Cervical Adenocarcinoma in Women With Nasopharyngeal Carcinoma (NPC)

PRITAM SINGH, MBBS, MRCOG, MMED,' A. ILANCHERAN, MBBS, MRCOG, MMED,'

AND AIDAN P. O'REILLY, MBBS, MRCPATHS S. S. RATNAM, MD, FRCOG, FRCS, FRACS,* LIM-TAN SO0 KIM, MBBS, MRCPATH,t

Multiple primary cancers account for only 0.38% of all cases in the Singapore Cancer Registry. The close temporal association of nasopharygneal carcinoma (NPC) in three Chinese women with uterine cervical adenocarcinoma was observed in our department within a 3-month period; one other case was extracted from the local literature. Although NPC is a common neoplasm in local Chinese women, uterine cervical adenocarcinomas comprise only 8% of cervical cancers locally. The close occurrence of these cancers does not seem to be related to the therapy used for cervical cancer and suggests that an association of the Epstein-Barr virus (EBV) with uterine cervical adenocarcinoma should be further investigated.

Cancer 641152-1155, 1989.

ULTIPLE PRIMARY CARCINOMAS OCCumng in the M same individual are generally attributable to com- mon or related etiologic factors, host susceptibility, or the oncogenic action of agents used in the treatment of the index cancer. The occurrence of multiple tobacco-related primaries in the upper aero-digestive tracts is well docu- mented. In women, multiple primaries in the breast, ovary, and endometrium are probably related to common risk factors such as reproductive history and hormonal profiles. The increased risk of lymphoreticular malignan- cies in women treated with radiation therapy for uterine cervical carcinoma is probably related to the oncogenic effect of therapeutic radiation. '

During a recent 3-month period, we encountered three cases of adenocarcinoma of the uterine cervix in women with nasopharygneal carcinoma (NPC). An extensive

From the *Department of Obstetrics and Gynecology, National Uni- versity of Singapore, National University Hospital; the ?Department of Pathology, Singapore General Hospital; and the $Department of Pa- thology, National University of Singapore, National University Hospital, Singapore.

The authors thank the following individuals for reporting the biopsies of the nasopharynx and cervix: Dr. Lim-Tan So0 Kim (Case 1); Dr. Ho May Sian, Dr. H. C. Seah, and Dr. A. P. O'Reilly (Case 2); and Dr. T. Mathew and Professor R. Sinniah (Case 3). The authors also thank Pro- fessor R. Sinniah, MD, PhD, FRCPI, FRCPA, FRCPath, for assistance and Professor K. Shanmugaratnam, MD, PhD, FRCPath, for advice and valuable criticism.

Address for reprints: Pritam Singh, MRCOG, MMed, Department of Obstetrics and Gynecology, National University Hospital, 5 Lower Kent Ridge Road, Singapore 05 I 1.

Accepted for publication January 17, 1989.

search of the literature showed one other case locally in which an NPC occurred not long after the diagnosis of a uterine cervical adenocarcinoma had been made.' We re- port these cases because such an association has not been recorded previously and may be of interest in studies on the cause and pathogenesis of uterine cervical adenocar- cinoma.

Case Reports

Case I

A 65-year-old Chinese woman of the Teochew dialect group presented in September 1986 with vaginal bleeding of 2 months duration. A pelvic examination showed a clinically obvious in- vasive cervical carcinoma spreading into both parametria but not reaching the lateral pelvic walls. A biopsy specimen of the cervix showed an invasive, moderately differentiated primary papillary adenocarcinoma (Fig. I). At the same time, several firm-to-hard enlarged lymph nodes were noticed in the upper region of the neck at the posterior margin of the sternomastoid muscle at the level of the angle of the mandible. The patient was referred to the Otorhinolaryngology Department and biopsy specimens of both postnasal spaces showed an infiltrating, un- differentiated primary NPC (Fig. 2) . The patient received radia- tion therapy for the NPC, followed by external pelvic radiation and radium brachytherapy for the uterine cervical cancer. She responded well and remained in remission from both cancers until March 1987, after which she defaulted follow-up. In May 1988, she presented with a recurrent uterine cervical tumor that was confirmed by biopsy. She refused any further therapy, except symptomatic treatment, and is currently alive.

