Hepatic Metastases from Carcinoma of the Uterine Cervix

GYNECOLOGIC ONCOLOGY ARTICLE NO.

70, 56 – 60 (1998)

GO985037

Hepatic Metastases from Carcinoma of the Uterine Cervix Gwi Eon Kim, M.D.,*,1 Sang Wook Lee, M.D.,* Chang Ok Suh, M.D.,* Tchan Kyu Park, M.D.,† Jae Wook Kim, M.D.,† Jong Taek Park, M.D.,‡ and Jae Uk Shim, M.D.‡ *Department of Radiation Oncology, †Department of Obstetrics and Gynecology, Yonsei Cancer Center, Yonsei University, College of Medicine, ‡Samsung Cheil Hospital, Seoul, Korea 120-752 Received July 31, 1997

for hematogeneous metastases, but it is the prevailing impression that hepatic metastasis represents a rare clinical event, even if such metastases are not necessarily an uncommon occurrence in postmortem findings [4 –9]. Recently, we encountered the unexpected appearance of hepatic metastasis in several patients with carcinoma of the uterine cervix. If such metastases are present, available treatment is not fully effective and prognosis for these patients is extremely poor regardless of various treatment modalities. Nevertheless, there was very limited information in the literature regarding hepatic metastases from carcinoma of the uterine cervix. Moreover, the natural history of patients with such metastasis has never been systematically reviewed. It prompted us to perform this survey in an attempt to expand current awareness on characteristic patterns of these patients. Such knowledge may undoubtedly make an important contribution in assessing the most appropriate diagnostic and therapeutic efforts for management of the patients. The aim of the present clinical study is to investigate the patterns of hepatic involvement and the outcome of patients with such metastases.

Objective. To investigate the patterns of hepatic involvement and the outcome of patients with hepatic metastases from carcinoma of the uterine cervix. Methods. Of 1665 patients with carcinoma of the uterine cervix, 20 patients with hepatic metastases were detected clinically during the course of the disease. Clinical presentation and detailed patterns of hepatic involvement were retrospectively reviewed for these patients. Comparative analysis between patterns of hepatic metastases and survival data was also undertaken. Results. Hepatic metastasis from carcinoma of the uterine cervix were nearly always accompanied by uncontrolled locoregional diseases and/or extrahepatic metastases, whereas only 1 patient developed an isolated hepatic metastasis. Ninety percent of the hepatic metastases were metachronously detected. The median time from the appearance of primary carcinoma to detection of hepatic metastases was 39 months, but late metastases after 5 years were not uncommon. Metastatic lesion in 16 patients consisted of multiple tumors distributed in either one or both anatomical lobes, whereas only 4 patients had a solitary lesion confined to a single lobe. Patients with hepatic metastases were unlikely to survive 2 years with a median survival of 10 months. Conclusion. Favorable patterns of hepatic metastases in patient with carcinoma of the uterine cervix were not major determinants of favorable survival if components of extrahepatic disease were concomitantly present. © 1998 Academic Press

MATERIALS AND METHODS Between January 1985 and December 1991, a total 1665 patients with invasive carcinoma of the uterine cervix were treated at the Department of Radiation Oncology, Yonsei University, College of Medicine, Yonsei Cancer Center Hospital, in Seoul, Korea. Among them, 20 patients with hepatic metastases were detected by clinical or radiologic examination during the course of the disease. For all cases, the clinical records were reviewed retrospectively. A few of the hepatic metastases were detected by incidental findings on the baseline or follow-up abdominopelvic computed tomography (CT) scans which were routinely performed in order to evaluate the paraaortic lymph node status at 1 and 3 years after treatment. All hepatic metastases were proven by ultrasound-guided, fineneedle aspiration biopsy. Detailed patterns of hepatic involvement and the extent of the disease were evaluated on the basis of the radiologic findings. The salvage treatment for hepatic metastases was individualized for every patient. Ten patients received intrave-

