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Carcinoma of the uterine cervix and schistosomiasis
Int. J. Gynecol. Obetet., 1989.29: 263-268 International Federation of Gynecology and Obstetrics
263
Carcinoma of the uterine cervix and schistosomiasis G. El Tabbakh” and M.A. Hamzab Departments o~Obstetrics and Gynecology and bPathology, Alexandria Medical School, Alexandria (Egypt)
@cciv~December IOth, 1987) (Revised and accepted July 7th, 1988) Abstrnct The relation between cervical cancer and schistosomal infection is controversial. A case of well differentiated adenocarcinoma associated with schistosomicrsis of the cervix is presented. A 45-year-old female complaining of intermenstrual bleeding had a polypoid ulcerated cervical mass. Biopsy revealed well differentiated adenocarcinoma and bilharzial ova with terminal spine embedded in the tumor tissue. The relation between cancer cervix and schistosomiask is discussed.
Keywords: Cancer cervix; Schistosomiasis. Introduction Schistosoma worms are trematode parasites which inhabit the mesenteric, portal, vesical and pelvic venous plexuses. The three main species which infect man are Schistosoma hematobium, S. mansoni and S. japonicum. In addition, there are records of human infection with the following species: S. bovis, S. matthei, S. rodhaini and S. intercalatum. Schistosomiasis is endemic in most African countries, in parts of South America and the Caribbean area, in Persia, Iraq, China and Japan. Schistosomiasis of the female genital tract is not infrequently encountered in endemic areas [S]. The cervix is the most common site of infection [1,12,13]. The rich network of venous anastomosis between the 0020-7292/89/$03.50 0 1989 International Federation of Gynecology and Obstetrics Published and Printed in Ireland
bladder and the genital tract offers an explanation for the more common finding of S. hematobium in genital tract lesions than S. mansoni [9]. Cervical schistosomiasis may take one of three different forms [12]: (1) endocervical polypoid excrescences; (2) indurated area with zones of ulceration or erosion; (3) cauliflower mass which bleeds on touch, thus simulating cervical carcinoma [4]. Ulceration is the most characteristic pathological finding [13]. Microscopically there may be epithelial hyperplasia, hyperkeratosis, acanthosis, intra-epithelial keratinization and leukoplakic changes [ 12,131. Dysplastic changes with prickle cell hyperplasia or anaplasia and absence of keratinization may occasionally be found [ 131. The inflammatory reaction may be in the form of a granuloma or diffuse. Old infection with calcified ova may be associated with no appreciable reaction [12]. Clinically patients may present with vaginal discharge, dyspareunia and dysmenorrhea [8,13]. El Margoub [8] suggested an association between schistosomal cervicitis and the development of antisperm antibodies. On the other hand, schistosomal lesions may be found incidentally on routine histologic examination of cervical biopsy. Youssef et al. [ 131 suggested that schistosomal infection of the cervix was precancerous. The relation between cervical cancer and schistosomal infection is still controversial. The association of cervical carcinoma and schistosomiasis had been reported by several investigators [ 1,2,13]. Case Report
264
Tabbakh and Hamza
Almost all reported cases of cervical cancer coincidental with schistosomiasis have been of the squamous cell type [1,10,13]. In this regard, a report of a case of adenocarcinoma of the cervix occurring with cervical schistosomiasis is presented and the relation between schistosomiasis and cervical cancer is reviewed. Case report A 45year-old, second gravida, second para from a village on the Nile delta presented with intermenstrual bleeding of 5 months duration. There was a past history of schistosomiasis and antibilharzial treatment. Abdominal examination revealed no enlargement of the liver or spleen. Pelvic examination revealed an enlarged, indurated cervix with a polypoid ulcerated mass and bilateral parametrial involvement. A cervical biopsy was performed.
