Some Characteristics of Metastasis in Man E. V. Sugarbaker, MD
The studies of experimental cancer metastasis are only truly meaningful to the degree that knowledge applicable to the therapeutic problem of cancer metastasis in man ensues from them. The salient features of cancer metastasis in man, therefore, are important to the laboratory researcher, for they provide a framework for which the relevance of an experimental model system must be judged. This brief discussion of some of the clinical characteristics of metastasis in man demonstrates the wide spectrum of biologic behavior and the complex multifaceted nature of this problem. It must be concluded that a complex interaction between tumor cells and host mechanisms eventually governs whether or not metastasis occurs in man. (Am J Pathol 97:623-632, 1979)
THE LITERATURE RELATED TO experimental metastasis continues to grow at an increasingly rapid rate. Much of the data generated in the studies has been of high quality and the conclusions well substantiated for the many experimental tumor systems that have been utilized. However, a thorny and infrequently printed question is, How relevant are these experimental models to the problem of cancer metastasis in man? One of the difficulties faced by the basic scientist, and, in fact, by many medical specialists, in attempting to face this question of model relevance is that few attempts have been made to provide some assessment of the clinical characteristics of metastasis in man. The objective of this presentation will be to describe concisely the most salient characteristics of metastasis in man. In order to accomplish this, it will be necessary to draw upon diverse sources of clinical data, and it must be emphasized from the outset that a central, unifying hypothesis evolving from these data is not apparent to this author. Rather than impose any such artificial cohesion, an attempt will be made to set forth a group of salient characteristics, some of which may even be mutually exclusive, with the need for future resolution of apparent incompatibilities. Sources of Limitations of Data on Clinical Metastasis
The prime objective of clinical interactions between the physician and the patient with cancer is therapeutic, ie, to eradicate the neoplastic disFrom the Department of Surgery, Division of Oncology, University of Miami School of Medicine, and the Veterans Administration Hospital, Miami, Florida. Supported in part by VA Merit Review 8212-12, a grant from the Chatlos Foundation, and NCI Grant CA-14395-01. Presented at the Sixty-third Annual Meeting of the Federation of American Societies for Experimental Biology, Dallas, Texas, April 8, 1979. Address reprint requests to Dr. Everett V. Sugarbaker, Associate Professor of Surgery, University of Miami School of Medicine, P.O. Box 016310, Miami, Florida 33101. 0002-9440/79/1207-0623$01 .00 623 ©D American Association of Pathologists
624
SUGARBAKER
American Journal of Pathology
ease and restore a normal life expectancy to the patient. However, as a natural by-product of the search for better therapies, many observations on the biologic behavior of cancer metastasis have been made. The major sources of information about cancer metastasis in man are listed in Table 1. First, striking individual or clinical observations, such as the spontaneous regressions of metastasis,l disease explosions,2 long-delayed or dormant metastasis,3 localization of metastases at sites of trauma,4 and other "anecdotal" findings from single patients or small series of patients are often documented as case reports in the literature. These striking observations draw attention to some of the most unusual aspects of metastatic behavior. Such striking deviations from the central range of biologic behavior of cancer in man stimulate thought and generate hypotheses as to mechanisms involved. The obvious limitations of such data is the fact that few data points are generated, so that such observations cannot be used to substantiate any given hypothesis, and no statistical significance can be assigned. A second major source of information is generated by clinical-surgicalpathologic data evolving from careful clinical disease staging and from surgical specimens excised during surgical treatment. Clinical characteristics of the primary tumor, either observed clinically or examined by the pathologist, can be correlated with other clinical and/or pathologic findings in adjacent lymph nodes and other organs. In addition, autopsy data add information on the terminal phases of cancer metastasis. Third, treatment results for large series of patients with histologically classified and clinically staged tumors can be assessed in terms of the organ sites and the timing of metastatic appearance after treatment. The research tool employed for these data is that of the tumor registry. Finally, more recent employment of randomized prospective clinical trials has increased the quality of the biologic data related to metastasisalthough, again, it must be emphasized that these observations are byproducts of a therapeutic attempt. In addition, it must be emphasized that in the human model only a "seTable 1 -Data Base for Characterization of Metastasis in Man 1. Anecdotal observations 2. Clinicopathologic correlations Clinical disease staging Surgical-pathologic correlations
Autopsy findings 3. Treatment results Tumor registry 4. Random prospective clinical trials
Vol. 97, No. 3 December 1979 TEXT-FIGURE 1-Relation of tumor size to dissemination in surgical cases. In two large series of patients undergoing mastectomy and axillary node dissection, a clear association of tumor size with the incidence of axillary metastasis is seen. In addition, a similar relationship exists for carcinoma of the colon until extreme tumor sizes are reached. It is important to realize that these are resected surgical cases, and either many very large lesions are technically unresectable, or patients present with obvious metastatic disease and surgery is not performed. In addition, a strong correlation between primary lung tumor size and survivorship at three months is also noted.
