Diagnosis and Surgical Treatment of Primary and Secondary Solid Hepatic Tumors in the Adult

Symposium on Liver, Spleen, and Pancreas

Diagnosis and Surgical Treatment of ~Primary and Secondary Solid Hepatic Tumors in the Adult Martin A. Adson, M.D.*

In the Bradshaw lecture of 197723 Sir Rodney Smith said in reminiscence, "In the early 1930s, then, a tumor of the liver in general posed no (surgical) problem because it was not believed that any treatment would be effective. By the late 1930s, it was recognized that excision was sometimes logical and the simple problem was-when?" Today, a variety of surgical and medical therapies are reported to benefit patients who have tumors of the liver. The problems of the patients are unchanged, but for the physician or surgeon who hopes to help them, the "when" involved in the choice of management is more complex. When might the risks, cost, and discomforts of resection be justified by benefit; when might other surgical efforts (devascularization or placement of tubes for regional infusion of cytotoxic agents) be proper; when might systemic chemotherapy used in gracious dosage schedules offer as much; and when should the healer "have the grace to let the sick man die in peace." 4 Unfortunately, with the passage of years and opportunities, good answers to these questions have not been found. The physician who looks for science and guidance in today' s medical and surgical literature will find disappointment, for understanding is hampered by the predominance of poorly constructed studies that neglect the scientific method. Despite our limited knowledge, some things are either true or likely: untreated hepatic cancer kills, as may some "benign" tumors; quiescence or spontaneous regression of such tumors is truly rare; cure that is attributable to cytologic agents and cure that is attributable to immunologic manipulations are equally uncommon; response to radiation therapy for hepatic metastases from visceral cancer is unpredictable; and, finally, surgical extirpation of a neoplastic lesion does rid the patient of that particular focus of tumor, but when should the procedure be done? Unfortunately, use of these contentions to benefit patients is limited by lack of knowledge of the natural history of the tumor that affects the specific patient that we try to help. Natural history is determined both by the stage of the tumor and by poorly understood biologic factors-specifics that seldom are defined clearly by *Professor of Surgery, Mayo Medical School, Rochester, Minnesota

Surgical Clinics of North America-Yo!. 61, No. 1, February 1981

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authors who select patients for various forms of treatment. Therefore, most reported results of treatment cannot be judged fairly, and the reader is exposed more often to the bias of authority than to properly constructed studies that involve untreated controls. This deficiency in reporting relates in part to neglected obligations of authorship but also has to do with the fact that the stage of disease can be defined with certainty only when obvious dissemination of tumor is present. In any event, most reported results of therapy reflect, in large part, the poorly defined selection of patients as well as the enthusiasm of the medical or surgical scientist who is moved to publish. Knowing this, and understanding some of my own biases and enthusiasms, let me consider the surgical management of hepatic tumors, then offer one kind of surgeon's (the resectionist's) view of alternative therapies. Space precludes consideration of all tumors. Therefore, cystic lesions (hydatid disease, simple cysts, polycystic disease, and cystadenomas) will not be discussed here. Also, comprehensive analysis of the world literature has not been requested by the editor. Thus, there is practical convenience in reporting personal experience, which I shall then try to view in critical perspective.

PRIMARY HEPATIC TUMORS Benign Solid Tumors of the Liver The three most common "benign" solid tumors of adults must be considered to be problems because two of them (cavernous hemangiomas and hepatocytic adenomas), although not malignant pathologically, are not always benign, or kindly, in the literal sense. The other tumor (focal nodular hyperplasia) is so poorly understood as to be considered in no way literally pleasant. In many organ systems, nonmalignant tumors may be either easily removed or safely observed. Thus, knowledge of their natural history is either obvious, easily determined, or unimportant. However, the presence of a "benign" tumor in the liver begets special problems: its nature may not be determinable without surgical evaluation, the risk of removing large hepatic tumors or small centrally located lesions is significant, and small samples obtained by needle biopsy (or even by operative wedge biopsy) may not be representative. Moreover, even when the histopathologic nature of a lesion'is known, there remains for these three tumors some uncertainty about their natural threat to life as compared with the risk of their surgical removal. Thus, the most perplexing problems of management of benign tumors of the liver relate to our lack of knowledge of their natural history. That is, (and this is surprising) we do not know whether or not they will grow if ignored!

Cavernous Hemangiomas How should cavernous hemangiomas be viewed in this light? Such lesions once were rarely seen by clinicians because only those large enough to cause discomfort, or to be seen or felt, were called to the attention of the physician. But now, with common use of sophisticated imaging techniques, these lesions are being seen much more often. Arteriographic studies done to

