GYNECOLOGIC

ONCOLOGY

33, 189-192 (1989)

Pulmonary Metastasis from Carcinoma of the Uterine Cervix MASASHI IMACHI, M.D., Department

of Obstetrics

NAOKI TSUKAMOTO,M.D., and Gynecology,

Kyushu

University

TOSHITAKAMATSUYAMA, M.D., Faculty

of Medicine,

Maidashi

3-l-1,

AND HITOO NAKANO, Higashi-ku,

Fukuoka

M.D.

812, Japan

Received October 28, 1987

Of 817 patientswith carcinomaof the uterine cervix that were treated and followed-up, 50 (6.1%) developedpulmonary metastases.The incidenceof pulmonary metastasiswas3.2% in stage I, 5.0% in stageII, 9.4% in stageIII, and 20.9% in stageIV disease.The incidenceof pulmonary metastasisin patients with adenocarcinomaand undifferentiated carcinomawas higher. Of the patients in whom lung metastases were detected,41.7% had no symptoms;96%wasdiagnosed within 2 yearsfrom the initiation of treatment. All patientshad abnormalshadowsin chestX rays. We recommendthat chest X rays be obtained every 2 months within the 8 monthsafter treatmentand every 6 monthsthereafter. Eighty-one percent of the patients had local recurrenceor other distant metastaticlesions.The main treatment for thesepatients waschemotherapy,and CAP was effective for the patients with adenocarcinoma.Surgicalresectionof the pulmonary lesionmay be an effective treatment for the patientswho have no lesionsin other sites. Q 1989 Academic Press, Inc.

Pulmonary metastasis from carcinoma of the uterine cervix is relatively rare, and only a few reports have appeared in the English literature [l-4]. This rej?ort is the result of a study of pulmonary metastasis in 50 patients with carcinoma of the cervix at our institution. MATERIALS

AND METHODS

From January 1975 to December 1985, 817 patients with carcinoma of the uterine cervix were seen and treated at the Kyushu University Hospital. Patients with microinvasive carcinoma of the cervix were excluded. The clinical stages (FIGO) of these patients were as follows: I, 312; II, 281; III, 181; and IV, 43. Of 817 patients, 50 patients developed pulmonary metastases during the follow-up period. At the time of diagnosis of carcinoma of the cervix, these patients were between 23 and 82 years of age, with a mean of 56.7 years. As an initial treatment, 6 underwent radical hysterectomy, 12 underwent radical hysterectomy followed by postoperative radiotherapy, and 32 underwent radical radiotherapy.

RESULTS

Of 817 patients, 50 (6.1%) developed pulmonary metastases. The incidence of pulmonary metastasis was 3.2% in stage I, 5.0% in stage II, 9.4% in stage III, and 20.9% in stage IV (Table 1). The incidence of pulmonary metastasis in patients with stage IIb was higher than that in patients with stage IIa (5.8% vs 2.7%). Similarly, the incidence of pulmonary metastasis in patients with stage IIIb was higher than that in patients stage IIIa (9.8% vs 0%). In stage IV, the incidence of pulmonary mestastasis in patients with stage IVa was 4.3% and that in patients with stage IVb was 40.0%. However, 5 stage IVb patients already had lung metastasis when the cervical cancer was detected. The incidence of pulmonary metastasis in patients with stage IVb who had no pulmonary metastases at initial treatment was 20.0%. Histologically, 90.3% of 817 patients had squamous cell carcinoma, 5.3% adenocarcinoma, 3.7% adenosquamous carcinoma, and 0.5% undifferentiated carcinoma. Five and six-tenths percent of the patients with squamous cell carcinoma and 6.7% of the patients with adenosquamous carcinoma developed pulmonary metastasis, while 11.6% of adenocarcinoma and 25.0% of undifferentiated carcinoma developed pulmonary metastasis (Table 2). In patients with squamous cell carcinoma, the incidence of pulmonary metastasis with keratinizing type was O%, that with large cell nonkeratinizing type was 9.1%, and that with small cell type was 16.7% (Table 3). In patients with adenocarcinoma, the incidence of pulmonary metastasis with well-differentiated carcinoma was 11 .S%, that with moderately differentiated carcinoma was 25.0%, and that with poorly differentiated carcinoma was 33.3% (Table 4). As stated above, 5 patients already had pulmonary metastases at the time of initial therapy. In the other 45 patients, the mean interval from the initiation of treatment to detection of pulmonary metastasis was 11.7 months (range, 2-46 months). In 56% of the patients pulmonary

189 0090-8258/89 $1 SO Copyright 0 1989 by Academic Press, Inc. All rights of reproduction in any form reserved.