INTRODUCTION Improved radiotherapeutic and surgical techniques have resulted in a better control of the pelvic disease and prolonged survival of patients with carcinoma of the uterine cervix, in whom clinical manifestation of distant metastases becomes more frequently apparent. Generally, hematogeneous dissemination occurs less frequently in carcinoma of uterine cervix, although advanced stage with bulky disease, endometrial extension, and regional lymph node metastases [1–3] have been suggested as poor prognostic indicators with an increasing rate of distant metastases. To our knowledge, the lungs and bone are by far the most common sites 1 To whom correspondence and reprint requests should be addressed at Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, CPO Box 8044, Seoul, Korea 120-752.

0090-8258/98 $25.00 Copyright © 1998 by Academic Press All rights of reproduction in any form reserved.

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TABLE 1 Case Summary of 20 Patients with Hepatic Metastases from Carcinoma of the Uterine Cervix Initial presentation

Case 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Age 52 52 62 59 68 50 52 53 42 56 61 54 54 52 42 52 37 68 52 63

Pathologic subtype LCK LCK LCK LCK LCK LCK LCNK LCNK LCNK LCNK LCNK LCNK LCNK LCNK LCNK LCNK Small cell Small cell Small cell Adenoca

Pattern of hepatic metastases

Stage (FIGO)

Size (cm)

Initial treatment

Interval to metastases (months)

1b 2a 2b 2b 2b 4b 1b 1b 2a 2a 2b 2b 2b 4b 4b 4b 1b 1b 2a 2b

333 332 434 333 333 .6 232 .6 434 433 333 433 333 .6 .6 .6 232 232 433 435

S1R S1R R R S1C1R R S S S1R R R R S1R C1R R C1R C1R R S R

40 39 50 16 39 11 39 93 98 29 82 28 133 0 0 6 26 6 85 62

Extrahepatic metastases Size (cm)

Distribution

Multiplicity

LR

PA/SCL

EDM

Salvage chemotherapy (cycle)

4–8 4–8 .8 .8 4–8 4–8 4–8 2.5 2.0 10 4–8 4 10 1.5 2.5 4–8 2.5 5 3 3

bilobar bilobar unilobar bilobar bilobar bilobar unilobar unilobar bilobar bilobar unilobar bilobar unilobar bilobar bilobar bilobar unilobar unilobar unilobar unilobar

.4 .4 .4 .4 .4 .4 1 .4 2 .4 .4 .4 1 2 2 .4 1 1 2 2

2 2 1 1 2 1 1 1 1 1 1 2 1 2 1 1 2 2 1 1

1/2 1/2 1/1 2/2 1/2 2/2 2/2 1/2 1/1 2/2 1/2 2/1 1/1 1/1 2/2 2/2 1/1 2/2 2/2 2/2

2 1 1 1 1 1 1 1 1 1 1 1 1 2 1 1 1 2 1 2

2 6 no no no no 13 3 5 no 11 4 6 no no no 6 no no 3

Outcome (months) D D D D D D D D D D D D D D D D D D D D

(10) (9) (5) (2) (7) (4) (13) (6) (11) (1) (24) (11) (15) (2) (15) (7) (10) (2) (10) (16)

Note. LCK, large cell keratinizing; LCNK, large cell nonkeratinizing; R, radiotherapy; S, surgery; C, chemotherapy; LR, local recurrence; PA/SCL, paraaortic/supraclavicular lymph nodes failure; EDM, extrahepatic distant metastases; D, dead.