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evaluate other visceral disease may disclose these lesions, and the conscientious physician who evaluates vague abdominal complaints by use of radionucleotide scans, ultrasonography, or computed tomography may be told by a radiologist that there is in the liver a tumor, which may or may not relate to the patient's discomfort. Fortunately, now cavernous hemangiomas may be distinguished from other more serious lesions by noninvasive techniques. Not long ago, such differentiation depended upon angiographic study. However, refinements of computed tomography have been shown to have great accuracy in the definition of this tumor. 16 At last, there is a tool that might let us learn more about the natural history of such lesions and also help with our decisions about management of individual patients. Unfortunately, little is known now of the natural history of cavernous hemangiomas of the liver. The surgical literature is interesting in its neglect of truly relevant observations. As Starzl2 7 has said, "Until recently, the surgical literature about cavernous hemangiomas consisted mainly of periodic scholarly reviews for which the stimulus frequently was an unusual operative experience with one or two cases." This oblique criticism of the efforts of other surgeons to contend is found in his report of 15 patients with cavernous hemangiomas treated safely by resection. It is true that most of his patients were symptomatic; however, four lesions that were found incidentally were asymptomatic. Also, in our own institution, many lesions of this sort have been removed simply because they were there. My predecessors, colleagues, and I have removed 20 cavernous hemangiomas without operative mortality. 28 Thus, we know that the experienced hepatic surgeon may remove certain lesions of the liver with little risk to life. However, it remains to be determined when such efforts might be truly justified. Clearly, there is need to know more about the natural history of asymptomatic cavernous hemangiomas, for competent surgeons may be inexperienced in hepatic surgery; if they are convinced by authoritative opinion of the need to remove all such lesions, they may, in their operative inexperience, blunder. Therefore, I hope that future reports will involve study of the natural history of asymptomatic lesions. We are investigating this problem. 28 Preliminary observations of two groups of patients (one group comprised patients who were evaluated surgically but not treated by resection and the other comprised patients with lesions seen angiographically by happenstance) indicate that true growth of these tumors does not occur. Rather, they may increase in size by ectasia. The extent to which this change may threaten life cannot be foreseen for individual patients. Intercavitary hemorrhage may cause rapid enlargement, and such hematomas may become infected; rarely, acute hemoperitoneum may occur witlHnit trauma (but biopsy is a more common cause of life-threatening hemorrhage). 1 have seen one patient who had recurrent life-threatening hemobilia from a very, very small cavernous hemangioma. However, such events are rare, and most small- or moderate-sized lesions (less than 10 em) of this sort may be considered to be congenital anomalies that involve little threat to life. Fortunately, now the size of a lesion may be monitored by noninvasive techniques. Thus, we feel safe in observing most

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lesions of small or moderate size (even though I have removed one such lesion by right hepatic lobectomy in the case of an aging biker who depended for transportation upon a 750 cc motorcycle). There are, however, two real problems involved in the management of cavernous hemangiomas of the liver. Difficult decisions relate to (1) large lesions (or lesions that abut the interlobar plane) that are not causing symptoms but that with enlargement may become resectable only with high risk and (2) very large symptomatic lesions in young patients that can be resected only with risk considerably greater than that of routine hepatic lobectomy. It is for such patients that more knowledge of the natural history of these tumors will have great value. I still do not know how best to treat such patients but hope that our ongoing study will help with such decisions.

Focal Nodular Hyperplasia There is discomfort in the obligation to write about focal nodular hyperplasia, for so little is known about this lesion. These tumors, composed of nodules of mature hepatocytes outlined by biliary ductal hyperplasia or by bands of fibrous connective tissue, also have been called focal or hamartomatous cirrhosis. Such lesions are not disposed to malignant change, and most are small. They have become clinically significant only as the incidence of hepatocytic adenomas related to the use of oral contraceptives has increased. Both lesions pose a problem to the clinician because there is disagreement about their propensity to develop life-threatening hemorrhage. Problems in management are complicated by lack of noninvasive diagnostic techniques for differentiation of these two lesions. Computed tomography offers little, and even though typical gross pathologic features of either lesion may be seen angiographically, such studies too often are equivocal. Also, it is unreasonable to ask the pathologist to differentiate between these two lesions in the study of small samples taken by percutaneous needle biopsy. Thus, certain diagnosis usually depends upon surgical evaluation. It is then that the surgeon would like to know more about the nature and natural history of both focal nodular hyperplasia and hepatocytic adenomas. Whether focal nodular hyperplasia represents a reaction to injury and thus is evidence of a reparative or regenerative process rather than a true neoplasm still is unknown. 6 •32 However, on the basis of personal experience and study, I think that it is likely that similar gross and histopathologic changes may result from a variety of causes. This is because even though most such lesions are small (less than 5 em) and asymptomatic and although most (85 per cent) are solitary, 10 to 15 per cent of such tumors are either large and symptomatic or multiple. Also, such lesions have been seen to "grow" and some to regress in sizeY The small lesion has significance only because it must be differentiated from a hepatocytic adenoma, a tumor often related causally to the use of oral contraceptives, which may bleed and may either harbor malignant foci or become malignant. In contrast, focal nodular hyperplasia has no malignant potential and its relationship to exogenous hormones remains unproven. Even though most students of hepatic pathology believe that focal nodular hyperplasia is disposed neither to malignant transformation nor to clinically significant hemorrhage, this contention is challenged by one very competent pathologist, Christopherson,5 who has reported hemorrhage from 6

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of 44 patients with focal nodular hyperplasia studied in his registry. And he is supported in this view by a respected surgeon, Mays, 19 who, as all surgeons must, does trust his surgical pathologist. However, the preponderance of evidence is against their view, 8 •11 •14 •31 and until the gap between histopathologic observations and clinical realities is filled by some reasonable truth, I am content to consider an asymptomatic tumor of small or moderate size that a surgical pathologist "calls" focal nodular hyperplasia to have no significant threat to life (providing that Lou Weiland, the respected colleague upon whom I depend for histopathologic gospel, agrees with that pathologic interpretation). Thus, if in the course of surgical evaluation such lesions may be removed safely, that should be done. However, it is safer to obtain representative biopsies from and leave behind lesions that may be removed only with a significant operative risk. There remain for consideration those few (10 per cent or less) examples of focal nodular hyperplasia that present as very large symptomatic tumors. I have removed two lesions of this sort. Major discomforts have been relieved, but both patients have persistence of mild hepatic dysfunction. It is likely that such tumors, though histopathologically similar to smaller lesions, are in some way fundamentally different from the more common examples of focal nodular hyperplasia.