METASTASIS IN MAN
625
100
80
.....0
60 % 40 ..-,
-
20-. 1
2
3
4 5 6 SIZE OF TUMOR IN c
16
lected" group of patients is available in which the biologic characteristics of metastasis can be observed. This is the unfortunate subset of patients who were not cured of their initial malignancy. The Correlation Between Primary Tumor Size and Incidence of Metastasis
In several common clinical cancers (adenocarcinoma of the colon and breast) it has been clearly established that the size of the primary tumor correlates with the statistical probability of finding histologically proven metastases in regional lymph nodes. The surgical therapies in these two cancers in many large series of patients have consistently included removal of the primary cancer in continuity with the regional lymph nodes (breast with axillary nodes and colon with mesenteric nodes). The diameter of the primary cancer in excised surgical specimens can be directly measured, and the excised lymph nodes can be examined microscopically for metastases. As seen in Text-figure 1, a definite statistical relationship exists between the measured tumor diameter and the incidence of observed metastasis. On the other hand, some of the smallest breast cancers develop axillary metastases; and at the other end of the spectrum, some large cancers do not metastasize. These exceptions to the otherwise definite correlation of size and metastasis strongly support the contention that there are subsets of patients in the histologic disease categories in which the event of metastasis is more greatly affected by other variables than by primary tumor size alone. These biologic variants, which metastasize even at very small tumor sizes, have attenuated the results of the major national programs that have attempted to diagnose clinical cancers at small tumor sizes.
626
American Journal of Pathology
SUGARBAKER
The Varying Metastatic Potential of Cancer
Because statistically tumor size is an important parameter of metastasis, size can become a reference point in our attempt to characterize metastasis in man. Let us define metastatic potential as the statistical probability of metastasis in relationship to the size of the primary tumor. Then, in clinical cancer work, it is important to find an example in which the primary tumor can be accurately measured and the incidence of regional nodal metastasis reasonably well approximated. In man, there is a group of squamous cell carcinomas originating from multiple anatomic sites within the head and neck area, which are known to vary widely in metastatic potential. Importantly, for the purposes of this discussion, the primary tumor site can be directly examined, and the diameter of the primary tumor directly measured (T staging). The presence or absence of metastasis to the regional lymph nodes can be closely approximated by careful clinical examination of the neck. Lindberg 5 reported such observation, and Table 2 (permission for reproduction granted) is modified after his data. FPor example, tumors of the tongue and floor of the mouth demonstrate a strong statistical correlation between primary tumor T stage (size) and the presence of regional neck metastasis, as has been discussed in reference to adenocarcinoma of the breast and colon. On the other hand, squamous cell carcinoma of the nasopharynx, tonsil, and the base of the tongue show no significant correlation between primary tumor T stage and the presence of neck metastasis. In these latter tumors, a very high incidence of neck metastasis is present, regardless of the size of the Table 2-Demonstration of Wide Variation in Metastatic Potential in Squamous Cell Carcinoma of Several Head and Neck Sites % Lesions presenting with neck metastases*
T,
T2
T3
T4
83 89 84 93 Nasopharynx 84 75 71 70 Base of tongue 89 70 68 70 Tonsil 73 79 69 63 Hypopharynx 59 66 41 39 Supraglottic larynx 76 67 30 25 Oropharyngeal walls 76 47 30 14 Mobile tongue 53 43 29 11 Floor of mouth 67 54 37 11 RMT-AFPt 77 65 36 8 Soft palate, Uvula Reproduced with permission from Lindberg.5 * Those lesions presenting with the highest incidence of neck metastases also presented with more advanced neck disease (2044 cases of head and neck cancer, M. D. Anderson). T1 = < 2 cm (diameter); T2 = > 2 cm s 4 cm; T3 = > 4 cm s 6 cm; T4 = > 6 cm and massive tumors.
t Retromolar trigone and anterior faucial pillar.
