Adenoid cystic carcinoma of the cervix.S Dixit, S Singhal, R Vyas, A Murthy, HA Baboo
Dept. of Radiotherapy, Gujarat Cancer and Research Center, Asarwa, Ahmedabad.
Adenoid cystic carcinoma constitute around 0.4 to 1.7% of all carcinomas of cervix. It generally presents in elderly age group, however few cases in younger age have also been reported. Majority of cases present in early stage. Though concluding statement regarding the results cannot be made from the cases accumulated from the various reported series, nonetheless this review shows that radiotherapy too is effective in early stage and even in stage I results with radiotherapy appear better than surgery. In advanced stage outcome is invariably poor. In early stage main pattern of failure is distant metastasis. Both local and distant failure are observed in stage III and IV. Though lung is the commonest site of metastases (51%), abdominal cavity and brain are also found to be involved in some cases. Limited experience shows effectiveness of high doses of cisplatin and multiagent chemotherapy. Cases of early stage disease having risk for metastases and local failure should be identified and managed with multimodality treatment using surgery for bulky disease with post-operative radiotherapy and chemotherapy. In advanced stages combination of chemotherapy and radiotherapy is required. Exenterative surgery for central failure has been used effectively. Overall no evidence of disease rate is found to be about 48%, with mean follow-up of 39 months.
Keywords: Age Factors, Carcinoma, Adenoid Cystic, diagnosis,epidemiology,therapy,Cervix Neoplasms, diagnosis,epidemiology,therapy,Combined Modality Therapy, Female, Follow-Up Studies, Human, Neoplasm Staging, Prognosis, Survival Rate, Treatment Outcome,
Commonest side for adenoid cystic carcinoma (ACC) are the salivary glands and the respiratory tract. Occasionally it is found in the mucous membrane of head and neck, skin and breast. In the female genital tract, it has been rarely described in the Bartholin's gland and the uterine cervix. Adenoid cystic carcinoma appearing in cervix was first reported by Paalman and Counseller. In other parts of the body adenoid cystic carcinoma does not have favourable prognosis. Local infiltration, vascular, lymphatic and neural invasion with late metastases are its characteristic features. Behaviour, general characteristics, histogenesis and histopathology have been discussed in various individual cases, reported from time to time, but only through retrospective review of reported cases certain valuable and common feature shared by adenoid cystic carcinoma ACC of the cervix could be highlighted. This review and collective analysis of cases reported in the literature have changed certain views and facts, which were brought forward by individual reporting. As by sixth and seventh decade, ACC of cervix was considered as the disease of the postmenopausal women, having strong association with high parity and black race, and surgery was the treatment of choice,. However reviewed reports in the later decades suggested that there were cases found in the premonopausal and below thirty age group,, with no association to parity and any race, and radiotherapy had equally good or better results compared to surgery in early stages,,,. Considering the importance of the review of this infrequent disease, literature is reviewed with particular emphasis on the treatment of adenoid cystic carcinoma of cervix, and its outcome.
General features. Overall incidence of ACC, of cervix is found to be around 0.4to 1.7% of all carcinoma of cervix,,. There is no consensus regarding total number of cases of ACC of cervix reported in the English literature. Philips et al reported a case in 1985 and claimed to have found 59 other cases in English literature. However Berchcuk et al could find 86 cases in 1985. Another series could trace 120 cases reported in the English literature up to 19898. Difference in the total number of cases reported may be due to the difference in the acceptance criterion of ACC of cervix,. There was also confusion regarding solid variant of adenoid cystic carcinoma and poorly differentiated adenocarcinoma,,. Others also included the more specified and distinct entity of adenoid basal cell carcinoma ABC of cervix,,,.
Average age of presentation is found to be 20 years older than squamous cell carcinoma of cervix,. It is claimed that only seven ACC of cervix reported so far in the literature were below 40 years of age. It has distinct characteristics in terms of natural course, therapeutic responsiveness and metastatic pattern as compared to squamous cell carcinoma of cervix. ACC of cervix is found to be aggressive with high tendency to local recurrence and it also metastasizes early to lymph nodes and distant sites as compared to other counterpart of origin,. Five and 10 years survival of adenoid cystic carcinoma of the salivary gland is reported about 62 and 39% respectively while for cervix these figures are reported as about 37-40% for four months to 12 year follow-up. Most of the cases presented with vaginal bleeding as chief symptoms. Histopatholigicaily most of them were found to be associated with squamous or focally adenosquamous invasive or noninvasive carcinomas or dysplasia. Majority of cases presented in early stages. it is possible to detect ACC of the cervix cytologically at early stages ,,. Positive Papanicolaou smear wag found in eight percent of cases in a series. Even in the absence of colposcopically visible lesion, cytologic examination of Papanicolaou smear was positive. No predilection to any race was foundg. Majority of cases were multiparous, however no relation of parity and occurrence of ACC of cervix is commented.