Hepatocytic Adenomas Benign hepatocellular tumors (hepatocytic adenomas) are a different matter. Most are associated with the use of oral contraceptives, 20 •22 many (one third) threaten life by bleeding, and some may undergo malignant change. 12 •31 Therefore, such lesions are best removed. Unfortunately, this dictum is challenged by those who hold that such tumors regress after use of oral contraceptives is discontinued. 7 This advice would be acceptable were it not for the fact that intercavitary hemorrhage and rupture with hemoperitoneum have been reported with equal frequency after stopping hormonal medications. Moreover, postpartum hemorrhage has been reported in patients who conceived after oral contraceptives were discontinued. I hope to keep an open mind, but now it does seem reasonable to remove most hepatocytic adenomas. At times, one may wish to discontinue use of oral contraceptives, then observe the course of some patients who have very small lesions (though they, too, may bleed) or to observe, after stopping use of hormones, very large lesions that may be removed only with great operative risk. This practice may be justified if the size of the lesion and the clinical status of the patient can be observed properly by a surgeon able to contend promptly with spontaneous hemorrhage from such a tumor. However, the risks of such observation must be considered in relation to the diagnostic uncertainty involved in evaluation. The limitations of needle biopsy for diagnosis are such that observation may involve watching a cancer grow; thus, I have become surgically reluctant only in special circumstances.

PRIMARY MALIGNANT HEPATIC TUMORS This leads us to consider primary malignant tumors of the liver, lesions that may be difficult to differentiate from benign tumors without extensive

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evaluation. Most (more than 90 per cent) are cancers, and most of these (90 per cent) are hepatocellular carcinomas rather than cholangiocarcinomas. (There is not space to consider lymphomas or other sarcomas.) When findings are considered worldwide, surgical management of such lesions has given disappointing results. This is because in Asia primary malignant hepatic tumors most often are associated with nutritional cirrhosis;17 in the Southern Hemisphere, epidemiologic factors and other biologic determinants preclude successful extirpation of most lesions.U Also, in the United States, most malignant tumors of the liver are seen to be associated with alcoholic cirrhosis. Unfortunately, multicentricity and limited hepatic reserve compromise surgical efforts for such patients. However, in the United States a significant number of hepatocellular or cholangiolar carcinomas that are unassociated with cirrhosis appear to be solitary, grow spherically by pushing rather than by invading, and may grow to large size without involving regional lymph nodes 11 or giving evidence of hematogenous spread when they are clinically evident.

Personal Experience with Resection of Primary Solid Liver Tumors Although selection is involved in the referral of and opportunity to treat such patients, it is still reasonable for me to report my experience with the resection of lesions of patients that I have been asked to see. Since this experience has been reported recently in detail, 3 it will be considered only briefly here. That report involved personal experience with 60 patients who had benign and malignant solid tumors (excluding cavernous hemangiomas). Benign lesions were included because preoperative differentiation from malignant lesions was seldom possible, and the basic "surgical" decision about management oflarge symptomatic tumors seldom related to the tumor's histologic nature. All but one of the patients were adults. None had cirrhosis. This fact, the predominance of relatively differentiated tumors (Broder's grade 1 and 2), and the infrequency of multicentric tumors in this series involved both medical and surgical selectivity. Presenting symptoms and signs related chiefly to the size of the lesion. Two thirds of the patients had pain attributable either to gradual expansion of large tumors or to tumor necrosis with intercavitary hemorrhage. Forty-six of the resected tumors were malignant; 43 were hepatocytic cancers (malignant hepatomas); and only 3 were cholangiocarcinomas. Although malignant tumors were seen with nearly equal frequency in men and women, benign tumors in men were uncommon (only two were seen). Fourteen tumors were benign, 2 were huge hamartomas, and 12 were hepatocytic adenomas. The association between benign and malignant tumors and the use of oral contraceptives was clearly evident. Such medications had been used by three fourths of the women with benign tumors and one third of the women who had malignant hepatomas. Lesions varied in size from 5 to 29 em in diameter, with an average size of 13 em. Most often, the extent of resection was determined by the size of the lesion, even though some smaller tumors situated near the hepatic hilus required hemihepatectomy for removal. Thirty of the 60 patients required hemihepatectomy, trisegmentectomy was done for 12 patients, 15 had seg-

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mentectomies or large wedge resections done, and 3 received resection of the caudate lobe. Operative mortality was considered to be acceptable in light of the magnitude of resection required, and hospital mortality (three deaths, or 5 per cent) related more to heroic efforts than to the risks of standardized major resection. All patients (13) who survived resection of benign lesions are living and well without evidence of recurrent or new tumors 2 to 18 years postoperatively, and the 3-, 5-, and 10-year survival rates of the 41 patients who survived resection of malignant tumors are 65 per cent, 35 per cent, and 33 per cent, respectively.

