviruses (e.g., types 16, 18, 31, 33, and 35) and genital squamous cell dysplasia and carcinoma. 1-5 Some authors have proposed an immunity defect that predisposes individuals to recalcitrant genital warts, which thus enhances the risk of the development of dysplasia and malignant transformation. 1· B-s Interestingly, impaired immunity has been implicated in female genital condyloma infections associated with malignant disorders in case reports.9·10 Condyloma acuminatum is usually thought of as a disease affecting younger, sexually active women; however, a correlation between the presence of cervical intraepithelial neoplasia and viral cytologic lesions caused by human papilloma viruses is more common in women over the age of 30. 1· 6 • 11 In at least one study implicating immunosuppression and malignant disorFrom the Department of Obstetrics and Gynecology, Duke University Medical Center. Received for publication November 30, 1987; accepted April 20, 1988. Reprint requests: Kenneth F. Trofatter, Jr., MD, PhD, Departments of Obstetrics and Gynecology, University of Tennessee Medical Center at Knoxville, 1924 Alcoa Highway, Knoxville, TN 37920.
ders in condyloma infections, the older patients were found to have the most recalcitrant infections. 9 There is a need for more information concerning the relationship between age, human papillomavirus infections, and associated disease states. This study focused on 16 women ;;;<40 years of age who were initially seen for management of recalcitrant condyloma acuminatum. A high incidence of neoplasia, particularly lymphoma, and genital squamous cell dysplasia and carcinoma was found. The factors relating condyloma in women ;;;<40 years to malignant disorders and immunosuppression are discussed.
Methods Patients included in this study were referred from throughout the southeastern United States to Duke University Medical Center between November 1982 and July 1984 with recurrent condyloma acuminatum. Recurrent status was designated in patients in whom at least 6 months of topical therapy had failed with > 10 attempts at therapy with podophyllum resin, trichloroacetic acid, or ablative surgical therapy. A complete history, physical examination, and baseline laboratory studies were obtained. Histologic confirmation of condyloma acuminatum was required. From a total of 77 women, 16 were aged ;;;<40. Examination of epidemiologic factors in a control population was obtained by randomly choosing 77 subjects matched by age and race being seen for gynecologic problems other than condyloma acuminatum. Comparison of data obtained from groups of patients aged ;;;<40 and those aged <40 and from normal control subjects by X2 statistical analysis.
429
430
Marshburn and Trofatter
August 1988 Am J Obstet Gynecol
Table I. Clinical data of patients aged Genital squamous dysplasia I neoplasia
Case
with recalcitrant condyloma acuminatum
~40
Hysterectomy (reason)
Other neoplasia
Immunosuppression therapy
+
Carcinoma in situ of arm
40
CIN 2
2
40
3
41
VIN 3, vulvar carcinoma (stage I)
4
41
5
42
6
46
CIN + VIN 3
7
47
CIN 3
8
48
9
48
10
49
11
49
12
53
13
55
14
57
15
59
16
63
Azathioprine + prednisone
Chronic glomerulonephritis, renal transplant, general atopy
Prednisone
Cushing's disease, PCOD, hirsutism, hypothyroidism, hypertension
+ Carcinoid of appendix, pituitary adenoma (ACTH-proclueing)
+
(DUB)
+
Irregular menses, chronic bronchitis, cutaneous warts, general atopy
+
Obesity, hypertension
+
(DUB)
+
(DUB/CIN)
+
Hirsutism
(DUB/CIN)
+
CIN 3, VIN
(Pelvic relaxation)
Idiopathic colitis Pneumocystis carinii pneu-
(CIN)
monia
+
(Unknown)
+
(DUB)
Breast carcinoma CIN 2: vaginal carcmoma (stage I)
+
+
Non- Hodgkin's lymphoma Non-Hodgkin's lymphoma
+
+
+
+
+
+
(Pelvic relaxation) (Unknown) (CIN)
+
Non-Hodgkin's lymphoma
Prednisone
Diabetes, obesity, hypertension Diabetes, general atopy Peptic ulcers, verruca vulgaris
Prednisone
(Pelvic relaxation)
+
Endometrial
Concurrent medical problems
H ypogammaglobulinemia, chronic active hepatitis Hypertension, obesity
CIN = Cervical intraepithelial neoplasia; VIN = vulvar intraepithelial neoplasia; ACTH = adrenocorticotropic hormone; DUB = dysfunctional uterine bleeding; PCOD = polycystic ovarian disease.