nous chemotherapy with various combination regimens containing cisplatin and variable schedules (3–13 cycles), but the remaining 10 patients were closely followed without definite treatment. Table 1 summarizes the clinical features and the outcome of all 20 patients with hepatic metastases from carcinoma of the uterine cervix. Survival data and curves were calculated and plotted using the Kaplan-Meier method. The survival time for all patients with hepatic metastases from carcinoma of the uterine cervix was estimated from the date of detection of hepatic metastases. In addition, the median survival time was determined using the following variables: (i) timing of metastases; (ii) metastasesfree interval; (iii) number, distribution, and size of metastases; (iv) presence of extrahepatic diseases; and (v) addition of salvage chemotherapy. Wilcoxon rank sum test and log rank test were used to determine whether the survival difference in each variable was of statistical significance. RESULTS Clinical Presentation of Hepatic Metastases Of the 1665 patients who had invasive carcinoma of the uterine cervix, 20 patients (1.2%) developed hepatic metastases during the course of the disease. Only 1 patient (5%) developed an isolated hepatic metastasis alone without other evidence of extrahepatic diseases, whereas the remaining 19 patients (95%) were accompanied by uncontrolled locoregional pelvic diseases and/or widespread extrapelvic metastases. Thirteen (65%) of the 20 patients with hepatic metastases had persistent

or recurrent carcinoma in the pelvic cavity and 11 patients (55%) were accompanied by the paraaortic and/or supraclavicular lymph node metastases, with or without extrahepatic metastases component. In 16 (80%) of the 20 patients, hepatic metastases were accompanied by extrahepatic metastatic diseases to the lungs in 5 cases, to the bones in 5 cases, to the lungs and bones in 3 cases, and peritoneal carcinomatosis in 3 cases. Nine of the 16 patients with extrahepatic metastases component were accompanied by the paraaortic or supraclavicular lymph node metastases, but in the other 7 patients, there was no evidence of the paraaortic and/or supraclavicular lymph node failure. The detailed associated treatment failure patterns are summarized in Table 2. Hepatic metastases were synchronously detected at the time of initial presentation in 2 patients (10%). One patient with synchronous hepatic metastasis simultaneously presented the paraaortic and supraclavicular lymph node metastases (Case 14) and the other patient had a concomitant presentation of pulmonary and hepatic metastases without any clinical evidence of the paraaortic or supraclavicular lymph node involvement (Case 15). In 18 patients (90%), metachronous hepatic metastases were discovered during the remaining course of the patients’ disease process. Such metastases were presented as the first site of recurrence in 12 patients, but in the remaining 8 patients, they were found as the site of the second recurrence with a considerable interval following the initial treatment failure. In 6 of the 11 patients with the paraaortic and/or supraclavicular lymph node failure, hepatic metastases were documented simultaneously with these failures, whereas the

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TABLE 2 Associated Extrahepatic Organ Involvement According to Pelvic Disease Control in Patients with Hepatic Metastases from Carcinoma of Uterine Cervix Controlled pelvic disease (N 5 7)

Uncontrolled pelvic disease (N 5 13)

Total No. of patients (N 5 20)

2 (10%) 4 (20%) 2 1 0 1 0 (0%) 0 0 0 0 1 (5%)

0 (0%) 5 (25%) 1 2 2 0 7 (35%) 2 2 1 2 1 (5%)

2 (10%) 9 (45%) 3 3 2 1 7 (35%) 2 2 1 2 2 (10%)

PA/SCL failure alone PA/SCL 1 extrahepatic metastasis Lung Bone Lung and bone Peritoneal carcinomatosis Extrahepatic metastasis alone Lung Bone Lung and bone Peritoneal carcinomatosis No other failure Note. PA/SCL, paraaortic and/or supraclavicular lymph node.

paraaortic and/or supraclavicular lymph node failure preceded diagnosis of hepatic metastases in the other 5 patients. In 10 of the 16 patients with extrahepatic metastases, these extrahepatic metastases became simultaneously apparent with hepatic metastases, but in the remaining 6 patients, systemic metastases to the lung and/or bone preceded the development of hepatic metastases. For the entire patients, the median time between diagnosis of the uterine cervical cancer and evolution of hepatic metastases was about 39 months with a wide range of 0 to 133 months. In 6 of the 18 patients with metachronous presentation, the late hepatic metastases appeared more than 5 years after diagnosis of the carcinoma. Figure 1 shows the cumulative incidence of patients with hepatic metastases as a function of the time interval after diagnosis of carcinoma of the uterine cervix.