Reported Experience of Others Reports of other surgeons are confirmatory with respect to acceptable risks of resection of primary hepatic malignant tumors and encouraging postoperative survival rates. Fortner's 9 early experience with a complicated vascular isolation perfusion technique used for resection of 41 advanced primary and secondary hepatic malignant tumors involved a high hospital mortality rate (17 per cent). However, with subsequent use of"standardized" resective techniques,1.2 5 hospital mortality following 61 resections was 4 per cent. He calculated actuarial three-year survival rates for 13 survivors of "curative" resections as 88 per cent; the rate was 31 per cent for 16 patients who survived "palliative" resections of primary hepatic malignant tumors . Starzl' s 26 report of a 3.3 per cent operative mortality following resections done for 30 patients who had lesions so large as to require trisegmentectomy is evidence for the safety of such major resections done by the very experienced surgeon. The subsequent duration of survival of his 19 patients who had resection of primary hepatic malignant tumors is encouraging. However, the size of the sample and the recency of most of these operations precludes calculation of long-term survival rates. Foster and Berman in their comprehensive and scholarly monograph 11 summarized the reported experience of many surgeons; the two-, three-, and five-year survival rates of 91 cirrhotic patients who survived resection were 72, 60, and 34 per cent, respectively. Their retrospective collective review involved the early experience of most surgeons and thus reflected an unacceptable operative mortality rate that is now avoidable. Also evident in their review is the unfavorable influence of hepatic cirrhosis associated with hepatic cancer. For such patients, the risk of resective surgery is increased by problems with hemostasis in the cirrhotic liver and by its limited functional reserve. Also, long-term survival often is precluded by the progressive, nonmalignant process or by multicentric growth. The unfavorable influence of cirrhosis that coexists with hepatic malignant tumors is reported convincingly by Asian authors. 1 ~ Thus, it is clear that some patients with a primary hepatic malignant tumor may benefit from resective surgery. However, the results of such treatment must be viewed with a perspective that is not given to the surgeon who is asked to see a selected group of patients in a referral practice. One's pleasure in apparent control of some tumors is eroded by uncertainty about the natural history of these malignant tumors and by concern that aggressive

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surgical treabnent may benefit only a small proportion of patients with this disease. It is true that these questions might be answered by prospective randomized trials, but most surgeons (and most of my medical colleagues) do not see moral justification for denying patients the apparent benefits of resection when no reasonable therapeutic alternative is available for those patients to be used as "controls" in such studies. Moreover, Foster and Berman11 report three observations concerning primary hepatic malignant tumors that encourage the hepatic resectionist to persist. First, most tumors kill soon after they are clinically apparent; second, their worldwide survey showed that nearly 50 per cent of patients with primary hepatic malignant tumors had no extrahepatic metastases at the time of death; and third, their 1974 nationwide liver tumor survey showed that a significant proportion of patients who had primary hepatic malignant tumors resected lived long thereafter. Thus, it seems reasonable to consider many primary hepatic malignant tumors a "surgical" disease. Although in some parts of the world, epidemiologic and biologic factors may be determinants of disease that is seldom manageable by surgery, there is justification for resection of many primary hepatic malignant tumors seen in the Western world and the Northern Hemisphere. Many tumors that are unassociated with cirrhosis are solitary or unilobar, and most are cellularly differentiated cancers that push rather than invade. Resection of such lesions now can be done with acceptable operative risk. Without further study, it is hard to know what proportion of patients who have primary hepatic malignant tumors might be benefited with resective treabnent. However, it is likely that some reported rates of resectability are determined either by surgical reluctance or by inexperience. Thus, it seems reasonable to resect these lesions whenever possible, then to see what effect adjuvant therapies might have upon survival. I see no justification for resection of only half of the resectable hepatic metastases that one is asked to treat in the interest of prospective randomized therapeutic trials.

METASTATIC TUMORS OF THE LIVER The variety of tumors that may involve the liver by metastasis is so great that the specifics of their management cannot be considered here. Therefore, principles and concepts of resective treabnent must be viewed in relation to personal and reported experience with colorectal cancer, the most common malignant disease that attracts the interest of the surgeon in its spread to the liver. Other visceral cancers are most often untreatable by virtue of uncontrolled regional spread when they involve the liver. Nevertheless, concepts of management learned from dealing with colorectal cancer may be applied to those other visceral cancers that are cellularly differentiated and do spread to the liver when or after the primary lesion has been controlled. Consideration of surgical management of hepatic metastases is complicated by many indeterminable variables that relate to the stage and natural history of both the primary and secondary lesion. Pessimism is justified by