1152

No. 5 CERVICAL ADENOCARCINOMA AND NPC - Singh et a/. 1153

FIG. 1. Patient 1. Biopsy specimen of the cervix shows a papillary adenocarcinoma of the endocervical type with atypical villous epithelium supported by connective tissue stroma (H & E, original magnification X100).

Case 2 A 38-year-old Chinese woman of the Hainanese dialect group

was referred in September 1986 for further management after the removal of a well-differentiated papillary adenocarcinoma growing as a polypoid lesion of the uterine cervix. In January 1986 (only 8 months earlier), she saw an otorhinolaryngologist for a right-sided neck swelling due to an enlarged lymph node. At this point, a right postnasal space biopsy confirmed the ex- istence of an undifferentiated NPC. She was treated with radio- therapy that caused a resolution of both the cervical lymphade- nopathy and the nasopharyngeal tumor. The slides ofboth biopsy specimens were reviewed and the diagnoses reconfirmed. Clin- ically, the cervix had an area of raised granular tissue at the 0s. As a result, we allocated the patient’s condition to International Federation of Obstetrics and Gynecology (FIGO) Stage IB cer- vical carcinoma and proceeded to perform a radical hysterectomy and pelvic lymphadenectomy. An histopathologic examination

showed granulation tissue at the site of biopsy but no residual cervical tumor; all pelvic lymph nodes also were negative. The patient has been observed regularly and was well as of May 1988.

Case 3

A 57-year-old Chinese woman of the Hokkien dialect group saw her gynecologist in October 1986 for abnormal vaginal bleeding. At this time, a 4-cm, polypoid uterine cervical tumor was noticed that on biopsy showed an infiltrating, poorly dif- ferentiated cervical adenocarcinoma (Fig. 3). In June 1980, she saw an otorhinolaryngologist after 3 months of nasal bleeding. A hard, fixed cervical lymph node was noticed on the left side and a left postnasal space biopsy confirmed the presence of an undifferentiated NPC. The patient received full radiation therapy with complete clearance of symptoms and resolution of disease in both the nasopharynx and cervical lymph nodes. She had remained well on follow-up. When two of us (P.S., LA) reviewed

FIG. 2. Patient I . Biopsy specimen of the nasopharynx shows an infiltrating, undifferentiated carcinoma with sheets of malignant epithelial cells interspersed with mature lymphocytes (H & E, original magnification X200).

1154 CANCER September I 1989 Vol. 64

her condition for further management of the uterine cervical cancer, an obvious hemorrhagic friable tumor still confined to the cervix was found (FIG0 Stage IB); an intravenous urogram, chest radiograph, and other investigations were all normal. The patient underwent a radical hysterectomy with pelvic lymph- adenectomy. Histopathologic study confirmed residual poorly differentiated adenocarcinoma in the cervix, but all lymph nodes were negative for tumor. On regular follow-up visits, she remains free of tumor recurrence as of April 1988.

Discussion

Multiple primary carcinomas are relatively uncommon in Singapore, with only 103 cases of 26,848 cases of cancer registered during a 1 O-year period ( 1968 to 1 977).3 This is partly due to the adoption of strict criteria for the reg- istration of multiple cancers. Only cases in which both primaries are confirmed histologically and where the pos- sibility of one being a metastasis of the other has been excluded are registered. Moreover, tumors involving con- tiguous epithelial surfaces of adjacent organs and multi- centric primaries arising in the same organ or in paired organs are excluded. Deficiencies in the follow-up of pa- tients and a low necropsy rate also may have contributed to the low frequency of multiple cancers in the Singapore registry.