Microscopic examination revealed numerous glandular formations invading the deeper subepithelial tissues of the cervix. The glands in some fields, had angular contour (Fig. 1) and in another, a papillary pattern was seen (Fig. 2). Their lining epithelium was high columnar with stratification in some glands (Fig. 3). The intervening fibrous stroma showed heavy lymphocytic infiltration. Embedded within the tumor tissue were two calcified bilharzial ova with terminal spines. Absence of the bilharzial granulomatous reaction around the ova was noticed (Fig. 4). The histopathologic diagnosis was that of well differentiated adenocarcinoma of the cervix associated with cervical bilharziasis. Discussion As far as we know this is the first report of adenocarcinoma of the cervix associated with schistosomiasis. In their group of 121 patients
Well differentiated adenocarcinoma of the cervix. Angular glands infiltrating stroma. Note calcified bilharzial ova with Flg. 1. terminal spine. (H and E x 300). ZntJ Gynecol Obstet29
Cancercerv~ andschbta9omicrris
Fig. 2.
265
Well differentiated adenocarcinoma of the cervix showing papillary pattern of the tumor cells. (H and E x 300).
with cervical schistosomiasis, Youssef et al. [ 131 found one case of carcinoma in situ and 16 cases of invasive carcinoma (15 squamous cell and one clear cell carcinoma), i.e. an incidence of 13.2Vo. Badawy [2] reported three
cases of squamous cell carcinoma superimposed on schistosomiasis of the cervix out of 32 cases of schistosomal cervicitis. Berry [3] reported two cases of cervical squamous cell carcinoma associated with schistosomiasis.
Well differentiated adenocarcinoma of the cervix. Lining epithelium of the glands is tall columnar with stratification in some areas. (I-Iand E x 300).
Fig. 3.
CaseReport
266
Tabbakh and Hamza
Well differentiated adenocarcinoma of the cervix. Note calcified bilharzial ova with terminal spine, absence of bilhar,zial Fig. 4. granulomatous reaction and numerous lymphocytes in the intervening stroma. (H and E x 300).
Charlewood et al. [S] reported a 22-year-old woman with squamous cell carcinoma and schistosomiasis. In Iraq, Al-Adnani and Saleh [l] reported the association of schistosomiasis with cervical cancer in one of seven cases of cervical schistosomiasis. Although most reports of cervical malignancies have been associated with S. hematobium [ 1,2,13], Coelho et al. [7] reported 16 cases of invasive and microinvasive squamous cell carcinoma and 51 cases of severe dysplasia and carcinoma in situ associated with S. mansoni infection in Brazil. It appears that cervical carcinoma developing on top of cervical schistosomiasis have certain characteristics in common. Most patients are younger than is usual for cervical cancer in general. Even in advanced lesions, bleeding and discharge are often slight. The lesion is less friable and shows a higher degree of differentiation than is usual for nonbilharzial cervical cancer [ 131. The case presented in this report was 45 years old (the common age for cervical cancer), her lesion was not friable and was well differentiated. Int J Gynecoi Obstet29
The relationship of cervical schistosomiasis to cervical cancer is controversial. Youssef et al. [13] and Charlewood et al. [5] believe that schistosomiasis is precancerous. However, Williams [12] does not share their opinion. Factors which support a carcinogenic role for schistosomiasis include: (1) Reports of association between cervical cancer and schistosomiasis [ 1,2,5,13]. The incidence of cervical cancer in patients with cervical schistosomiasis is higher than the incidence of cervical cancer in the general population [1,2,13]. (2) The presence of schistosomal ova was recorded to cause epithelial changes which can be regarded as precancerous, such as basal cell hyperplasia, anaplasia and leukoplakia [13]. (3) Strong evidence that schistosomiasis infection of the bladder predisposes that organ to carcinoma [6]. In Egypt cancer of the bladder is common, its geographic distribution in the country corresponds to that of schistosomal infection and is encountered at a relatively younger age in patients who have
Cancer cervk andschirtosomiads