Vol. 97, No. 3 December 1979
METASTASIS IN MAN
627
primary tumor. Cancer of the nasopharynx, therefore, can be described as having a very high metastatic potential, while the metastatic potential of lesions in the tongue and floor of the mouth could be termed moderate. This concept of metastatic potential can provide a useful classification of human cancer. Tumors of high metastatic potential would also include the nearly uniformly lethal small cell carcinoma of the lung and undifferentiated carcinoma of the thyroid gland. At the lowest end of the spectrum are basal cell carcinomas of the skin, which rarely metastasize despite reaching very large primary tumor sizes. A second characteristic of metastasis in man, therefore, is that there is wide variation in metastatic potential not only by histologic characteristics, but even, within tumors of the same histologic type, by anatomic site. It would seem appropriate for experimental model systems of metastasis to attempt to approximate the metastatic potential of the type of human malignancy that is under study. A central problem in clinical oncology is that for an individual patient (as opposed to a large series of patients) precise assessment of metastatic potential cannot be made. Thus, radical surgery may be performed; and despite the apparent success of the technique, the patient eventually may succumb to metastases that become apparent with time. Of equal importance is the fact that without individualized assessment of metastatic potential, even randomized prospective clinical trials could produce spurious results. Since study design cannot include stratification for this most important biologic variable, more patients could be included in one study arm than another, thus influencing treatment results. Variation in the Timing of Metastasis From Dormancy to Early Disease Explosions
In Text-figure 2, the site and timing of the first metastasis after surgical excision of malignant melanoma of the trunk is diagrammed. In this recently reported series,6 nearly one-half of the systemic organ metastases occurred in the 5-10-year period of postoperative observation. Such delayed recurrences have been termed "dormant metastases" and stimulated many hypotheses and studies as to the nature of host defenses that apparently contain such tumor cells for such a prolonged period of time.3 At the early end of the spectrum, disease explosions are fortunately infrequently observed. These explosions have caused several authors 2 to hypothesize that the primary tumor may have an inhibitory effect on the growth of disseminated tumor cells. Within this theoretic framework, once the primary tumor is removed, rapid growth rates return to disseminated tumor cells. Figure 1 is a roentgenogram of the chest showing multiple pulmonary metastases that appeared 4 months after surgical resection of a primary extremity fibrosarcoma. Immediately prior to surgery, the patient
628
SUGARBAKER
American Journal of Pathology
had undergone full chest tomograms to exclude small metastases and none were found. At the first postoperative roentgenogram, 4 months later, multiple metastases were seen. Despite these extremes in the posttreatment diagnosis of gross metastasis, for most patients who are not cured by initial treatments, metastases become apparent within a 2-3-year time span. Varying Growth Potential of Occult Regional Lymph Node Metastases
Either by study design in randomized, prospective clinical trials, or because differences of opinion existed within the medical community as to the efficacy of regional lymph node dissection, there are interesting comparisons of the incidences of occult (not clinically palpated) metastases in regional lymph nodes with the numbers of gross metastases appearing during clinical follow-up if lymph glands remain intact. As has been recently reviewed,7 less than 10% of the occult metastases identified in papillary carcinoma of the thyroid ever grow to palpable clinical status within a 15-year follow-up interval. Similarly, in carcinoma of the breast, 40% of the axillary surgical specimens were positive for occult metastatic disease. However, in the parallel group of patients in which the axilla was not removed, only 15% have become positive with up to 5 years of observation. Thus, the growth potential of occult lymphatic metastases in carcinoma of the breast can be approximated at 37.5%. On the other hand, in malignant melanoma and squamous cell carcinoma, similar comparisons give an estimate of essentially 100% growth potential for these two different histologic types. Thus, even after metastasis has occurred, there is significant variation in the human model as to the growth potential of micrometastatic regional lymphatic disease. Organ Patterns of Metastasis in Man
As has been recently discussed,8 for malignancies of low or moderate metastatic potential, the organ patterns of metastasis in man are dominantly explained by the anatomic routing of tumor cells from the primary site to the first set of regional lymph nodes or organs. Despite this influence of anatomic routing on initial metastases, subsequent secondary metastases to distant organs demonstrate some specific organ tropisms. For instance, frequent metastases of adenocarcinoma of the gastrointestinal tract to the ovary and of malignant melanoma to the small bowel mucosa and the relatively greater propensity of breast cancer to metastasize to bone are examples of such organ tropism. For tumors of very high metastatic potential, metastases appear widely, early in the disease course, and organ tropism, if present, is masked by this rapid neoplastic progression.