190

IMACHI

TABLE 1 Clinical Stage and Pulmonary Metastasis

ET AL.

TABLE 3 Squamm Cell Carcinomaand Pulmonary Metastasis

Pulmonary metastasis Clinical stage I II III IV Total

Pulmonary metastasis

No.

%

101312 14/281 17/181 9143 501817

3.2 5.0 9.4* 20.9* 6.1

Cell type Small cell Large cell nonkeratinizing Keratinizing

No.

%

W5 231254

16.7 9.1

o/33

0*

* Significant compared with large cell nonkeratinizing

(F < 0.05).

* Significant compared with the stage I and II (P < 0.01).

metastasis was diagnosed within 8 months, and in 96% of the patients within 24 months (Fig. 1). The interval for patients with adenocarcinoma (24.0 months) was longer than that for those with squamous cell carcinoma (10.6 months) and adenosquamous carcinoma (4.5 months). Of the patients in whom pulmonary metastases were detected, 41.7% had no clinical symptoms. Table 5 shows clinical symptoms at the time of diagnosis of pulmonary metastasis. The diagnosis of pulmonary metastasis in patients without symptoms was made by routine periodic chest X rays. Fifty-four percent had metastatic lesions in bilateral lungs. The most common roentgenographic pattern was multiple nodules (45.8%) (Table 6). In patients with squamous cell carcinoma, 20.8% showed reticular pattern and all eight patients with reticular pattern by chest X rays had squamous cell carcinoma. On the other hand, the roentgenographic pattern of pneumonia-type was recognized in 40.0% of patients with adenocarcmoma. All 50 patients had abnormal shadows in chest X rays. Bronchoscopy was performed in 9 patients and carcinoma was confirmed histologically in 5 (56%). Sputum cytologies were obtained in 26 patients and 7 (26%) were positive. However, as a whole, pulmonary metastases were detected in only 16% of 50 patients by histologic and/or cytologic studies. Thirty percent of the patients with squamous cell carcinoma had positive sputum cytology, while no

TABLE 4 Adenocarcinomaand Pulmonary Metastasis Pulmonary metastasis Tumor differentiation

No.

“ro*

Well Moderately Poorly

2/17 l/4 l/3

11.8 25.0 33.3

* Statistically not significant.

FIG. 1. The interval from the initiation of treatment to detection of pulmonary metastasis.

TABLE 2 Cell Type and Pulmonary Metastasis Pulmonary metastasis Cell type Squamous cell Adenosquamous Adenocarcinoma Undifferentiated Others Total * Statistically not significant.

No.

%*

41/738 2/30 5/43 l/4

5.6 6.7 11.6 25.0

o/2 501817

0 6.1

TABLE 5 Clinical Symptoms Symptoms No symptoms Cough Dyspnea Sputum Chest pain Fever

No. of cases

%

20 15 8 4 4 4

41.7 31.3 16.7 8.3 8.3 8.3

PULMONARY

METASTASIS

TABLE 6 Findings of Chest X Rays Findings Multiple nodules Solitary nodule Reticular Pleural effusion Atelectasis Pneumonia-type

No. of cases

%

22 9 8 4 3 2

45.8 18.8 16.7 8.3 6.3 4.2

patients with adenocarcinoma had positive sputum cytology. Sixty percent (3/5) of the patients with reticular pattern in the chest X ray had positive sputum cytology, while only 20% with multiple nodules and none with solitary nodule had positive cytology. Only 18.8% of the patients had neither local recurrence nor other distant metastasis at the time of diagnosis of pulmonary metastasis. Local recurrence was detected in 20.8%, bone metastasis in 33.3%, and liver metastasis in 20.8% of the patients (Table 7). The main treatment for the patients with pulmonary metastasis was chemotherapy. Thirty-two of 50 patients received chemotherapy. Nine of 20 patients who received more than two courses of chemotherapy showed disappearance of abnormal shadows in chest X rays. In adenocarcinoma, a combination chemotherapy consisting of cis-platinum, Adriamycin, and cyclophosphamide (CAP) was administered. Of the 6 patients who received CAP for an average of 4.5 courses, 5 patients had disappearance of abnormal shadows in chest X rays. However, in squamous cell carcinoma, the response to chemotherapy was poor. Thirty-three percent (3/9) had disappearance of abnormal shadows by a combination chemotherapy consisting of c&platinum and peplomycin (PP), and 40% (2/5) by BM (bleomycin and mitomycin C) therapy. Currently, FACV (5FU, Adriamycin, cyclophosphamide, vincristine) is being tried in patients who had a poor response to PP therapy. We had 1 patient who underwent TABLE 7 Local Recurrenceand Other Distant Metastatic Lesions Site Bone Liver Local Virchow’s node Paraaortic node Skin Brain Right supraclavicular node Peritonitis carcinomatosa