repeated schistosomal infection of the bladder [2]. (4) A possible connection between liver cell carcinoma and chronic schistosomiasis. Nakashima et al. [lo] found S. japonica infection in 24 out of 227 cases of hepatocellular malignancy (10.6%). This was significantly higher than the incidence of this carcinoma without schistosomiasis (2.78%). On the other hand the following factors do not support a carcinogenic role for schistosomiasis: (1) Cervical cancer is not more frequent in endemic areas of schistosomal infection. Other causes for cervical cancer must be proposed in areas where schistosomiasis is absent. (2) Williams [12] studied 14 cases of schistosomiasis of the cervix and found no evidence of malignancy or premalignant changes in any of the cases. (3) Association does not prove causality. The basic issue of casuahty is extremely complex. Consistency of the evidence supporting a causal relationship should be found using various study methodologies. It is concluded that although the evidence demonstrating a causal effect for schistosomiasis in cervical cancer is not yet definitive, schistosomiasis should be considered a risk factor for the development of cervical cancer. It is recommended that all patients with genital tract schistosomiasis be treated with special attention towards precancerous changes. On account of its possible precancerous potential, patients from endemic areas should be thoroughly examined for evidence of genital tract schistosomiasis. Cervical cytology and biopsy are needed to confirm the diagnosis. Treatment consists of drug therapy, surgery or both. Specific drugs include praziquantel, oxamniquine, and metrifonate. Praziquantel is now considered to be the drug of choice for treating all species of schistosomes that infect man. The drug is safe and effective when it is given in single or divided oral doses on the same day. These properties make praziquantel particularly suitable for
261
population-based chemotherapy, although the cost of the drug may limit its use. Although not effective clinically against S. hematobium and S. japonicum, oxamniquine has proven to be effective for treatment of S. mansoni infections, particularly in South America, where the sensitivity of most strains may permit single-dose therapy. Metrifonate has been used with considerable success in the treatment of S. hematobium infections, but the drug is not effective against S. mansoni and S. japonicum. Metrifonate is relatively inexpensive and can be used in conjunction with oxamniquine for treatment of mixed infections with S. hematobium and S. man-
soni. Mass treatment, health education and snail destruction are the three measures necessary to eradicate the disease. References
4
5
6
Al-Adnani MS, Saleh KM: Schistosomiasis of the female genital tract in Southern Iraq. Iraq Med J 27: 8.1979. Badawy AH: Schistosomiasis of the cervix. Br Med J I: 369,1%2. Berry A: A cytopathological and histopathologlcal study of bilharziasis of the female genital tract. J Path01 Bacterio132: 325. 1966. Bland KG, Geltand M: The effects of schistosomiasis on the cervix uteri in the African female. J Obstet Gynaecol Br Commonw 77: 1127,197O. Charlewood GP. Shippel S, Renton H: Schistosomiasis in gynaecology. J Obstet Gynaecol Br Commonw 56: 367, 1949. Chevler EM, Awwad I-X. Ziegler JL, El Sebai I: Cancer of the bilharzial bladder. Int J Radiat Oncol Biol Phys 5: 821.1979. Coelho LHMR, Carvalho G, Carvalho JM: Carcinoma in situ and invasive squamous cell carcinoma associated with schistosomiasis of the uterine cervix. A report of three cases. Acta Cytol23:45. 1979. El Margoub S: Anti-spermatozoal antibodies in infertile women in the cervicovaginal schistosomiasis. Am J Obstet GynecollZ2: 781,1972. Gerfara M: Schistosomiasis in South Central Africa: Johannesburg and Cape Town. Postgraduate Press, Capetown, 1950. Nakashima T, Okuda K, Kojiro M: Primary liver cancer coincident with schistosomiasis japonica. A study of 24 necropsies. Cancer36: 1483.1975. Schwartz DA: Hehninths in the induction of cancer. II. Schistosoma haematobium and bladder cancer. Trop GeogrMed33: 1,198l. Case Report
268 12
13
Tobbokh and Homo WUiams AO: Pathology of schistosomiasis of the uterine cervix due to S. haematobium. Am J Obstet Gynccol98: 184.1967. Yousscf AF, Fayad MM, Shafcck MA: Biiziasis of the cervix uteri. J Obstet Gynaccol Br Commonw 77: 847. 1970.