METASTASIS IN MAN
Vol. 97, No. 3 December 1979
629
RL/N ( j34)
100
80 c I
60-
7d
_/n/rans# (NV=3)
t _, 2
,,*--' 4
Sl,semlc (N=18)°
40-
20
84 48 60 96 120 18 24 3036 Time Months After Treatment of Primary TEXT-FIGURE 2-The time of the diagnosis of the first metastasis occuring after wide excision of malignant melanoma of the trunk is seen. Local recurrences (LR) and regional lymph node recurrences (RLN) occur on an earlier time frame than do first metastases in systemic organ sites. In this study, approximately half of the first systemic metastases occurred during the 5-10-year period of observation.
0
6
12
Other anecdotal clinical observations demonstrate that the dominant pattern of metastasis can be altered by acute tissue trauma or inflammation.4 Additionally, corticosteroid therapy and/or chemotherapy have been observed to alter a typical pattern of metastasis in man." Apparent Host Resistance to Primary Tumor and Metastasis May Vary
Regression zones are not uncommonly seen in a primary malignant melanoma (Figure 2). Histologic examination of such regression zones usually reveals an area of dermal atrophy with some free melanin pigment or macrophage-contained pigment. At the interface of such a zone with melanoma cells, an intense host mononuclear cell reaction is usually seen. In Figure 3 is shown a patient whose primary lesion was apparently completely destroyed by the host reactive process; yet regional nodal metastasis occurred and required surgical extirpation. Some 3-5% of all malignant melanomas present with regional nodal metastasis; yet a primary malignancy cannot be identified. It seems likely that host reactivity has eliminated the primary tumor in such patients; yet metastases occur. This evidence suggests a variation in the responsiveness in primary tumors and metastases to host reactive (possibly immune) mechanisms. Such a phenomenon is also demonstrable experimentally.9 Cellular Heterogeneity of Primary Malignancies in Man
Metastasis presumably represents a clone developing from a single cell (or small clump of tumor cells). Characteristics of the metastasis, there-
630
SUGARBAKER
American Journal of Pathology
fore, must correlate with the characteristics of possibly heterogeneous subpopulations of cells within the primary tumor. In Figure 4 is seen multiple in-transit metastases occurring in a patient who had undergone resection of a primary tumor near the ankle. Of interest is the marked variation in pigment production in these metastases. Some are black and others are unpigmented, supporting the hypothesis that the primary tumor contained a heterogeneous cell population with respect to pigment production. References 1. Everson TC: Spontaneous regression of cancer. Ann NY Acad Sci 114:721-735, 1964 2. Sugarbaker EV, Thornthwaite J, Ketcham AS: Inhibitory effect of a primary tumor on metastasis, Cancer Invasion and Metastasis: Biologic Mechanisms and Therapy. Edited by SB Day, WP Laird, Myers, P Stansly, S Garattini, MG Lewis. New York, Raven Press, 1977, p 227 3. Sugarbaker EV, Ketcham AS, Cohen AM: Studies of dormant tumor cells. Cancer 28:545, 1971 4. DerHagopian RP, Sugarbaker EV, Ketcham AS: Inflammatory oncotaxis. JAMA 240:374-375, 1978 5. Lindberg R: Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 29:1446-1449, 1972 6. Sugarbaker EV, McBride CM: Melanoma of the trunk: The results of surgical excision and anatomic guidelines for predicting nodal metastasis. Surgery 80:22-30, 1976 7. Sugarbaker EV: Cancer metastasis: A product of tumor-host interactions. Year Book Medical Publishers. 3(7), 1979 8. Sugarbaker EV: Patterns of metastasis in human malignancies, Cancer Metastasis. Edited by Fidler IJ. New York, Marcel Dekker, 1977 9. Sugarbaker EV, Cohen AM: Altered antigenicity in spontaneous pulmonary metastases from an antigenic murine sarcoma. Surgery 72:155-161, 1972
Figure 1--Multiple pulmonary metas tases are seen. Four months pre viously this patient had undergone full chest tomograms, which were unremarkable. A large primary sarcoma of the extremity was resected. The first postoperative chest roentgenogra showed extensive metastatic disease, which is consistent with the hypothe sis that the primary tumor can exhibit an inhibitory effect over dissemi nated-but occult-tumor cells.