No. of cases

%

16 10 10 7 7 4 2 2 2

33.3 20.8 20.8 14.6 14.6 8.3 4.2 4.2 4.2

OF CERVICAL

CANCER

191

a pulmonary lobectomy after chemotherapy. This patient was a 41-year-old woman and had a stage Ib squamous cell carcinoma of large cell nonkeratinizing type. A metastatic lesion in the left lower lung field was found 2 years after radical hysterectomy. Despite PP therapy, abnormal shadows in chest X rays did not disappear and she underwent a pulmonary lobectomy. She has had no recurrence during the last 14 months. As stated above, some of the lung metastases had responded to chemotherapy; however, the outcomes of these 50 patients were poor. The mean interval from diagnosis of pulmonary metastasis to death in 38 patients was 7 months (median, 3 months; range, l-59 months). The outcome of the patients who had reticular pattern in the chest X rays was poorer than that of those who had a solitary nodule. DISCUSSION Pulmonary metastasis is relatively rare in patients with carcinoma of the uterine cervix [3,4]. The incidence of pulmonary metastasis from the cervical cancer in our study was 6.1% (50/817). It was similar to those reported by others, such as 5.1% by D’Orsi et al. [51, 5.8% by Carlson et al. [4], 2.2% by Peeples et al. [6], 6.4% by Sostman and Martthay [7], and 9.1% by Tellis and Beechler [l]. The incidence of pulmonary metastasis in autopsy cases was higher, such as 15% by Warren [8], 19% by Hendriksen [9], and 33% by Badib et al. [3]. The incidence of developing pulmonary metastasis increased as the clinical stage advanced, i.e., 3.2% in stage I, 5.0% in stage II, 9.4% in stage III, and 20.9% in stage IV (Table 1). This result is comparable to what was reported in the literature [l]. In our study, the incidences of pulmonary metastasis in stages IIa and IIIa were lower (2.7 and 0%) than those in stage IIb and IIIb (5.8 and 9.8%), respectively. The incidence of pulmonary metastasis in patients with adenocarcinoma and undifferentiated carcinoma seemed to be higher than that in patients with squamous cell carcinoma (Table 2). However, there was no statistical significance. We have previously noted that the incidence of positive peritoneal cytology was higher in patients with adenocarcinoma than that in patients with squamous cell carcinoma [lo]. The higher tendency of patients with adenocarcinoma to develop pulmonary metastasis may be another indicator of a poor prognosis as is the higher incidence of positive peritoneal cytology. In patients with squamous cell carcinoma, the incidence of pulmonary metastasis was higher in those with small cell type than in those with keratinizing or large cell nonkeratinizing type (Table 3). In patients with adenocarcinoma, the incidence of pulmonary metastasis seemed to be higher in poorly differentiated adenocarcinoma (Table 4).

