By Dr. Bhanumathy Pillay Pathologist
The treatment of squamous cell carcinoma of the cervix, depending on the size of the tumour, clinical stage of the disease, cell type and extent of extrauterine spread, is by surgery, radiotherapy or a combination of both. Though considerable sophistication and refinement of techniques have resulted in radiotherapy being one of the primary modes of treatment, irradiation failures ranging from 10% in stage I cases to 55% in stage III disease have been reported. In addition, postradiation dysplasia, a morphologic abnormality of cervical epithelium following radiation, is an acknowledged complication with prognostic and clinical significance. While cervical cytology is well recognized as an effective tool in the detection of the pre-invasive stages of cervical cancer, the value of postradiation cytologic assessment in picking up treatment failures, recurrences and radiation-induced atypias is less well known.
With regard to the frequency and timing of cytologic examinations, there is much variation from centre to centre. Some take a pre-radiation smear by scraping the tumour area or the vaginal cul de sac with which subsequent post-radiation smears are compared. If a combination of radium application and roentgentherapy is used, a second smear is done at the end of the first mode of treatment and before the beginning of the second. A third smear is taken one to two weeks after complete treatment, followed by another after three or four months. Subsequent smears either at six monthly or yearly intervals are done depending on the post-treatment cytologic findings and the clinical condition of the patient. In a small percentage of cases severe postradiation inflammatory and reactive changes in the genital tract may hinder adequate sampling. This usually occurs when sampling is attempted during therapy or soon after therapy. In a few cases, about 10% or less, it may be difficult to distinguish malignant cells from benign cells showing pronounced radiation effect, in which case a repeat smear after a few weeks (4-6) may be necessary for a conclusive opinion.
Graham and Graham in 1954 described radiation response (RR) in benign cells as an indicator of response to therapy and final outcome. The RR is ascertained from certain morphological changes in benign squamous cells. If more than 75% of the cells manifest these changes, the patient is considered to show a favourable or good response to radiation. When the changes are seen in less than 60% of the cells, the response is considered poor. The five-year survival figures in their study, for the good-response and poor-response groups were 65% and 8% respectively. Conflicting reports are available in the literature with regard to the value of RR as a prognostic indicator, some supportive and others non-corroborative. There is practical value in the recognition of therapeutic failures, which is that alternate treatment, such as radical surgery may be offered to the patients. For best results therefore, the therapist needs to identify these cases as early as possible to modify or alter treatment accordingly. A patient highly sensitive to radiation can afford to have her dose reduced to avoid undesirable side effects, specially damage to adjacent structures.
Persistent and Recurrent Carcinoma
Unless significant vaginal stenosis and inflammatory fibrosis prevent satisfactory sampling, cytology is a good guide for following up patients treated for cervical cancer. If there is no cancer-free period at any time during or after treatment, the term "radiation-persistent" cancer is used and the cells of these tumours do not show the characteristic radiation features. Recurrent carcinomas are early (appearing at least 1 month after completion of radiation), or late (appearing 5 years or more after therapy) and often show little or no radiation effect. The presence of malignant cells, whether persistent or recurrent, is always an indicator of grave prognosis. Radiation changes are similar in both benign and cancer cells but malignant cells have been observed to decrease at a faster rate. Gupta et al report that within 15-24 days of therapy, the percentage of cancer cells came down to 7+3.7. Some workers believe that the presence of malignant cells in the first postradiation smear has no clinical significance, but that their presence after 4 months is associated with poor prognosis. The experience of Mclennen and Mclennen however, is that the finding of malignant cells in smears at any time after completion of radiation has grave significance and should prompt the clinician to look diligently for the source and plan different treatment strategies. Campos gives much importance to the presence of cancer cells at the end of complete treatment and accepts this as a forecast of relapse and progression of the tumour, even if there is no clinical evidence of disease. On the other hand, a negative cytology, particularly in those with advanced stages of cancer, does not indicate a cure. This has been explained by the hypothesis, supported by Paunier et ai, that in this group of patients the tumour is radiosensitive and is destroyed locally by the radiation, resulting in a negative cytology report. But the presence of tumour in the pelvis or regional lymph nodes, outside the effective range of radiation, renders it uncontrollable. In this regard Brunschwig has shown that clinical staging of cervical carcinoma is not exact as in surgical specimens and that tumour may extend beyond the limits estimated by clinical examination. Cytohormonal assessment of a postradiation smear may also have some value in predicting outcome. An elevated karyopyknotic index (cornification index), in a patient who has not had oestrogen therapy, has been reported to herald recurrence of tumour.
Postradiation Dysplasia (PRD)
This is an abnormal cellular response that appears after irradiation for cervical cancer, morphologically resembling classical dysplasia, with the additional features typical of radiation damage. The latent period for development of this lesion has been reported to range from 6 months to 21 years. Considerable care and skill are necessary to distinguish this from residual or recurrent carcinoma and an exaggerated radiation response in benign epithelial cells. The first clue to the possible development of PRD is the appearance on the smear of superficial squamous cells at any time after 6 months following completion of radiotherapy - those patients who show an atrophic smear pattern at the end of therapy and maintain this pattern are considered at low risk for developing PRD. The clinical significance of PRD is its high rate of progression to invasive carcinoma as well as its association with persistent or recurrent cancer in the pelvis or in distant sites. It is also considered as a "malignancy associated change", a response to the presence of residual tumour elsewhere in the body. When PRD develops within 3 years of completion of radiation therapy it carries a much poorer prognosis than when it develops after a latent period of 3 years or more. The incidence of PRD is about 23% while its progression rate varies from 30-50%. Classical dysplasia, on the other hand, has a progressive potential of about 15%.
Nuclear DNA studies, using Feulgen microspectrophotometry of cytologic samples, have classified PRD into diploid, polyploid and aneuploid types. In one such study, it was shown that the aneuploid type was associated with a high rate of early recurrent cancer and a significantly lower 5 year survival rate. The diagnosis of PRD must be followed through with careful pelvic examination, colposcopy and other diagnostic aids, to detect foci of abnormal epithelium and residual or recurrent tumour, so that other aggressive treatment methods, generally radical surgery, can be used to improve patient survival.
Despite certain limitations in some cases due to sampling and interpretative difficulties, cytologic follow-up has a definite and worthwhile role in the surveillance of irradiated cervical cancer patients for whom periodic and lifelong cervical cytology examinations must form an essential part of the post-treatment programme.
Figure 1. Irradiated malignant cell-dark nucleus with degenerative vacoules
Figure 2. Post Radiation Dysplasia - dysplastic cell in a background of post-radiation changes
Figure 3. Post-radiation atypia-benign macrocytosis