Figure 2-Large, malignant mela
noma of the sole of the foot. In the central portion of this lesion is a white regression zone. Pathologic evalua tion through this area revealed dermal atrophy and free pigment or macro phage-contained pigment. At the bor der with viable tumor an intense mononuclear cell infiltrate was observed.
2
,040
3
4
Figure 3-Two years previously, a black mole, which intermittently bled, gradually disappeared. About 18 months after its disappearance, a mass appeared in the right groin, which, on biopsy, proved to be metastatic malignant melanoma. This observation suggests that host defense to malignant melanoma can vary between primary tumor and metastasis. Figure 4-Multiple in-transit satellites are seen in this extremity several years after wide excision of a malignant melanoma of the ankle region and approximately 18 months after inguinal node dissection for metastatic disease. Of interest is the fact that many of the "clones" are amelanotic and some deeply pigmented. Since these metastases can be viewed as "clones" growing from single cells, this observation is consistent with the hypothesis that the primary tumor contains a heterogeneous population of tumor cells, at least with respect to pigment production.
The studies of experimental cancer metastasis are only truly meaningful to the degree that knowledge applicable to the therapeutic problem of cancer metastasis in man ensues from them. The salient features of cancer metastasis in man, therefore, are important to the laboratory researcher, for they provide a framework for which the relevance of an experimental model system must be judged. This brief discussion of some of the clinical characteristics of metastasis in man demonstrates the wide spectrum of biologic behavior and the complex multifaceted nature of this problem. It must be concluded that a complex interaction between tumor cells and host mechanisms eventually governs whether or not metastasis occurs in man. (Am J Pathol 97:623-632, 1979)
THE LITERATURE RELATED TO experimental metastasis continues to grow at an increasingly rapid rate. Much of the data generated in the studies has been of high quality and the conclusions well substantiated for the many experimental tumor systems that have been utilized. However, a thorny and infrequently printed question is, How relevant are these experimental models to the problem of cancer metastasis in man? One of the difficulties faced by the basic scientist, and, in fact, by many medical specialists, in attempting to face this question of model relevance is that few attempts have been made to provide some assessment of the clinical characteristics of metastasis in man. The objective of this presentation will be to describe concisely the most salient characteristics of metastasis in man. In order to accomplish this, it will be necessary to draw upon diverse sources of clinical data, and it must be emphasized from the outset that a central, unifying hypothesis evolving from these data is not apparent to this author. Rather than impose any such artificial cohesion, an attempt will be made to set forth a group of salient characteristics, some of which may even be mutually exclusive, with the need for future resolution of apparent incompatibilities. Sources of Limitations of Data on Clinical Metastasis
The prime objective of clinical interactions between the physician and the patient with cancer is therapeutic, ie, to eradicate the neoplastic disFrom the Department of Surgery, Division of Oncology, University of Miami School of Medicine, and the Veterans Administration Hospital, Miami, Florida. Supported in part by VA Merit Review 8212-12, a grant from the Chatlos Foundation, and NCI Grant CA-14395-01. Presented at the Sixty-third Annual Meeting of the Federation of American Societies for Experimental Biology, Dallas, Texas, April 8, 1979. Address reprint requests to Dr. Everett V. Sugarbaker, Associate Professor of Surgery, University of Miami School of Medicine, P.O. Box 016310, Miami, Florida 33101. 0002-9440/79/1207-0623$01 .00 623 ©D American Association of Pathologists
624
SUGARBAKER
American Journal of Pathology