Int J Gynecol Obstet 29
Address for raprintsz G. El Tabbakb ?? Sbatby MatarrdtyHospital Akxalldria Wpt
263
Carcinoma of the uterine cervix and schistosomiasis G. El Tabbakh” and M.A. Hamzab Departments o~Obstetrics and Gynecology and bPathology, Alexandria Medical School, Alexandria (Egypt)
@cciv~December IOth, 1987) (Revised and accepted July 7th, 1988) Abstrnct The relation between cervical cancer and schistosomal infection is controversial. A case of well differentiated adenocarcinoma associated with schistosomicrsis of the cervix is presented. A 45-year-old female complaining of intermenstrual bleeding had a polypoid ulcerated cervical mass. Biopsy revealed well differentiated adenocarcinoma and bilharzial ova with terminal spine embedded in the tumor tissue. The relation between cancer cervix and schistosomiask is discussed.
Keywords: Cancer cervix; Schistosomiasis. Introduction Schistosoma worms are trematode parasites which inhabit the mesenteric, portal, vesical and pelvic venous plexuses. The three main species which infect man are Schistosoma hematobium, S. mansoni and S. japonicum. In addition, there are records of human infection with the following species: S. bovis, S. matthei, S. rodhaini and S. intercalatum. Schistosomiasis is endemic in most African countries, in parts of South America and the Caribbean area, in Persia, Iraq, China and Japan. Schistosomiasis of the female genital tract is not infrequently encountered in endemic areas [S]. The cervix is the most common site of infection [1,12,13]. The rich network of venous anastomosis between the 0020-7292/89/$03.50 0 1989 International Federation of Gynecology and Obstetrics Published and Printed in Ireland
bladder and the genital tract offers an explanation for the more common finding of S. hematobium in genital tract lesions than S. mansoni [9]. Cervical schistosomiasis may take one of three different forms [12]: (1) endocervical polypoid excrescences; (2) indurated area with zones of ulceration or erosion; (3) cauliflower mass which bleeds on touch, thus simulating cervical carcinoma [4]. Ulceration is the most characteristic pathological finding [13]. Microscopically there may be epithelial hyperplasia, hyperkeratosis, acanthosis, intra-epithelial keratinization and leukoplakic changes [ 12,131. Dysplastic changes with prickle cell hyperplasia or anaplasia and absence of keratinization may occasionally be found [ 131. The inflammatory reaction may be in the form of a granuloma or diffuse. Old infection with calcified ova may be associated with no appreciable reaction [12]. Clinically patients may present with vaginal discharge, dyspareunia and dysmenorrhea [8,13]. El Margoub [8] suggested an association between schistosomal cervicitis and the development of antisperm antibodies. On the other hand, schistosomal lesions may be found incidentally on routine histologic examination of cervical biopsy. Youssef et al. [ 131 suggested that schistosomal infection of the cervix was precancerous. The relation between cervical cancer and schistosomal infection is still controversial. The association of cervical carcinoma and schistosomiasis had been reported by several investigators [ 1,2,13]. Case Report
264
Tabbakh and Hamza
Almost all reported cases of cervical cancer coincidental with schistosomiasis have been of the squamous cell type [1,10,13]. In this regard, a report of a case of adenocarcinoma of the cervix occurring with cervical schistosomiasis is presented and the relation between schistosomiasis and cervical cancer is reviewed. Case report A 45year-old, second gravida, second para from a village on the Nile delta presented with intermenstrual bleeding of 5 months duration. There was a past history of schistosomiasis and antibilharzial treatment. Abdominal examination revealed no enlargement of the liver or spleen. Pelvic examination revealed an enlarged, indurated cervix with a polypoid ulcerated mass and bilateral parametrial involvement. A cervical biopsy was performed.