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theoretical and pragmatic views, for it would seem unlikely that a visceral cancer that has invaded the circulatory system would give up but one or two viable cells that might grow at a distance. Also, it seems unlikely that of many embolizing cells only one or two would come to grow in the liver, lung, or bone. Such happenings might be compared with having just one or two dandelions in one's yard! Foster10 has expressed the same concern about the possible limitations of resective surgery: "Much has been said and written in recent years about the systemic nature of cancer. Considerable evidence has accumulated that microscopic tumor emboli occur before many, if not most, primary tumors become overt. The immunologic and other defense mechanisms of the host are thought to be more important than early excision in determining the eventual prognosis of the patient with cancer. The concept of a disease which grows locally and which can be 'cured' by local excision is considered 'old fashioned' by many serious students of the biology of neoplasia." Nevertheless, even the skeptic who sees such things from the armchair or the cluttered desk must admit that the metastatic process is capricious as viewed in our prevailing ignorance and that extirpative therapy is not always irrelevant. Resection of some hematogenous metastases does appear to benefit some patients, either by removing a sole remaining focus of tumor or by, in some way, altering the relationship between a tumor and the host. Thus, resective therapy must be considered seriously, at least until some key to chemotherapeutic or immunologic control is found. It might be best to test this contention by use of prospective randomized trials that would involve not resecting half of the resectable metastatic hepatic lesions from patients that one is asked to see. However, even though I criticize others for not testing their therapies in this way, I have not felt morally or scientifically justified in randomizing all resective treatment. This attitude requires some explanation. Nearly 20 years ago, Dr. John Waugh, my mentor, studied his experience with resection of hepatic metastases from a variety of visceral cancers. His report, published a year or so after his untimely death, 35 gave evidence of benefit to some patients so treated. Twenty per cent of the 25 patients lived for five or more years, and operative mortality was 4 per cent-an acceptable risk: benefit ratio relating to surgical management.

Personal and Institutional Experience Aware of Waugh's experience, several of my colleagues and I subsequently removed metastatic tumors of the liver whenever surgical risk seemed to be acceptable. However, even within our institution, some surgeons remained skeptical about such efforts and for philosophic reasons observed and biopsied such lesions without removing them. Thus, in 1975, when we 33 studied retrospectively the experience of our institution with resection of colorectal metastases to the liver done for 60 patients, we were able to find in our files a group of retrospective controls matched by age and sex who had hepatic metastases of comparable size and number that, at the time time of resection of the primary lesion, were biopsied but not removed. The survival of this group of historical "controls" was compared with the survival of patients who had had such lesions removed. The results were surprising: no patient whose metastatic lesion was biopsied and left behind

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lived for 5 years; however, 42 per cent of the 40 patients who had apparently solitary metastases excised lived for 5 or more years, and 28 per cent of them lived for 10 or more years. That study moved us to extend our experience to the management of other patients with metastatic liver cancers. In recent years, the use of biologic markers (carcinoembryonic antigen assay), scanning techniques used by the concerned physician or surgeon, and hope for help for patients with large symptomatic metastases has involved us in decisions about the management of metastatic tumors that are larger, symptomatic, or appeared months or years after resection of the primary lesion. (All but seven of the lesions studied retrospectively in our earlier study33 were less than 5 em in diameter, and most were found and removed when the primary lesion was resected.) This continuing study, which a year ago involved 34 patients treated for metastatic lesions so large as to require major hepatic resection, has been reported recently in detaiU That study led us to believe that (1) the size of a hepatic metastasis is not a major determinant of survival after resection and that (2) the apparent benefits of resections (approximately 20 per cent long-term survivors) were justified by an acceptable (5 per cent) operative risk. These simplistic conclusions will be viewed more critically later in this article. Recently (October 1980), the status of those patients who were living at the time of the last report has been reassessed. Also, during the last year, 12 additional patients have had resection of hepatic metastases from colorectal cancer, but they will not be considered here because, for reasons to be discussed later, patients treated by hepatic resection less than three years ago should not be considered in our assessment of results. Nevertheless, extended observation of the 24 patients who had large hepatic metastases resected three or more years ago confirms our earlier impressions. Four of 15 patients (25 per cent) who had hepatic metastases resected five or more years ago are living without evidence of recurrence (22, 22, 11, and 5 years postoperatively); and 10 of 24 patients (49 per cent) so treated are known to be living three or more years after resection of their hepatic metastases. Noteworthy is the fact that of the 24 patients managed by hepatic resection three or more years ago, 6 had multiple hepatic lesions removed and 6 others had evidence of extrahepatic metastases when hepatic resection was done. No patient who had extrahepatic metastases lived for more than two years after resection of the hepatic lesion; however, 4 of the patients who had multiple (but unilobar) hepatic metastases removed lived for four or more years. (One died of cancer 52 months after hepatic resection, but three are still living without evident recurrence 4, 41J2, and 5 years after hepatic resection.)

Experience of Others Long-term survival of some patients who have had hepatic metastases resected has been reported by others. Fortner9 has resected metastases from 17 patients with colorectal cancer who had no evidence of other regional or distant metastases. Seventy-two per cent of patients who had such "curative" resections survived for three or more years, whereas none of the 6 patients

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who had hepatic metastases resected despite the presence of other distant unremoved metastases lived for more than two years. (These data are comparable to ours, for we have not excluded resections done in the presence of extrahepatic metastases from our analysis.) Wanebo 29 compared the length of survival of 25 patients who had solitary hepatic metastases resected with the fate of 18 patients who had similar lesions identified but unresected. Twenty-eight per cent of patients who had the liver metastasis removed survived free of disease for five years, whereas none of the patients who were left with unresected lesions lived for five years. Foster11 recently has summarized concisely that part of his remarkable nationwide tumor survey and collective review of the literature that is concerned with survival after liver resection done for secondary tumors. The operative mortality rate of liver resection of all metastatic tumors reported in his extensive survey and review was 11 per cent. However, the exclusion of series that were reported in an earlier era shows a more acceptable (5 per cent) operative risk. He found 46 (22 per cent) five-year survivors among 206 patients who survived resection of hepatic metastases from colorectal cancer and were followed for at least five years. Large size and multiplicity of resected metastases adversely affected survival but not absolutely, and "the interval of time between resection of the primary tumor and resection of the liver metastasis was seen to have little effect upon eventual outcome."