ease and restore a normal life expectancy to the patient. However, as a natural by-product of the search for better therapies, many observations on the biologic behavior of cancer metastasis have been made. The major sources of information about cancer metastasis in man are listed in Table 1. First, striking individual or clinical observations, such as the spontaneous regressions of metastasis,l disease explosions,2 long-delayed or dormant metastasis,3 localization of metastases at sites of trauma,4 and other "anecdotal" findings from single patients or small series of patients are often documented as case reports in the literature. These striking observations draw attention to some of the most unusual aspects of metastatic behavior. Such striking deviations from the central range of biologic behavior of cancer in man stimulate thought and generate hypotheses as to mechanisms involved. The obvious limitations of such data is the fact that few data points are generated, so that such observations cannot be used to substantiate any given hypothesis, and no statistical significance can be assigned. A second major source of information is generated by clinical-surgicalpathologic data evolving from careful clinical disease staging and from surgical specimens excised during surgical treatment. Clinical characteristics of the primary tumor, either observed clinically or examined by the pathologist, can be correlated with other clinical and/or pathologic findings in adjacent lymph nodes and other organs. In addition, autopsy data add information on the terminal phases of cancer metastasis. Third, treatment results for large series of patients with histologically classified and clinically staged tumors can be assessed in terms of the organ sites and the timing of metastatic appearance after treatment. The research tool employed for these data is that of the tumor registry. Finally, more recent employment of randomized prospective clinical trials has increased the quality of the biologic data related to metastasisalthough, again, it must be emphasized that these observations are byproducts of a therapeutic attempt. In addition, it must be emphasized that in the human model only a "seTable 1 -Data Base for Characterization of Metastasis in Man 1. Anecdotal observations 2. Clinicopathologic correlations Clinical disease staging Surgical-pathologic correlations
Autopsy findings 3. Treatment results Tumor registry 4. Random prospective clinical trials
Vol. 97, No. 3 December 1979 TEXT-FIGURE 1-Relation of tumor size to dissemination in surgical cases. In two large series of patients undergoing mastectomy and axillary node dissection, a clear association of tumor size with the incidence of axillary metastasis is seen. In addition, a similar relationship exists for carcinoma of the colon until extreme tumor sizes are reached. It is important to realize that these are resected surgical cases, and either many very large lesions are technically unresectable, or patients present with obvious metastatic disease and surgery is not performed. In addition, a strong correlation between primary lung tumor size and survivorship at three months is also noted.
METASTASIS IN MAN
625
100
80
.....0
60 % 40 ..-,
-
20-. 1
2
3
4 5 6 SIZE OF TUMOR IN c
16
lected" group of patients is available in which the biologic characteristics of metastasis can be observed. This is the unfortunate subset of patients who were not cured of their initial malignancy. The Correlation Between Primary Tumor Size and Incidence of Metastasis
In several common clinical cancers (adenocarcinoma of the colon and breast) it has been clearly established that the size of the primary tumor correlates with the statistical probability of finding histologically proven metastases in regional lymph nodes. The surgical therapies in these two cancers in many large series of patients have consistently included removal of the primary cancer in continuity with the regional lymph nodes (breast with axillary nodes and colon with mesenteric nodes). The diameter of the primary cancer in excised surgical specimens can be directly measured, and the excised lymph nodes can be examined microscopically for metastases. As seen in Text-figure 1, a definite statistical relationship exists between the measured tumor diameter and the incidence of observed metastasis. On the other hand, some of the smallest breast cancers develop axillary metastases; and at the other end of the spectrum, some large cancers do not metastasize. These exceptions to the otherwise definite correlation of size and metastasis strongly support the contention that there are subsets of patients in the histologic disease categories in which the event of metastasis is more greatly affected by other variables than by primary tumor size alone. These biologic variants, which metastasize even at very small tumor sizes, have attenuated the results of the major national programs that have attempted to diagnose clinical cancers at small tumor sizes.