Origin: Adenoid cystic carcinoma at other site is malignancy of myoepithelial cells . In cervix these tumours originate from metaplasia of basal layer of adenexa cell or from any of multipotent endocervical reserve cells,. Presence of associated squamous cell differentiation in most of cases suggest that tumour arises from some subcolumnar reserve cells in the transformation zone, which are thought to be progenitor of most other cervical carcinomas,. However immunofluorescene study showed them to have two different types of antigenically different types of the filaments, actin and keratin. Actin suggests myoepithelial differentiation, which is not a component of cervix. It was presumed that, probably myoepithelial like traits represent a characteristic acquired secondarily in the process of the malignant transformation. Some authors claim that adenoid cystic pattern is a nonspecified pattern of presentation by squamous cells or adenocarcinoma cells. However more logical hypothesis is that ACC of cervix is the neoplasm of the multipatent cervical cells; least differentiated areas express adenoid cystic pattern and better differentiated areas represent squamous or adenocarcinoma pattern. Whatever may be the origin or categorization of ACC of cervix, the fact remains that this tumor behaves aggressively and needs separate therapeutic attention.
Management: It is difficult to make any conclusion regarding the management of the ACC of cervix through analysis of cases reported in varied period of the time, from different institutions with diverse modes of treatment and varied period of the follow-up. However these analyses would lead to make a broad generalization regarding therapeutic responsiveness of these tumours.
In the present review, reports related to ACC of the cervix in which response was not commented,,, or with tumour stage zero and those of adenoid basal cell carcinoma of the cervix ABC were not considered. (ABC) of the cervix is a different entity; it is a slow growing tumour and amenable to simple hysterectomy with long period of disease free status and good survivallg and therefore has to be considered separately form ACC of cervix. There were total 71 cases of ACC of cervix enlisted for the present analysis. There were 34 cases in FIGO stage I, 21 in stage II, 10 in stage III and 4 in stage IV. In two cases stage was not known. Except 5 cases all took complete radical treatment (I of stage, 1,2 of stage II, 2 of stage III).
Stage I: Out of 33 cases who received complete treatment, 14 cases were treated with radiotherapy (4 with intracavitary radium alone and rest with combination of the external and intracavitary treatment) and 19 cases were treated with surgery with or without post-operative radiotherapy (13 surgery alone, 6 with surgery and radiotherapy). In the radiotherapy group 12 of 14 cases were living disease free for more than two years (maximum 11 years, mean 5.5 years), with total no evidence of disease rate (NED rate) of 92.8% (13/14). In the surgery group out of 19 cases five were disease free with minimum two years follow-up (mean 3 yrs and 2 months, maximum 5.3 years), with total NED rate of 57.8% (11/19). In the surgery alone group NED rate was 61.5% (8/13) and in surgery plus radiotherapy group it was 50% (316). [Table - 1]
Looking at the results, patients treated with radiotherapy had better outcome compared to the cases treated with surgery. Difference in the response rate between two groups may partly be affected by varied follow-up period and un-investigated factors as lymph nodes involvement, lymphatic and vascular invasion, which wore riot known in most of the radiotherapy treated cases. Poor results in state I who were treated with combination of radiotherapy and surgery may be due to selection of unfavourable cases in this group. In failure analysis except one all failures occurred in surgically intervened cases and all failures had distant metastases [Table - 2]. Whether surgical intervention increases the distant metastases rate is a point of further analysis. Majority of cases that failed had distant metastases in omentum, central nervous system and lung. Pre-operative radiotherapy, chemotherapy could be contemplated in such circumstances. Other series also state that results with radiotherapy are better as compared to surgery. Prempree et al on reviewing the literature observed that in stage I, 71.4% patients remained disease free after radiotherapy and 50% after surgery. Ding and Woodruff  reviewed 57 reported cases and found 50% and 77% cases of stage lb remained disease free when treated with surgery and radiotherapy respectively.
Stage II: Reports of 19 patients who took complete treatment are analysed. Three patients were of IIa, all of them died of distant metastases at 3.4, 6, and 6.5 years. Two of them were treated with radical surgery, including periaortic lymph node biopsy, dissection and one case was treated with radical radiotherapy. Of the romaining patients (lib cases), 2 were treated with surgery and 14 with radiotherapy. Results are shown in [Table - 1]. Overall, stage II NED (No evidence of disease) rate of 31.5% (6/19) was found. This suggests that in stage II radiotherapy is equally effective as surgery.
Among 13 failures, 7 were having relapse only distant site, 2 had both locally and at distant sites and 4 had only locally. It suggests necessity of reinforcement of treatment strategy locally as well as systemically. If the possibility of faulty radiotherapy technique and big disease volume are assumed to be responsible for those local failures, the main site of relapse still appears to be the distant site. This emphasises the need of combination of radiotherapy and surgery or radical radiotherapy alone in all and adjuvant chemotherapy in selected cases of stage II disease.
Stage III: Eight patients took complete radiotherapy treatment. Only one patient remained disease free at 11 months and none remained disease free for more than two years with NED rate of 12.5% (l/8). Except one all 7 recurrences developed within two year period of treatment-,,,, [Table - 3].