NPC, a rare neoplasm in most countries, occurs with a relatively high frequency among the Chinese, especially among those derived from the southern provinces of China of the Cantonese dialect group. The incidence rates of NPC among the Singapore Chinese are among the highest in the world, with annual age-standardized inci- dence rates of 8.1 per 100,000 in males and 7.0 in females during the period from 1978 to 1 982.4 Cancer of the uter- ine cervix was the cancer that ranked fourth among the

FIG. 3. Patient 3. Biopsy specimen of the cervix shows an infiltrating. poorly differentiated carcinoma with acute inflammatory and lymphoplasmacytic infiltrates (H & E, original magnification X 150).

Singapore Chinese females (after breast, colorectal, and lung) during this period, with an annual incidence rate of 17.0: most of these uterine cervical cancers (87%) were squamous cell carcinomas.

The first question that arises from this report is whether carcinomas of the nasopharynx and uterine cervix have occurred in the same individuals by chance. We consider this to be unlikely because three cases of this association occurred in a 3-month period in one gynecological unit and all the uterine cervical cancers are adenocarcinomas that comprise only approximately 8% of uterine cervical malignancies 10cally.~ The occurrence of uterine cervical adenocarcinoma in these cases is not attributable to the treatment of NPC because in two of the cases the tumors occurred synchronously (Patient 1 ) or within 8 months (Patient 2). In the third case (Patient 3) , in which cervical adenocarcinoma developed 6 years after NPC, the index tumor was treated only by local radiation to the head and neck region. In the fourth case, which was reported pre- viously,2 the NPC was diagnosed only 21 months after the cervical adenocarcinoma and the index cervical cancer had been treated by radium brachytherapy and external pelvic radiation. Consequently, we are inclined to believe that the same or related etiologic factors may have op- erated in both tumors. The validity of this proposition can only be studied by analyses of larger series of cases in different populations, particularly in Oriental popula- tions where the incidence of NPC is much higher than in white populations. There is now a considerable body of evidence that the Epstein-Barr virus (EBV) is closely as- sociated with the genesis of NPC.s,6 Studies on the viral cause of uterine cervical cancer have been largely con- cerned with herpes simplex virus type 2 (HSV-2)’ and human papilloma virus (HPV) types 16 and 18.8 A pos-

No. 5 CERVICAL ADENOCARCINOMA AND NPC * shgh et d. 1155

sible association of uterine cervical adenocarcinoma with EBV should therefore be investigated in view of the as- sociation of this neoplasm with NPC.

REFERENCES

I. The Working Group of the International Radiation Study Group on Cervical Cancer. Summary chapter. In: Day NE, Boice JD Jr, eds. Second Cancer in Relation to Radiation Treatment for Cervical Cancer. Lyon: International Agency for Research for Cancer, 1983; 137-181 (IARC Scientific Publications no. 52).

2. Tan BC. Double primary malignant neoplasms. Sing Med J 1974;

3. Shanmugaratnam K, Lee HP, Day NE, eds. Cancer Incidence in 151212-2 17.

Singapore 1968-1 97'7. Lyon: International Agency for Research on Cancer, 1983: 144 (IARC Scientific Publications no. 47).

4. Lee HP, Day NE, Shanmugaratnam K, eds. Trends in Cancer In- cidence in Singapore 1968-1982. Lyon: International Agency for Re- search on Cancer, 1988; 13 (IARC Scientific Publications no. 91).

5. Epstein MA, Achong BG, eds. The Epstein-Barr Virus. Berlin: Springer-Verlag, 1979.

6. Henle W, Henle G. Epstein-Barr virus and human malignancies. Adv Viral Oncol 1985; 5:201-238.

7. Aurelian L. Evidence for a viral aetiology of squamous cell carci- noma. In: Griffiths CT, Fuller AF, eds. Gynecologic Oncology. Boston: Martinus Nijhof, 1983; 1-62.

8. Gissmann L, Schneider A. Human papilloma virus DNA in pre- neoplastic and neoplastic genital lesions. In: Pet0 R, Zur Hausen H, eds. Banbury Report 2 1: Viral Etiology of Cervical Cancer. New York: Cold Spring Harbor Laboratory, 1986; 217-224.