Microscopic examination revealed numerous glandular formations invading the deeper subepithelial tissues of the cervix. The glands in some fields, had angular contour (Fig. 1) and in another, a papillary pattern was seen (Fig. 2). Their lining epithelium was high columnar with stratification in some glands (Fig. 3). The intervening fibrous stroma showed heavy lymphocytic infiltration. Embedded within the tumor tissue were two calcified bilharzial ova with terminal spines. Absence of the bilharzial granulomatous reaction around the ova was noticed (Fig. 4). The histopathologic diagnosis was that of well differentiated adenocarcinoma of the cervix associated with cervical bilharziasis. Discussion As far as we know this is the first report of adenocarcinoma of the cervix associated with schistosomiasis. In their group of 121 patients
Well differentiated adenocarcinoma of the cervix. Angular glands infiltrating stroma. Note calcified bilharzial ova with Flg. 1. terminal spine. (H and E x 300). ZntJ Gynecol Obstet29
Cancercerv~ andschbta9omicrris
Fig. 2.
265
Well differentiated adenocarcinoma of the cervix showing papillary pattern of the tumor cells. (H and E x 300).
with cervical schistosomiasis, Youssef et al. [ 131 found one case of carcinoma in situ and 16 cases of invasive carcinoma (15 squamous cell and one clear cell carcinoma), i.e. an incidence of 13.2Vo. Badawy [2] reported three
cases of squamous cell carcinoma superimposed on schistosomiasis of the cervix out of 32 cases of schistosomal cervicitis. Berry [3] reported two cases of cervical squamous cell carcinoma associated with schistosomiasis.
Well differentiated adenocarcinoma of the cervix. Lining epithelium of the glands is tall columnar with stratification in some areas. (I-Iand E x 300).
Fig. 3.
CaseReport
266
Tabbakh and Hamza
Well differentiated adenocarcinoma of the cervix. Note calcified bilharzial ova with terminal spine, absence of bilhar,zial Fig. 4. granulomatous reaction and numerous lymphocytes in the intervening stroma. (H and E x 300).
Charlewood et al. [S] reported a 22-year-old woman with squamous cell carcinoma and schistosomiasis. In Iraq, Al-Adnani and Saleh [l] reported the association of schistosomiasis with cervical cancer in one of seven cases of cervical schistosomiasis. Although most reports of cervical malignancies have been associated with S. hematobium [ 1,2,13], Coelho et al. [7] reported 16 cases of invasive and microinvasive squamous cell carcinoma and 51 cases of severe dysplasia and carcinoma in situ associated with S. mansoni infection in Brazil. It appears that cervical carcinoma developing on top of cervical schistosomiasis have certain characteristics in common. Most patients are younger than is usual for cervical cancer in general. Even in advanced lesions, bleeding and discharge are often slight. The lesion is less friable and shows a higher degree of differentiation than is usual for nonbilharzial cervical cancer [ 131. The case presented in this report was 45 years old (the common age for cervical cancer), her lesion was not friable and was well differentiated. Int J Gynecoi Obstet29
The relationship of cervical schistosomiasis to cervical cancer is controversial. Youssef et al. [13] and Charlewood et al. [5] believe that schistosomiasis is precancerous. However, Williams [12] does not share their opinion. Factors which support a carcinogenic role for schistosomiasis include: (1) Reports of association between cervical cancer and schistosomiasis [ 1,2,5,13]. The incidence of cervical cancer in patients with cervical schistosomiasis is higher than the incidence of cervical cancer in the general population [1,2,13]. (2) The presence of schistosomal ova was recorded to cause epithelial changes which can be regarded as precancerous, such as basal cell hyperplasia, anaplasia and leukoplakia [13]. (3) Strong evidence that schistosomiasis infection of the bladder predisposes that organ to carcinoma [6]. In Egypt cancer of the bladder is common, its geographic distribution in the country corresponds to that of schistosomal infection and is encountered at a relatively younger age in patients who have
Cancer cervk andschirtosomiads
