Objectives: Solid-organ transplant recipients are at increased risk of developing cancer including cervical cancer compared with woman in the general population, mostly due to long-term immunosuppressive therapy. The Papanicolaou smear remains the primary method of screening cervical pathology including preinvasive and invasive lesions. The objective of this study was to evaluate Pap smear findings in solid-organ transplant recipients, determine the prevalence of abnormal smears, and compare these patients with the general population.

Materials and Methods: We retrospectively examined 111 women patients who received liver or kidney transplant between January 1990 to December 2012 at Başkent University Ankara Hospital. Pap smear findings were compared with normal control patients matched for same age and technical procedure of cervical cytology. To selection of control patients, propensity score matching program was performed. All Pap smears were re-examined according to Bethesda 2001 criteria.

Results: In 111 transplant patients, 2 patients (1.8%) had atypical squamous cells of undetermined significance, 8 patients (7.2%) had low-grade squamous intraepithelial lesion, 15 patients (13.5%) had Candida infection, 2 patients (1.8%) had Trichomonas vaginalis, 1 patient (0.9%) had herpes simplex infection, 13 patients (11.7%) had bacterial vaginosis, 15 patients (13.5%) had reactive changes due to inflammation, and 18 patients (16.2%) had atrophy. When we compared our results with the control group, there were statistically significant differences (P ≤ .05) between the 2 groups in epithelial cell abnormalities (low-grade squamous intraepithelial lesion), Candida infection, bacterial vaginosis, and atrophy.

Conclusions: Pap smear screening potentially may help recognize cervical preinvasive and invasive lesions. The risk of developing cervical intraepithelial neoplasia is greater in transplant recipients because of immunosuppressive therapy. The incidence of low-grade squamous intraepithelial lesion was significantly greater in transplant recipients than the general population. Intensive follow-up with Pap smear in transplant recipients is important in the early detection of these lesions.

Key words : Cervical cancer, Immunosuppression, Kidney transplant, Liver transplant, Pap smear

Introduction

Solid-organ transplant recipients are at an increased risk of infectious diseases, autoimmune diseases, and malignancy including uterine cervical cancer compared with woman in the general population, mostly due to long-term immunosuppressive therapy. The mechanisms by which immuno­suppressive treatment increases malignancy include DNA damage due to immunosuppressive drugs, altered DNA repair, reduced immunologic tolerance of neoplastic cells, and the increased changes of infection with oncogenic viruses such as the human papillomavirus (HPV).^1,2

The Papanicolaou (Pap) smear remains the primary method of screening cervical pathology including preinvasive and invasive lesions and is associated with a reduction in the incidence and mortality from cervical cancer. The Bethesda system is used for reporting cervical or vaginal cytologic diagnoses and was re-evaluated in 2001.³ Abnormal results include atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LGSIL or LSIL), high-grade squamous intraepithelial lesion (HGSIL or HSIL), atypical squamous cells but cannot exclude HSIL (ASC-H), squamous cell carcinoma, atypical glandular cells not otherwise specified (AGC-NOS), adenocarcinoma in situ (AIS), or atypical glandular cells suspicious for AIS or cancer (AGC-neoplastic).³ Progression of cellular abnormalities and preinvasive disease can lead to the development of cervical cancer.

The objective of this study was to evaluate Pap smear findings in solid-organ transplant recipients, determine the prevalence of abnormal smears, and compare results between these patients and the general population according to the Bethesda 2001 criteria. In addition, features such as atrophy, inflammation, and the presence of organisms were compared between solid-organ transplant recipients and the general population.

Materials and Methods

Patients
A retrospective analysis was made of 603 women patients including children and adolescents who received liver or kidney transplant between January 1990 to December 2012 at Başkent University, Ankara Hospital, Ankara, Turkey. Donor treatment and kidney and liver transplant surgery were performed according to standardized procedures. The study was approved by the Ethical Review Committee of the institute. All protocols conformed to the ethical guidelines of the 1975 Declaration of Helsinki.

Cervical Pap smears that were performed in 111 women after transplant were included in this study to examine the effect of normal control subjects matched for age and technical procedure of cervical cytology who were selected randomly with the propensity score matching program. All Pap smears were re-examined according to Bethesda 2001 criteria (Figure 1).

Statistical analyses
Data analyses were performed with statistical software (SPSS, version 15.0, IBM Corporation, SPSS Inc., Armonk, NY, USA). The chi-square test was used to compare appropriate variables in patients. Results were considered statistically significant when P ≤ .05.

Results

The mean age of the patients who had solid-organ transplant and control subjects was 36.71 years (range, 18-59 y). In the solid-organ transplant recipients, 89 patients received kidney transplant and 22 received liver transplant. The mean interval to Pap smear after transplant was 52.14 ± 43.35 months (range, 1-192 mo).

Candida infection was detected in 20 subjects, including 15 solid-organ transplant patients (13.5%) and 5 control subjects (2.3%) (Table 1). There were 3 Trichomonas vaginalis infections including 2 solid-organ transplant patients (1.8%) and 1 control subject (0.5%). Only 1 patient who had solid-organ transplant (0.9%) had herpes simplex infection. Only 2 control subjects (0.9%) had Actinomyces infections. Solid-organ transplant patients had a significantly higher incidence of Candida infection than control subjects; there was no statistically significant differences between solid-organ transplant patients and control subjects regarding other microorganisms (Table 1). A shift in flora suggestive of bacterial vaginosis was detected in 22 Pap smears, including 13 solid-organ transplant patients (11.7%) and 9 control subjects (4.1%); this difference was statistically significant (P ≤ .05). Chlamydia micro­organisms, reactive changes due to intrauterine devices, and reactive changes due to radiation were not detected in either group.