Results of Resection Viewed in Perspective This reported experience with the results of resection of metastatic hepatic lesions does indicate that such treatment may be beneficial to some patients. Most of all, these studies may also reveal the capricious nature of the metastatic process. They do leave unanswered two important questions-how often can such treatment be considered and Sir Rodney Smith's question, when is excision logical? The Incidence of Occurrence of Resectable Metastases. There is little disagreement about the first question. Foster10•11 has written "Liver metastases are found in 10 to 30 per cent of patients at the time of laparotomy for excision of their primary tumor. About one fourth of these patients have 'resectable' liver secondaries that are defined by a solitary nodule or disease limited to a single lobe or segment." The reports of others are similar. Wanebo and colleagues 29 studied the 10 per cent of patients with "operable" colorectal cancer seen within a 24-year period at the Memorial Sloan-Kettering Cancer Center who were found to have hepatic metastases. Of 217 such patients, 60 (nearly one third) had other unresectable regional or distant metastases. Of the remaining two-thirds (157 patients), 73 (46 per cent) had "resectable" hepatic metastases: 50 were solitary and 23 unilobar. Wood's 34 study reports only the extent of involvement seen in patients found to have hepatic metastases but shows a similar distribution in 117 patients. Seventy-seven per cent had widespread bilobar hepatic involvment; 10 per cent had multiple metastases confined to one segment or lobe, and 13 per cent had apparent solitary metastatic lesions. These are humbling statistics; only approximately one fourth of hepatic metastases are technically resectable. However, even though such data must

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give the hepatic resectionist perspective and a sense of insignificance (for even if all such surgeons were able to keep the risk of hepatic resection below 5 per cent, they might save fewer of their fellows than would the legislator or propagandist who fosters the proper use of seatbelts during family outings), one's efforts to help the occasional patient should not be compromised by pessimistic generalizations.

Resective Treatment Viewed in Relation to the Natural History of Hepatic Metastases. There remains to be considered one other aspect of hepatic resections done for hepatic metastases: a more critical evaluation of the results of such treatment. No surgeon who can safely remove large portions of the liver has been inclined to randomize his or her efforts, and, to date, no statistician committed to strict randomization in the search for truth has learned how to resect hepatic lesions. Thus, we still do not really know to what extent long survival after resection might be determined by the natural history of the disease of selected patients. We are left trying to compare reported results of resective treatment with historic controls reported in various studies of the natural history of malignant disease. "Although the natural history of a disease is the basic standard against which the results of treatment are measured, little is known about the natural history of cancer of the colon and rectum." So began a report of the fate of 583 patients seen in our institution who had either untreatable disease or disease capable of palliation only. 21 That study, published more than 15 years ago, contributed largely to understanding of the natural history of colorectal cancer. However, patients reported there cannot be used for specific comparison with patients who appear to have resectable hepatic metastases as the only evident site of residual tumor. The study did show that quiescence or spontaneous regression of cancer is truly rare, for only 4 of the 583 patients lived for more than five years after diagnosis of subsequently untreated cancer. Since then, others have studied more specifically the natural history of hepatic metastases from colorectal cancer. Jaffe 15 found that mean survival times of patients with untreated solitary, multiple unilobar, or multiple bilobar hepatic metastases did relate to this extent of involvement (136 days, 93 days, and 72 days, respectively). However, these differences were found to be statistically insignificant-perhaps because many of the patients also harbored other untreated extrahepatic metastases. Unfortunately, even though about 20 per cent of all three groups of patients were living 10 months after definition of hepatic metastases, the survival curves presented were not extended beyond 300 days. Thus, from that report we cannot determine the incidence oflong-term survival in these three groups of patients, observations essential for comparison of survival after resective treatment. The length of survival of Wanebo's 29 18 patients with apparent solitary unresected metastases shows clearly that the nature and extent of hepatic involvement is a major determinant of prognosis. Seventy-two per cent of those patients lived for two years, 33 per cent for three years, and 17 per cent for four years. A similar, but less impressive, influence of the "solitariness" of hepatic metastases was shown in our control group of patients reported earlier. 33 Thirty-eight per cent of patients with solitary unresected metastases lived for