repeated schistosomal infection of the bladder [2]. (4) A possible connection between liver cell carcinoma and chronic schistosomiasis. Nakashima et al. [lo] found S. japonica infection in 24 out of 227 cases of hepatocellular malignancy (10.6%). This was significantly higher than the incidence of this carcinoma without schistosomiasis (2.78%). On the other hand the following factors do not support a carcinogenic role for schistosomiasis: (1) Cervical cancer is not more frequent in endemic areas of schistosomal infection. Other causes for cervical cancer must be proposed in areas where schistosomiasis is absent. (2) Williams [12] studied 14 cases of schistosomiasis of the cervix and found no evidence of malignancy or premalignant changes in any of the cases. (3) Association does not prove causality. The basic issue of casuahty is extremely complex. Consistency of the evidence supporting a causal relationship should be found using various study methodologies. It is concluded that although the evidence demonstrating a causal effect for schistosomiasis in cervical cancer is not yet definitive, schistosomiasis should be considered a risk factor for the development of cervical cancer. It is recommended that all patients with genital tract schistosomiasis be treated with special attention towards precancerous changes. On account of its possible precancerous potential, patients from endemic areas should be thoroughly examined for evidence of genital tract schistosomiasis. Cervical cytology and biopsy are needed to confirm the diagnosis. Treatment consists of drug therapy, surgery or both. Specific drugs include praziquantel, oxamniquine, and metrifonate. Praziquantel is now considered to be the drug of choice for treating all species of schistosomes that infect man. The drug is safe and effective when it is given in single or divided oral doses on the same day. These properties make praziquantel particularly suitable for
261
population-based chemotherapy, although the cost of the drug may limit its use. Although not effective clinically against S. hematobium and S. japonicum, oxamniquine has proven to be effective for treatment of S. mansoni infections, particularly in South America, where the sensitivity of most strains may permit single-dose therapy. Metrifonate has been used with considerable success in the treatment of S. hematobium infections, but the drug is not effective against S. mansoni and S. japonicum. Metrifonate is relatively inexpensive and can be used in conjunction with oxamniquine for treatment of mixed infections with S. hematobium and S. man-
soni. Mass treatment, health education and snail destruction are the three measures necessary to eradicate the disease. References
4
5
6
Al-Adnani MS, Saleh KM: Schistosomiasis of the female genital tract in Southern Iraq. Iraq Med J 27: 8.1979. Badawy AH: Schistosomiasis of the cervix. Br Med J I: 369,1%2. Berry A: A cytopathological and histopathologlcal study of bilharziasis of the female genital tract. J Path01 Bacterio132: 325. 1966. Bland KG, Geltand M: The effects of schistosomiasis on the cervix uteri in the African female. J Obstet Gynaecol Br Commonw 77: 1127,197O. Charlewood GP. Shippel S, Renton H: Schistosomiasis in gynaecology. J Obstet Gynaecol Br Commonw 56: 367, 1949. Chevler EM, Awwad I-X. Ziegler JL, El Sebai I: Cancer of the bilharzial bladder. Int J Radiat Oncol Biol Phys 5: 821.1979. Coelho LHMR, Carvalho G, Carvalho JM: Carcinoma in situ and invasive squamous cell carcinoma associated with schistosomiasis of the uterine cervix. A report of three cases. Acta Cytol23:45. 1979. El Margoub S: Anti-spermatozoal antibodies in infertile women in the cervicovaginal schistosomiasis. Am J Obstet GynecollZ2: 781,1972. Gerfara M: Schistosomiasis in South Central Africa: Johannesburg and Cape Town. Postgraduate Press, Capetown, 1950. Nakashima T, Okuda K, Kojiro M: Primary liver cancer coincident with schistosomiasis japonica. A study of 24 necropsies. Cancer36: 1483.1975. Schwartz DA: Hehninths in the induction of cancer. II. Schistosoma haematobium and bladder cancer. Trop GeogrMed33: 1,198l. Case Report
268 12
13
Tobbokh and Homo WUiams AO: Pathology of schistosomiasis of the uterine cervix due to S. haematobium. Am J Obstet Gynccol98: 184.1967. Yousscf AF, Fayad MM, Shafcck MA: Biiziasis of the cervix uteri. J Obstet Gynaccol Br Commonw 77: 847. 1970.
Int J Gynecol Obstet 29
Address for raprintsz G. El Tabbakb ?? Sbatby MatarrdtyHospital Akxalldria Wpt