Reactive changes secondary to inflammation were detected in 34 patients, including 15 patients in the solid-organ transplant group (13.5%) and 19 patients in the control group (8.6%); there was no statistically significant differences between groups. Atrophy was detected in 25 patients, including 18 solid-organ transplant patients (16.5%) and 7 control subjects (3.2%); this difference was statistically significant (P ≤ .0001).

In the 333 subjects, 15 subjects had epithelial cell abnormalities (10 patients in the solid-organ transplant group and 5 control subjects) (Table 1). The ASC-US was detected in 5 patients, including 2 solid-organ transplant patients (1.8%) and 3 control subjects (1.4%); this difference was not statistically significant (P > .05). The LSIL was detected in 10 patients, including 8 solid-organ transplant patients (7.2%) and 2 control subjects (0.9%); the difference between the groups was statistically significant (P ≤ .05). The HSIL, squamous cell carcinoma, or glandular cell abnormalities were not detected.

Discussion

Solid-organ transplant recipients have a 3- to 4-fold increased risk of developing malignancy compared with the general population. The risk of cervical cancer also is increased. The incidence of cervical neoplasia in these patients is 11%.⁴ In organ transplant recipients, invasive cervical cancer may occur in 1% and in situ cervical cancer in 3.3% patients, and transplant recipients had a 3-fold higher incidence of in situ cancer than the general population.⁵ In contrast with other invasive cancer types, cervical cancer had no increased incidence in transplant patients.⁵ In our study, there was no cervical cancer in our patients. Routine use of Pap smears showed the absence of an increased incidence of invasive cervical cancer. The Pap test is easy to perform, has low cost, and is highly sensitive and specific. This cytologic screening test is re­commended for all women.

Long-term immunosuppressive therapy in solid-organ transplant recipients is an important risk factor for developing cervical cancer.^1,2 Calcineurin inhibitors (cyclosporine and tacrolimus) promote carcinogenesis, potentially through production of cytokines that regulate transforming growth factor β, metastasis, and angiogenesis. All immuno­suppressive agents affect the immunologic system, reduce immunologic tolerance of neoplastic cells, and increase infections with oncogenic viruses (such as HPV) that cause DNA damage.^1,2,6 Infections with HPV are frequent in solid-organ transplant patients and can lead to cervical cancer. Oncogenic HPV types such as HPV-16 are less common in LSIL (cervical intraepithelial neoplasia [CIN] 1) than HSIL (CIN 3), and nononcogenic HPV types are commonly observed in CIN 1 lesions. Mean time to progression from ASC-US to LSIL or worse, and from LSIL to HSIL or worse, was shorter in women with oncogenic HPV types than women with no HPV infection.⁷ In addition, Moscicki and coworkers showed that only HPV status at the current visit was associated with rate of regression, but they did not show an association between LSIL regression and HPV status at baseline in univariate analysis.⁸

A limitation of our study was that the HPV status of transplanted woman could not be determined. Paternoster and associates performed HPV tests and noted that there was an association between high-risk HPV infections and CIN lesions but no association between low-risk HPV infections and CIN lesions.⁴ In contrast, Origoni and associates reported no significant differences in the course of HPV infection between transplanted woman and control subjects.⁶ We believe that HPV vaccine before transplant and an HPV test are mandatory for solid-organ transplant patients to prevent HPV-related malignancy. In addition, it was reported previously that various antilymphoproliferative induction therapies were associated with reduced incidence of invasive cervical cancer.⁵

The Pap test screening for cervical cancer is useful to identify precancerous lesions of the cervix. In the current study, LSIL was observed in 8 solid-organ transplant patients and 2 control subjects. The statistically significant risk increase of LSIL was observed with solid-organ transplant in our study. Origoni and associates observed a significant difference between groups only for LSIL cytology, similar to the present results.⁶ In another study, Paternoster and coworkers reported on 151 transplant patients; 5 patients had HSIL and 5 patients had LSIL. They found that the incidence of intraepithelial lesion was greater in transplant patients than the general population.⁴

Another important effect of immunosuppression on cervical cytology appears to be on fungal infections. In our study, 15 of 20 Candida infections were in solid-organ transplant patients. A statistically significant difference in Candida infection was observed between the 2 groups. However, there were no significant differences between the 2 groups for Trichomonas vaginalis, Actinomyces, and herpes simplex virus infections. Another finding we observed in the Pap smear cytology was a shift in flora suggestive of bacterial vaginosis. In our study, we found significant differences between the 2 groups regarding bacterial vaginosis. It was possible to see the relation between atrophy and immuno­suppression for solid-organ transplant. Thinning of the squamous epithelium and reduced mucus production leads to atrophy because of using long-term immunosuppressive drugs. We observed significant differences between the 2 groups for atrophy. This issue and the presence of a shift in flora suggestive of bacterial vaginosis may have been due to disturbances in the estrous cycle; this was mentioned before in another study performed at our institution about Pap smear findings in chronic renal failure patients, in which we compared Pap smear findings between chronic renal failure patients and healthy control subjects according to the Bethesda 2001 criteria to determine whether there was increased risk of epithelial cell abnormalities in dialysis patients.⁹

In conclusion, we suggest that solid-organ transplant recipients are at greater risk of developing cervical precancerous lesions and cervical cancer because of immunosuppressive therapy. Our study also showed that the incidence of LSIL was increased significantly compared with the normal population. Therefore, Pap test screening and HPV vaccination should be performed before solid-organ transplant. Pap test and HPV test should be repeated at regular intervals to detect or prevent precancerous lesions and cervical cancer.

References:

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