Table II. Comparison of women (aged
~40
versus aged <40) with recurrent condyloma acuminatum
Group
Race
Smoker
Dysfunctional uterine bleeding
Age 2:40 (n = 16)
Black:3/l6 (19%) White: 13/16 (81%) Black: 13/61 (21%) White: 48/81 (79%) NS
9116 (56%)
10116 (63%)
6/16 (38%)
4116 (25%)
2116 (13%)
6/16 (38%)
37/61 (69%)
24/61 (41%)
24/61 (41%)
3/61 (5%)
9/61 (15%)
3/61 (5%)
NS
NS
NS
NS
NS
Age <40 (n = 61) Significance
Abnormal Papanicolaou tests
Immunosuppressive therapy
Diabetes mellitus
Malignant disorder
p<
0.001
NS = No significant difference.
Results
A summary of the data for women aged ;;.:40 is presented in Table I. Included are the results of evaluation for (1) presence of genital squamous cell dysplasia and
neoplasia, (2) presence of other neoplasia, (3) history of hysterectomy and reason, (4) smoking history, (5) immunosuppressive therapy, and (6) concurrent medical problems.
Condyloma acuminatum in women over age 40
Volume 159 Number 2
10080·
D
31/31 4/4 ;..;.;_;; Abnormal Pap Smears
~
~ Genital Squamous Cell
MaHgnancy
23/31
3/4
r-
%
of Tota I (n=77)
431
60· ~
2/4
40· 20·
n
0-20
21-30
31,...40 Age (years)
41-50
>51
Fig. I. Cumulative frequency distribution of abnormal Papanicolaou test results and genital squamous cell carcinoma in women with recurrent condyloma. Numbers above bars represent actual patient numbers.
A hysterectomy had been performed in 13 of 16 women: five for dysfunctional uterine bleeding, three for carcinoma iri situ of the cervix, one for endometrial hyperplasia with atypia, and five for benign or unknown reasons. An additional four women among the eight having had hysterectomy for carcinoma in situ or benign reasons gave a history of heavy and irregular menstrual periods. In all, nine of 16 women (56%) gave a history of abnormal uterine bleeding. Six of 16 women in the age group ;;340 had a history of malignant disorders (p < 0.001) (Tables I and II): Two had invasive stage I squamous cell carcinoma of the vulva or vagina and another three had a previous diagnosis of carcinoma in situ of the cervix or vulva. In addition, of the four women aged 35 to 40 (not included in Table I), two had a stage I vulvar carcinoma and another had vulvar carcinoma in situ. Three of the four women with invasive squamous cell carcinoma had had condyloma acuminatum for at least 5 years. Wom,en with in situ disease or no dysplasia showed a similar period of exposure. Fig. 1 illustrates the cumulative frequency of the incidence of abnormal Papanicolaou test results in genital squamous cell carcinoma. Statistical analysis within the age group ;;340 showed no difference in the incidence of genital squamous cell carcinoma, but did reveal a higher incidence of other malignant disorders (p < 0.001) (Table Ill). A notable finding was the presence of lymphoma in three of the women in the group aged ;;340. Two of these women had condyloma acuminatum diagnosed before the coexistent lymphoma was discovered. AdditionaJly, two of these patients with lymphoma had concomitant long-standing undefined immunodeficiency syndromes. Both of them had progressively deteriorating clinical courses, with death following within 1 year. Four patients with recurrent condyloma had received
Table III. Genital dysplasia and malignant disease in women with and without recurrent condyloma
Group
Recurrent condyloma Age <40 Age :2:40 Age-matched controls Age <40 Age :2:40
Genital dysplasia
Genital squamous carcznoma
Nongenital malignant disease
25/61 (41%) 6116 (38%)
2/61 (5%) 2/16 (13%)
1161 (5%) 5116* (31%)
0161 0116
1116 (6%)
3/61 (5%) 3/16 (19%)
l/61 (2%)
*P
oral corticosteroid therapy for various medical conditions including severe atopy, renal transplantation, and adrenal insufficiency. In all but the recipient of renal transplant, who also required azathioprine (lmuran), adjustment of corticosteroid therapy to the lowest therapeutic dose resulted in improvement of severe genital infection (our observation). Comparison of data in the groups of patients aged .;;40 and those ;;340 with recurrent disease is presented in Tables II and III. A significant difference was found in the higher incidence of total and nongenital malignant disorders in the group ;;340. In the group <40, two women had microinvasive squamous cell carcinoma of the vulva and another had chronic myelogenous leukemia. Also, two among the patients in the younger group with recurrent disease had severe hematologic disorders ( Fanconi's aplastic anemia) and were receiving androgenic steroids for these. Data present in Table IV show that women with recalcitrant condyloma acuminatum had a higher association of smoking (p < 0.001), dysfunctional uterine bleeding (p < 0.01), abnormal Papanicolaou test re-