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two years, and 15 per cent for three years, but none of the 46 patients lived for four or more years. Finally, the report of Wood et aJ.34 shows clearly "that survival for patients with liver metastases related to the extent of liver involvement with tumour." None of the 87 patients with widespread bilobar metastases lived for three years, whereas 13 per cent of 15 patients with solitary lesions and 10 per cent of those 11 with unilobar metastases lived for three or more years. These data were further analyzed by excluding patients who had no evidence of local tumor invasion, lymph node spread, or other distant metastases. The numbers are small, but 12 per cent of patients with untreated unilobar metastases lived for three years, and 28 per cent of patients with solitary metastases lived for three or more years, with only one patient (8 per cent) surviving for five years. None of these observations has the value that prospective randomized controls could have. However, they should make us circumspect in our view of the results of resective surgery done for hepatic metastases. We can conclude nothing from the patient who lives for two years after resection of a solitary metastasis (unless intolerable discomforts were relieved for that period of time). 2 Nevertheless, from what is known now, it is likely that long survival after resection of some hepatic metastases involves more than selection of patients or happenstance. Until more is known about the complexities of the metastatic process or until some chemotherapeutic or immunologic means of control is found, it seems reasonable to resect solitary or unilobar hepatic metastases from patients who have no other evidence of residual or recurrent cancer. Even though we do not know whether solitary or localized metastases are determined by caprice or by resistance of the host, as surgeons we should not be reluctant to capitalize upon this happening. I am distressed that many patients treated by hepatic resection are not benefited and therefore hope that in the future refinements in imaging techniques or in the use of biologic markers will enable us to select better those who might benefit from surgery. Failing that, I hope that cytotoxic or immunologic agents used alone or in conjunction with resective surgery will be found to have greater value .

Other Surgical Methods of Treabnent There remains to be considered other therapies that might help the patient with hepatic metastases that cannot be resected (the great majority of patients so affected). Unfortunately, the profuse literature that describes the results of regional infusion with chemotherapeutic agents or regional devascularization is difficult to analyze. There is not space to consider properly this aspect of treatment, but the view of one not involved in such efforts can be summarized briefly. In my review of this literature, I was impressed that (1) prospective randomized trials have been avoided (with one exception); 13 (2) that most authors fail to distinguish clearly between various stages of disease treated; (3) that reports generally lack precise or uniform criteria of response to therapy (and most do not distinguish between length and quality of life), with one exception.30 Also, most authors fail to consider the possible adverse effects of therapy upon survival. In this regard, it is usual fr¥ the mean

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survivals of those who respond to treahnent to be compared with those of patients who do not respond. Strangely, no author has suggested that poor survival of nonresponders might relate to the adverse effects of chemotherapeutic agents or to the adverse effects of hepatic ischemia, whereas most resectionists do admit to operative mortality and morbidity related to their efforts. We have not resorted to such modes of treahnent chiefly because my colleague, Dr. Charles G. Moertel, has never been convinced of the advantage of such therapies over systemic chemotherapy. It is noteworthy that his contention is supported by the one controlled randomized study 13 that compared systemic chemotherapy with regional infusion. Those authors concluded that "the two treahnent arms did not differ significantly in response rate, duration of response, survival or time to progression."

DIAGNOSIS OF HEPATIC TUMORS Diagnostic techniques useful to surgical decisions can be considered only briefly here. They may be used to answer two questions, what is the lesion and is it resectable? With the exception of cavernous hemangiomas, the nature of a lesion cannot be determined by noninvasive techniques. Thus, histopathologic diagnosis requires biopsy. However, I am convinced that percutaneous needle biopsy should be done only when there is definite evidence of unresectability of the lesion in question. This is because such sampling may lead to seeding of tumor that may compromise survival of patients subsequently treated by resective surgery. Resectability can be judged by radionucleotide scans, ultrasound, or computed tomography only for solitary lesions situated away from the hepatic interlobar plane or (on the left) the intersegmental plane; resectability can also be judged by demonstrating multiple lesions or bilobar involvement by tumor. Of these three diagnostic techniques, we have come to rely most upon computed tomography. In the interest of control of cost, we try to avoid use of multiple imaging techniques, and this test is more discriminating. Solitary lesions seen to be localized away from hilar ducts or blood vessels then are evaluated surgically without resort to further evaluation, with one exception. About 15 per cent of metastatic lesions are isodense with the surrounding normal liver and may not be seen on computed tomograms. Some of these are so well vascularized as to be seen angiographically. Thus, before undertaking resection of apparent solitary metastatic lesions "seen" by scanning techniques, we feel justified in using angiographic studies that may preclude consideration of surgical evaluation. Even though some very experienced hepatic surgeons 9 •25 seldom use angiographic studies in their preoperative assessment of patients, I feel that this test does provide anatomic relevance that is not offered by scanning techniques. Use of angiography may spare patients with unresectable tumors an unnecessary operation, and angiography does provide a map for safe travel, for it may show variations in hepatic vasculature or relationships between a tumor and the blood vessels to be preserved that have surgical relevance.

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SUMMARY The apparent efficacy and limitations of resective treatment have been considered. In summary, it can be said that some patients may be helped by removal of their hepatic tumors. At times, the need for and benefits of such treatment are obvious. All too often, however, decisions about proper treatment are less clear. In the future, physicians and surgeons may act more wisely only if more is known about the biology and natural history of hepatic tumors. In the meantime, surgeons must be circumspect in their efforts to help and should try to judge the results of their efforts objectively.