192

IMACHI

The mean interval from the initiation of treatment to detection of pulmonary metastasis was 11.7 months. Pulmonary metastasis was found within 8 months in 56% of the patients and within 24 months in 96%. Of the patients, 41.7% had no symptoms (Table 5). The routine chest roentgenogram was important for the early diagnosis of pulmonary metastasis. Then, how often should the routine follow-up chest X rays be obtained? In our study more than half of the pulmonary metastases were diagnosed within 8 months after treatment and the detection of pulmonary metastasis was rather rare thereafter. Therefore, we recommend taking chest X rays every 2 months within the 8 months after treatment and every 6 months thereafter. However, in the patients with adenocarcinoma, more frequent chest X rays should be obtained even after 8 months because of the possibility of late pulmonary metastasis. The most common abnormal pattern of the chest X rays was multiple nodules. Lymphangitis carcinomatosa from carcinoma of the cervix is rare [ 11,121. In our study, eight patients had reticular shadows in the chest X rays and the histologies of all these patients indicated squamous cell carcinomas. Sputum cytology is an important examination. Twenty-seven percent of the patients had abnormal cytologic findings in this study. The positive sputum cytology rate was especially high in the patients with lymphangitis carcinomatosa. Many patients (81%) had local recurrence and/or other distant metastases at the time of diagnosis of pulmonary metastasis. Tellis et al., [l] reported that 55% of their patients had other distant metastases, compared to 71% in our study. This fact shows that the disease is already a systemic disease at the time of diagnosis of pulmonary metastasis. Therefore, the main therapy for pulmonary metastasis should be chemotherapy. In this study 45% of 20 patients who received two or more courses of chemotherapy showed disappearance of abnormal shadows in chest X rays. PP and FACV were given to the patients with squamous cell carcinoma and CAP was given to the patients with adenocarcinoma. Moreover, in 83% (5/6) of the patients with adenocarcinoma, abnormal shadows in the lungs disappeared after treatment with CAP. However, the response of local recurrences and/or other metastatic lesions was poor. On the contrary, resection of pulmonary metastasis seems to be effective for the patients who had no lesions in the other site [1,13,141. In our study, a patient who had a persistent metastatic pulmonary

ET AL.

lesion despite PP therapy underwent pulmonary lobectomy. She has been alive and well with no evidence of disease for 14 months. In conclusion, the prognosis of the patients with pulmonary metastasis from carcinoma of the cervix is grave. However, a better survival may be expected by utilization of aggressive chemotherapy and, when indicated, by surgical resection of the metastatic lesion. REFERENCES 1. Tellis, C. J., and Beechler, C. R. Pulmonary metastasis of carcinoma of the cervix, Cancer 49, 17051709 (1982). 2. Schranb, S., Montcuquet, P., Horiot, J. C., and Mercier, M. Bronchial carcinoma after cervical carcinoma, Cancer 56, 2707-2710 (1985). 3. Badib, A. O., Kurohara, S., Webster, J. H., et a/. Metastasis to organs in carcinoma of the uterine cervix: Influence of treatment on incidence and distribution, Cancer 21, 434-439 (1968). 4. Carlson, V., Delclos, L., and Fletcher, G. H. Distant metastasis in squamous cell carcinoma of the uterine cervix, Radiology 88, 961-966 (1967). 5. D’Orsi, C. J., Bruckman, J., and Smith, E. Lung metastasis in cervical and endometrial carcinoma, Amer. J. Roentgenol. 133, 719-722 (1979). 6. Peeples, W. J., Inalsingh, C. H. A., Hazra, T. A., and Graft, D. The occurrence of metastasis outside the abdomen and retroperitoneal space in invasive carcinoma of the cervix, Gynecol. Oncol. 4, 307-310 (1976). 7. Sostman, H. D., and Martthay, R. H. Thoracic metastasis from cervical carcinoma: Current status, Invest. Radiol. 15, 113-119 (1980). 8. Warren, S. Studies on tumor metastasis: Distribution of metastasis in carcinoma of the cervix uteri, Surg. Gynecol. Obstet. 56, 742745 (1933). 9. Hendriksen, E. The lymphatic spread of carcinoma of the cervix and of the body of the uterus: A study of 420 necropsies, Amer. J. Obstet. Gynecol. 58, 924-942 (1949). 10. Imachi, M., Tsukamoto, N., Matsuyama, T., and Nakano, H. Peritoneal cytology in patients with carcinoma of the uterine cervix, Gynecol. Oncol. 26, 202-207 (1987). 11. Joannides, T., Tobias, J. S., and Kurer, M. Lymphangitis carcinomatosis arising from carcinoma of the cervix, Eur. .Z. Surg. Oncol. 11, 377-379 (1985). 12. Buchsbaum, H. J. Lymphangitis carcinomatosis secondary to carcinoma of cervix, Obstet. Gynecol. 36, 850-860 (1970). 13. Ishihara, T., Kikuchi, K., Ikeda, T., et al. Metastatic pulmonary disease, Biologic factors and modes of treatment, Chest 63, 227232 (1973). 14. McCormach, P. M., Baines, M., Beattie, E. J., et al. Pulmonary resection in metastatic carcinoma, Chest 73, 163-166 (1978).