Patterns of Hepatic Metastases The patterns and the extent of hepatic involvement were evaluated by abdominopelvic CT scan. All the metastatic lesions on CT scans included single or multiple nodules of variable size in either one or both anatomical lobes of the liver. Metastatic lesions in 18 cases (90%) were less dense than the normal liver and were relatively well marginated and only 1 case among them represented central necrosis with peripheral contrast enhancement. On the other hand, metastatic tumors in 2 cases (10%) were poorly circumscribed with infiltrative nature. Multiple metastatic lesions with variable sizes within the liver were present in 16 of the 20 patients (80%), whereas solitary lesion confined to a single lobe was observed in the remaining 4 cases (20%). A single large tumor with adjacent small satellite nodules localized in the same segment was included with the solitary lesion. Eleven of the 20 patients (55%) had the metastatic diseases in both anatomical lobes and the remaining 9 patients (45%) had metastatic lesions confined in a single lobe or segment. In 5 of the 16 patients with multiple lesions, metastatic deposits were confined to a single lobe and in the remaining 11 patients, tumors were distributed in both anatomical lobes. The size of metastatic tumor was defined as ‘‘small’’ when the largest diameter was ,4 cm and as ‘‘large’’ when it was $4 cm. Metastatic nodules in about two-thirds of the cases were present with larger tumor size of more than 4 cm. Survival

FIG. 1. Cumulative incidence of cases with hepatic metastases as a function of time interval between diagnosis of primary cancer of the uterine cervix and subsequent appearance of hepatic metastases.

Prognosis of the patients was extremely poor regardless of treatment. The median survival time of all patients was 10 months (mean 9 months) with a range of 1 to 24 months. Overall 1- and 2-year actuarial survival rates were 25 and 0%, respectively (Fig. 2). All 20 patients with hepatic metastases were followed until death, but there were no autopsied patients.

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FIG. 2. Overall survival rate of 20 patients with hepatic metastases from carcinoma of the uterine cervix.

The major causes of death were uremia, pelvic abscess, and subsequent development of sepsis due to uncontrolled pelvic diseases in five cases and massive hemorrhage in two cases. Three patients with abdominal carcinomatosis died of generalized peritonitis and intestinal obstruction and one patient died of cachexia due to widespread carcinomatosis, but hepatic failure was responsible for only one death. However, the exact cause of death could not be documented in three patients who died at another hospital and in five patients who were discharged for hospice care. Survival of patients with synchronous metastases was not different from that of patients with metachronous hepatice metastases (8 versus 8.5 months). Patients with a metastasis-free interval of more than 2 years had a favorable median survival time (10 months), when compared to patients with a metastasis-free interval of less than 2 years (3 months). There were no significant differences in survival patterns of patients between solitary (median survival, 10 months) and multiple hepatic metastases (median survival, 7 months). Eight patients with unilobar hepatic metastases confined to a single lobe had a median survival time of 10 months, compared with 7 months for those with bilobar hepatic metastases (P 5 0.20). Similarly, the size and number of liver metastases were found to be of no significant difference in median survival time. The median survival of patients who were treated with salvage chemotherapy was better than those with conservative management (11 versus 5 months) (Table 3). DISCUSSION The estimated incidence of hepatic metastases in this series of 1665 patients is 1.2% and this rate is similar to the other clinical series reported [10, 11]. Based on the limited information reported in the literature [4 –9], hepatic metastasis could be detected as part of disseminated carcinoma or an isolated liver metastasis [4]. In Carlson’s series, 87% of patients with such metastases exhibited multiple organ metastases and the liver was the sole site of cancer metastases in only 13% of patients