REFERENCES 1. Adson, M.A., and Beart, R.W.: Elective hepatic resections. SURG. CLIN. NORTH AM., 57:339360, 1977. 2. Adson, M.A. and van Heerden, J.A.: Major hepatic resections for metastatic colorectal cancer. Ann. Surg.,191:576-583, 1980. 3. Adson, M.A. and Weiland, L.H.: Resection of primary solid hepatic tumors. In press. 4. Buchan, J.: Witch Wood. London, Hodder and Stoughton, 1927, 195. 5. Christopherson, W.M., and Mays, E.T.: Liver tumors and contraceptive steroids: Experience with the first one-hundred registry patients. J. Nat!. Cancer Inst., 58:167-171. 6. Edmonson, H.A.: Tumors of the liver and intrahepatic bile ducts. Atlas of Tumor Pathology, Section VII, Fascicle 25. Armed Forces Institute of Pathology, 1958. 7. Edmonson, H.A., Reynolds, T.B., Henderson, B., et a!.: Regression of liver cell adenomas associated with oral contraceptives. Ann. Intern. Med., 86:180-182, 1977. 8. Fechner, R.E.: Benign hepatic lesions and oral contraceptives. A report of 7 cases and critical analysis of literature. Hum. Pathol., 8:255-268, 1977. 9. Fortner, J.G., Kim, D.K., Maclean, B., eta!.: Major hepatic resection for neoplasia: Personal experience in 198 patients. Ann. Surg., 188:363-311, 1978. 10. Foster, J.H.: Survival after liver resection for secondary tumors. Am. J. Surg.,135:389-394, 1978. 11. Foster, J.H. and Berman, M.M.: Solid liver tumors. Major Problems in Clinical Surgery, Vol. 22. Philadelphia, W. B. Saunders Company, 1977, 1-342. 12. Goldfarb, S.: Sex hormones and hepatic neoplasia. Cancer Res., 36:2584-2588, 1976. 13. Grage, T.B., Vassilopoulous, P.P., Shingleton, W.G., eta!.: Results of a prospective randomized study of hepatic artery infusion with 5-FU versus intravenous 5-FU in patients with hepatic metastases from colorectal cancer: A central oncology group study. Surgery, 550-555, 1979. 14. Ishak, K.G., and Rabin, L.: Benign tumors of the liver.. Med. Clin. North Am., 59:995-1002, 1975. 15. Jaffe, B.M., Donegan, W.L., Watson, F., eta!.: Factors influencing survival in patients with untreated hepatic metastases. Surg. Gynecol. Obstet., 127:1-11, 1968. 16. Johnson, C.M., Sheedy, P.F., Stanson, A., et a!.: Computed tomography and angiography of cavernous hemangiomas of the liver. Radiology,138: 115-122, 1981. 17. Lin, T.-Y.: Primary cancer of the liver. Scand. J. Gastroent., 5(Suppl. 6): 223-241, 1970. 18. Lin, T.-Y.: Results of197 hepatic lobectomies with a preliminary report on the use of a clamp to reduce blood loss. Ann. Surg.,177:413-421, 1973. 19. Mays, E.T., Christopherson, W.M., and Barrows, G.H.: Focal nodular hyperplasia of the liver. Possible relationship to oral contraceptives. Am. J. Clin. Pathol., 61:735-746, 1974. 20. Nime, F., Pickren, J.W., Vana, J., eta!.: The histology oflivertumors in oral contraceptive users observed during a national survey by the American College of Surgeons Commission of Cancer. Cancer, 44:1481-1489, 1979. 21. Pestana, C., Reitemeier, R.J., Moertel, C.G., eta!.: The natural history of carcinoma of the colon and rectum. Am. J. Surg., 108:836-839, 1964. 22. Rooks, J.B., Ory, H.W., Ishak, K.G., eta!.: Epidemiology of hepatocellular adenoma. J. A.. M. A., 242:644-648, 1979. 23. Smith, R.: Bradshaw Lecture, 1977. Tumours of the Liver. Ann. R. Coli. Surg. Engl., 61:87-99, 1979. 24. Sorenson, T.I.A., and Baden, H.: Benign hepatocellular tumors. Scand. J. Gastroenterol., 10:113-119, 1975. 25. Starzl, T.E., Bell, R.H., Beart, R.W., eta!.: Hepatic trisegmentectomy and other liver resections. Surg. Gynecol. Obstet., 141:429, 1975. 26. Starzl, T.E., Koep, L.J., Wei!, R.., eta!.: Right trisegmentectomy for hepatic neoplasms. Surg. Gynecol. Obstet., 150:208-214, 1980.

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27. Starzl, T.E., Koep, L.J., Wei!, R., et a!.: Excision treatment of cavernous hemangiomas of the liver. Ann. Surg., 192:25-21, 1980. 28. Unpublished data (Mayo Clinic authors). 29. Wanebo, H.J., Semoglou, C., Attiyeh, F.: Surgical management of patients with primary operatable colorectal cancer and synchronous liver metastases. Am. J. Surg., 135:81-85, 1978. 30. Webber, B.M., Soderberg, C.H., and Leone, L.A.: A combined treatment approach to management of hepatic metastases. Cancer, 42:1087-1095, 1978. 31. Weiland, L.H.: Personal communication. 32. Whelan, T.V., Jr., Baugh, J.H., and Chandor, S.: Focal nodular hyperplasia of the liver. Ann. Surg., 177:150, 1973. 33. Wilson, S.M., and Ads on, M.A.: Surgical treatment of hepatic metastases from colo rectal cancers. Arch. Surg., 111:330-333, 1976. 34. Wood, C. B., Gillis, C.R., and Blumgart, L.H.: A retrospective study of the natural history of patients with liver metastases from colorectal cancer. Clin. Oncol., 2:285-288, 1976. 35. Woodington, G.F., and Waugh, J.M.: Results of resection of metastatic tumors of the liver. Am. J. Surg., 105:24-29, 1963.

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