Considering high local as well as distant relapses, aggressive local and systemic treatment is required. Locally interstitial radiotherapy could be tried to deliver higher doses. Neutron therapy has shown encouraging results in advanced salivary gland tumors.
Stage IV: None of the four patients showed any response , and none of five patients who received incomplete4 treatment (1-1b,2- lib, 2-111b) achieved disease free status ,,,. In two cases stage was not known and were treated with radiotherapy, in which one developed local recurrence at one year and another died disease free at two year follow-up,,,, [Table - 3].
NED rate for all staged and treated cases was found to be of 48.4% (31/64), [32/66 if unstaged, 32/71 when incompletely treated group included] with follow-up ranging from one months to 11 years (mean 39 months).
Salvage treatment: Seven patients had undergone salvage treatment, either for persistent disease or for recurrence in this reviewed series. One patient was Ib four of Ib four of IIb,, and one of IIIb and one unstaged. All patients received radiotherapy as initial treatment. One case had persistent disease and three developed local pelvic recurrence at 2, 2 and 2.4 years respectively, and all four underwent exenteration treatment. In these four patients two remained disease free at 12 and 18 months. One died in post-operative period and one died of disease at five months after extenteration. Another patient of stage IIIb developed vaginal recurrence at two months, which was successfully treated with high energy electron. However, the patient died of pelvic recurrence and pulmonary metastases at 16 months. Other two patients developed recurrence at distal vagina and at labia majora at 3.10 and 5 years after initial treatment respectively,. Reirradiation was tried. The former remained disease free at 5.2 years and the latter died of vesico-vaginal fistula at 8 years. Total 3/7 patients could be salvaged, 2/4 by surgery and 1/3 through reirradiation.
Chemotherapy: Seven patients were given chemotherapy. Of three patients to whom cisplatin 100 mg/m square was given as an adjuvant chemotherapy, two (Ib) remained disease free at 12 and 64 months. In one patient adjuvant bleomycin was given and this patient was living with disease at 18 months10. Four patients were given salvage chemotherapy,,, for local or distant recurrences. Three patients achieved no or partial response. In these patients single agent chemotherapy in the form of bleomycin, adriamycin and 5 fluorouracil was tried. In one case multiagent combination chemotherapy as cisplatin 50 mg, cyclophosphamide 500 mg and adriamycin 50 mg per square metre was administered after local relapse and pulmonary metastases. This patient remained disease free for eight months. Total 3/7 cases achieved complete response, 2/3 cases from adjuvant treatment and 1/4 from salvage treatment. Limited chemotherapy experience suggests that high dose cisplatin and multiagent chemotherapy has therapeutic effect over ACC of cervix and adjuvant treatment would be more beneficial rather than as a salvage treatment. Including salvage treatment by chemotherapy, total 4/1 1 cases could be salvaged (36.3%).
Failure pattern and metastases: Distant metastases was the commonest feature. Autopsy of three cases at 9, 36, and 39 months revealed widespread abdominal and pulmonary metastases. Most common site of the distant relapse was lung, 20 of 31 patients who had distant metastases either alone or with pelvic failures, had their lungs involved (51%) High rate of lung metastases also reported by other authors in the range of 38.8% and 44%. Period of appearance of lung metastases ranged from five months to 36 months. Six patients were having multiple abdominal metastases appearing at 6-16 months of treatment, brain metastases were noted in three patients at two years and in two patients liver metastases were found at one and 16 months. One autopsy also revealed microscopic metastases in the heart. Two metastases appeared in the labia majora at 46 and 60 months. Majority of metastases appeared between 6-36 months, however late metastases in the labia majora were noted up to 60 months. In one analysis brain metastases were noted in the range of 2%. Of total 39 failures in 71 patients, nine cases had only pelvic failure, 15 failed both in the pelvis and at distant site and 15 other cases had only distant failure with no disease in the pelvis. Failure only at a distant site was noted in 6/9 in stage lb, 7/13 in stage lib. In advanced stages local as well as distant failure is noted in most of the cases. This suggests the scope of adjuvant chemotherapy in high risk cases of early stages and reinforcement of local and systemic treatment in advanced stages to improve the results. Further analysis is required to select treatment for these high risk cases.
Of 39 cases that developed relapse, 30 died of disease from one month to 96 months. There seems to be two type of presentation of ACC of cervix. Patients of the first type relapsed early and died of disease, mostly within 12 months while those of the other type had indolent course and were alive with disease for long time at 36 to 72 months,,, or remained disease free for a long period of the time,,.
Advanced disease (stage III and IV) and who received incomplete or no treatment fared poorly and succumbed to disease early. Apart from stage, lymph node involvement, vascular and lymphatic invasion and some histopathological factors might have affected the outcome. These factors could be used in deciding the course of the treatment. Like solid pattern of adenoid cystic carcinoma of other than cervix site has been found to have tendency to metastasise early.
Further studies and meta-analysis of reported cases in the past are required to asses these high risk factors to choose the effective treatment strategy.
[Table - 1], [Table - 2], [Table - 3]