[10]. This mode of presentation was almost consistent with the current study, in which the majority of hepatic metastases were nearly always accompanied by the uncontrolled pelvic diseases and/or extrapelvic metastases. In addition, we observed that metachronous hepatic metastases was far more prevalent than synchronous liver metastases. Of particular interest was the prolonged time interval from the diagnosis of the primary carcinoma to evolution of such metastases. The interval was occasionally protracted for over 5 years in about one-third of our cases, even if it was as relatively short as several months in a few cases including two with synchronous metastases. It is not evident whether the longer latent period is caused by a characteristic natural course of the disease or the late clinical detection of asymptomatic metastases or both. Extent of hepatic involvement is generally of great importance in making decision about treatment for the metastatic liver diseases. In our series, it was characterized by multiple metastases involving in either one or both lobes of the liver in the majority of cases, whereas only a few metastatic lesion consisted of a solitary metastasis confined to a single lobe. Moreover, such metastases presents a difficult clinical problem in management due to the presence of widespread extrahepatic metastases. Although hepatic resection in selected patients with a solitary metastatic nodule has been recommended as clinically relevant and a more common form of treatment [12], we are in agreement with the opinions that the great majority of patients with such metastases usually are not amenable to surgical treatment [9, 13]. None of our cases was a good

TABLE 3 Patterns and Outcome of Patients with Hepatic Metastases from Carcinoma of the Uterine Cervix

Variables Timing of metastases Synchronous Metachronous Metastases-free interval Less than 2 years More than 2 years Number of metastases Solitary Multiple Distribution of multiple metastases Unilobar Bilobar Size of metastases Small ,4 cm Large $4 cm Extrahepatic disease No Yes Chemotherapy No Yes

No. of patients

Median survival (months)

Wilcoxon rank sum test Log rank test

2 18

8 8.5

Z 5 0.000 P 5 0.999

6 14

3 10

Z 5 1.863 P 5 0.080

4 16

11 8

Z 5 0.569 P 5 0.576

9 11

10 7

Z 5 1.335 P 5 0.198

7 13

10 7

Z 5 0.875 P 5 0.392

1 19

2 10

Z 5 1.219 P 5 0.238

10 10

5 11

Z 5 2.810 P 5 0.011

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candidate tolerable to surgical resection, who had a solitary metastatic lesion confined to a single lobe, as well as no evidence of extrahepatic metastases. Abu-Ghazaleh et al. also has presented a case with metastatic carcinoma of the liver and the porta hepatis associated with enlarged paraaortic lymph nodes, who was unable to undergo even a palliative surgery [13]. Even though new modes of radiation treatment are being introduced for management of hepatic metastases, external beam irradiation alone has a limited role as a single modality in the curative approach to patients with these metastases. Without inclusive results, systemic chemotherapy has been the modality most often employed for these patients [14] because a significant number of patients had multiple nodules within both lobes and/or widespread extrahepatic diseases. However, effective combination of chemotherapeutic regimen and schedule has not been yet established. In contrast to the reports for hepatic metastases from colorectal cancers [15, 16], all our patients died within 2 years after detection of hepatic metastases regardless of treatment. Even if the addition of systemic chemotherapy indicates a better outcome, treatment results are contradictory because different selection criteria of patients and different treatment schedules were adopted. Another interesting finding in this review is that favorable patterns of hepatic metastases have a negligible influence on survival of patients. We had expected a more favorable survival pattern for patients with a solitary metastasis compared to those with multiple lesions, but nearly identical survival patterns were observed in both groups. Although the metastases-free interval prior to development of hepatic metastases did have a minimal impact on median survival time, neither the number of metastases nor the distribution of metastases within the liver was an important prognostic variable. It is unclear why the favorable patterns of hepatic metastases are independent of determining the prognosis. First of all, it does not seem logical to estimate the statistical significance on the basis of our data comprising only a few patients with a short life span. However, hepatic metastases are almost invariably accompanied by uncontrolled locoregional diseases and/or widespread extrahepatic metastases and also may be, on occasion, present for significant asymptomatic period of the time before hepatic failure, hepatic coma, and death [10]. In fact, various local factors such as infection, sepsis, intractable hemorrhage, and/or uremia by uncontrolled locoregional growth were the outstanding causes of death in some of our cases. It may be a possible explanation that the extent of hepatic involvement, in itself, has a negligible impact on survival. In summary, the majority of hepatic metastases were usually accompanied by unequivocal evidence of uncontrolled pelvic diseases and/or widespread metastases. The interval between diagnosis of the uterine cervical cancer and evolution of he-