432
Marshburn and Trofatter
August 1988 Am J Obstet Gynecol
Table IV. Comparison of women with and without recurrent condyloma Race
Group
Recurrent condyloma (n = 77) Age-matched controls (n = 77) Significance
Black: White: Black: White:
15/77 (20%) 62/77 (80%) 15/77 (20%) 62/77 (80%) NS
Smoker
Dysfunctional uterine bleeding
Abnormal Papanicolaou tests
1177 (1%)
50177 (65%)
35/77 (45%)
31/77 (40%)
32/27 (42%)
1177 (1%)
13/77 (17%)
18177 (23%)
6177 (8%)
NS
NS
p < 0.001
p < O.Dl
p < 0.001
Multiparity
Ectopic pregtuJrtcy
30177 (39%)
suits (p < 0.001), insulin-dependent diabetes mellitus (p < 0.001), and malignant disorders (p < 0.05). No difference was found between these women and the control population when analyzed for parity or history of ectopic pregnancy. Although patients in the study group (11177) had a higher use of immunosuppressive therapy than control patients (4/77), this did not achieve statistical significance (p = 0.1). Comment
Evidence of genital infection with human papillomavirus can be found in approximately 10% of sexually active women of reproductive age. A vast majority of patients in whom condyloma acuminatum develops will undergo remission spontaneously or with conventional therapy (e.g. podophyllum resin, trichloroacetic acid, or surgical ablation). The patients in whom treatment failed are the subjects of our study. The data presented herein focus on the population of women with recurrent genital condyloma who are :;=:40 years of age. An association between this age group and both malignant disease (squamous cell carcinoma of the genital tract and lymphoma) and immunosuppression was found. A wealth of evidence has linked human papillomavirus infection of the female genital tract with the development of dysplasia and even invasive carcinoma of the cervix and the vulva. 1· 5 Cofactors such as impaired immunity may allow persistence of human papillomavirus infection, which may possibly favor the development of intraepithelial neoplasia and cancer. 1• 6 Studies on age-related frequency in patients with viral lesions caused by human papillomavirus show that whereas viral lesions were more common in women in the late teens and early 20s, there was a significantly higher incidence of cervical intraepithelial neoplasia associated with viral lesions in women aged :;=:30.6 Clinical observation suggests thai earlier exposure to human papillomavirus may push this risk for carcinoma to an even younger age group. Our data support these findings. All four cases of invasive squamous cell carcinoma (three vulvar and one vaginal) occurred in women aged >32 years with two cases in the age group :;=:40. In addition, five of seven women receiving long-term immunosuppressive therapy or with a condition predisposing to an immuno-
deficient status had biopsy-proved intraepithelial neoplasia of the vulva or cervix. These findings support those of Schneider et al. 12 who found condyloma and cervical neoplasia to be more common in immunosuppressed renal transplant recipients. The average age of the four womeh with stage I vulvar carcinoma was 41, below the commonly accepted 65 to 70 years of age for peak incidence. We report, however, too few cases to assess whether this represents a significantly earlier onset of disease in women with condyloma. A striking finding is the incidence of lymphoma in three of the 16 women with recurrent condyloma acuminatum and an age :;=:40. The association of immunosuppression with lymphoma is recognized, although the issue of whether lymphoma is the cause or the result of an immunity defect is not settled. A high incidence of lymphoma in human allograft recipients who require immunosuppressive therapy has been reported.'· 13 Anderson et al. 14 demonstrated an impairment of skin test reactivity, a sensitive test of T cell function, in patients with malignant lymphoma, especially of the diffuse histiocytic and poorly differentiated types. These authors assessed immunologic status before radiation or chemotherapy, thus adjusting for an intrinsic and not an iatrogenically induced immunodeficiency in these patients. 