patic metastasis was variable, but late metastases over 5 years were not uncommon. In addition, prognosis for such patients was extremely poor regardless of the treatment. Finally, we feel that the favorable patterns of hepatic metastases in these patients may not be a major determinant of favorable survival if uncontrolled primary disease and/or extrahepatic metastases are concomitantly present. However, the essential question as to what is the most optimal guideline of treatment for these patients still remains to be answered. REFERENCES 1. Perez CA, Camel HM, Askin F, Breaux S: Endometrial extension of carcinoma of the uterine cervix: A prognostic factor that may modify staging. Cancer 48:170 –180, 1981 2. Fagundes H, Perez CA, Grigsby PW, Lockett MA: Distant metastases after irradiation alone in carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 24:197–204, 1992 3. Toita T, Nakano M, Higashi M, Sakumoto K, Kanazawa K: Prognostic value of cervical size and pelvic lymph node status assessed by computed tomography for patients with uterine cervical cancer treated by radical radiation therapy. Int J Radiat Oncol Biol Phys 33:843– 849, 1995 4. DeAlvarez R: The cause of death in cancer of the cervix uteri. Am J Obstet Gynecol 54:91–96, 1947 5. Brunschwig A, Pierce V: Necropsy findings in patients with carcinoma of the cervix: Implication for treatment. Am J Obstet Gynecol 56:1134 – 1137, 1948 6. Holzaepfel JH, Ezell HE: Site of metastases of uterine carcinoma. Am J Obstet Gynecol 69:1027–1038, 1955 7. Sotto LSJ, Graham JB, Pickren JW: Postmortem findings in cancer of the cervix: An analysis of 108 autopsies in the past 5 years. Am J Obstet Gynecol 80:791–794, 1960 8. Kelly JWM, Parsons L, Friedell GH, Sommers SC: A pathologic study in 55 autopsies after radical surgery for cancer of the cervix. Surg Gynecol Obstet 110:423– 432, 1960 9. Badib AO, Kurohara SS, Webster JH, Pickren JW: Metastasis to organs in carcinoma of the uterine cervix: Influence of treatment on incidence and distribution. Cancer 21:434 – 439, 1968 10. Carlson V, Delclos L, Fletcher GH: Distant metastases in squamous-cell carcinoma of the uterine cervix. Radiology 88:961–966, 1967 11. Barmeir E, Langer O, Levy JI, Nissenbaum M, DeMoor NG, Blumenthal NJ: Unusual skeletal metastases in carcinoma of the cervix. Gynecol Oncol 20:307–316, 1985 12. Kaseki H, Yasui K, Niwa K, Mizung K, Inoue K, Ota M: Hepatic resection for metastatic squamous cell carcinoma from the uterine cervix. Gynecol Oncol 44:284 –287, 1992 13. Abu-Ghazaleh SZ, Creasman WT: Unusual metastasis in carcinoma of the cervix uteri. Surg Gynecol Obstet 148:728 –730, 1979 14. Raggio M, Kaplan A: Case report: Carcinoma of the cervix metastatic to the liver presenting with obstructive jaundice. Gynecol Oncol 13:269 – 270, 1982 15. Hughes KS, Rosenstein RB, Songhorabodi S: Resection of the liver for colorectal carcinoma metastases: A multi-institutional study of long-term survivors. Dis Colon Rectum 31:1– 4, 1988 16. Steele G, Ravikumar TS: Resection of hepatic metastases from colorectal cancer. Ann Surg 210:127–138, 1989