14 Interestingly, women with recurrent condyloma also appear to have a defect in cell-mediated immunity as shown by abnormally low lymphocyte transformation responses to the mitogens phytohemagglutinin A, concanavalin A, and pokeweed mitogen. 15 In our study, two of the three patients with lymphoma had a long history of genital condyloma acuminatum before the diagnosis of the malignant disease. This suggests that recurrent condyloma in the older population may be a first indication of immunosuppression and a presenting sign associated with occult lymphoma. All three of our patients were over age 45. Two of the three patients died soon after presentation for treatment of condyloma. Interestingly, one had diffuse histiocytic lymphoma and the others a diffuse, poorly differentiated type, the classes of lymphoma cited previously as having a broader spectrum of T -cell malfunction. 14 Comparison of our total population of women and recurrent condyloma and matched controls showed a
Condyloma acuminatum in women over age 40
Volume 159 Number 2
Immunosuppressive therapy
Diabetes mellitus
Malignant disease
11/77 (14%)
12/77 (16%)
11/77 (14%)
4/77 (5%)
1177 (1%)
2177 (3%)
NS
p < 0.001
p < 0.05
significantly higher incidence of smoking, abnormal Papanicolaou test results, dysfunctional bleeding, and malignant disease. Only malignant disease was more common in the group aged ~40 when these factors were examined within the entire population of patients with recurrent condyloma. In summary, women over age 40 with recurrent condyloma acuminatum should be examined for the presence of immunosuppression and i~s underlying cause. A high index of suspicion for concomitant genital squamous cell and lymphoproliferative carcinoma should be realized. The search for coexistent diabetes mellitus or medications that may predispose to immunosuppression is important for optimal control of infection. We wish to thank john Soper, MD,Joe Lanman, PhD, and the staff at Duke University Medical Center for their comments and assistance in this study. REFERENCES 1. Meisels A, Morin C, Casas-Cordero M, Rabreau M. Human papillomavirus (HPV) venereal infections and gynecologic cancer. Pathol Annu 1983;18:277.
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2. Crum CP, Levine RV. Human papillomavirus infection and cervical neoplasia: new perspectives. Int 1 Gynecol Pathol 1984;3:376. 3. Steffen C. Concurrence of condylomata acuminata and bowenoid papulosis. Am1 Dermatopathol1982;4:5. 4. Ejeckam GC, Idikio HA, Nayak V, Gardiner 1P. Malignant transformation in an anal condyloma acumi'natum. Can 1 Surg 1983;26: 170. 5. Chuang T-Y, Perry HO, Kurland LT, Ilstrup DM. Condyloma acuminatum in Rochester, Minnesota, 1950-1978. Arch Dermatol 1984;120:476. 6. Virgiliis G, Mauri L, Masserini M, et al. Age-related frequency of viral lesions and their association with uterine cervical intraepithelial neoplasia. Tumori 1982;68:465. 7. Hoover R, Fraumeni 1F. Risk of cancer in renal transplant recipients. Lancet 1973;2:55. 8. Ferenczy A, Masaru M, Nagai N, Silverstein S, Crum C. Latent papillomavirus and recurring genital warts. N Engl 1 Med 1985;313:784. 9. Lowell DM, LiVolsi VA, Ludwig ME. Genital condyloma virus infection following pelvic radiation therapy: report of seven cases. Int 1 Gynecol Pathol 1983;2:294. 10. Shokri-Tabibzadeh S, Koss LG, Molnar 1. Romney S. Association of human papillomavirus with neoplastic processes in the genital tract of four women with impaired immunity. Gynecol Oncol 1981;12:5129. 11. Schmauz R, Owor R. Condylomatous tumors of vulva, vagina and penis. 1 Clin Pathol 1980;33:1039. 12. Schneider V, Kay S, Huyung ML. Immunosuppression as a high risk factor in the development of condyloma acuminatum and squamous neoplasia of the cervix. Acta Cytol 1983;27:220. 13. Penn I. Tumor incidence in human allograft recipients. Transplant Proc 1979;11:1047. 14. Anderson TC,1ones SE, Soehnlen B1, Moon TE, Griffith K, Stanley P. Immunocompetence and malignant lymphoma: immunologic status before therapy. Cancer 1981; 12:2702. 15. Seski 1C, Reinhalter ER, Silva J. Abnormalities of lymphocyte transformations in women with condylomata acuniinata. Obstet Gyriecol 1978;51: 188.