626
American Journal of Pathology
SUGARBAKER
The Varying Metastatic Potential of Cancer
Because statistically tumor size is an important parameter of metastasis, size can become a reference point in our attempt to characterize metastasis in man. Let us define metastatic potential as the statistical probability of metastasis in relationship to the size of the primary tumor. Then, in clinical cancer work, it is important to find an example in which the primary tumor can be accurately measured and the incidence of regional nodal metastasis reasonably well approximated. In man, there is a group of squamous cell carcinomas originating from multiple anatomic sites within the head and neck area, which are known to vary widely in metastatic potential. Importantly, for the purposes of this discussion, the primary tumor site can be directly examined, and the diameter of the primary tumor directly measured (T staging). The presence or absence of metastasis to the regional lymph nodes can be closely approximated by careful clinical examination of the neck. Lindberg 5 reported such observation, and Table 2 (permission for reproduction granted) is modified after his data. FPor example, tumors of the tongue and floor of the mouth demonstrate a strong statistical correlation between primary tumor T stage (size) and the presence of regional neck metastasis, as has been discussed in reference to adenocarcinoma of the breast and colon. On the other hand, squamous cell carcinoma of the nasopharynx, tonsil, and the base of the tongue show no significant correlation between primary tumor T stage and the presence of neck metastasis. In these latter tumors, a very high incidence of neck metastasis is present, regardless of the size of the Table 2-Demonstration of Wide Variation in Metastatic Potential in Squamous Cell Carcinoma of Several Head and Neck Sites % Lesions presenting with neck metastases*
T,
T2
T3
T4
83 89 84 93 Nasopharynx 84 75 71 70 Base of tongue 89 70 68 70 Tonsil 73 79 69 63 Hypopharynx 59 66 41 39 Supraglottic larynx 76 67 30 25 Oropharyngeal walls 76 47 30 14 Mobile tongue 53 43 29 11 Floor of mouth 67 54 37 11 RMT-AFPt 77 65 36 8 Soft palate, Uvula Reproduced with permission from Lindberg.5 * Those lesions presenting with the highest incidence of neck metastases also presented with more advanced neck disease (2044 cases of head and neck cancer, M. D. Anderson). T1 = < 2 cm (diameter); T2 = > 2 cm s 4 cm; T3 = > 4 cm s 6 cm; T4 = > 6 cm and massive tumors.
t Retromolar trigone and anterior faucial pillar.
Vol. 97, No. 3 December 1979
METASTASIS IN MAN
627
primary tumor. Cancer of the nasopharynx, therefore, can be described as having a very high metastatic potential, while the metastatic potential of lesions in the tongue and floor of the mouth could be termed moderate. This concept of metastatic potential can provide a useful classification of human cancer. Tumors of high metastatic potential would also include the nearly uniformly lethal small cell carcinoma of the lung and undifferentiated carcinoma of the thyroid gland. At the lowest end of the spectrum are basal cell carcinomas of the skin, which rarely metastasize despite reaching very large primary tumor sizes. A second characteristic of metastasis in man, therefore, is that there is wide variation in metastatic potential not only by histologic characteristics, but even, within tumors of the same histologic type, by anatomic site. It would seem appropriate for experimental model systems of metastasis to attempt to approximate the metastatic potential of the type of human malignancy that is under study. A central problem in clinical oncology is that for an individual patient (as opposed to a large series of patients) precise assessment of metastatic potential cannot be made. Thus, radical surgery may be performed; and despite the apparent success of the technique, the patient eventually may succumb to metastases that become apparent with time. Of equal importance is the fact that without individualized assessment of metastatic potential, even randomized prospective clinical trials could produce spurious results. Since study design cannot include stratification for this most important biologic variable, more patients could be included in one study arm than another, thus influencing treatment results. Variation in the Timing of Metastasis From Dormancy to Early Disease Explosions
In Text-figure 2, the site and timing of the first metastasis after surgical excision of malignant melanoma of the trunk is diagrammed. In this recently reported series,6 nearly one-half of the systemic organ metastases occurred in the 5-10-year period of postoperative observation. Such delayed recurrences have been termed "dormant metastases" and stimulated many hypotheses and studies as to the nature of host defenses that apparently contain such tumor cells for such a prolonged period of time.3 At the early end of the spectrum, disease explosions are fortunately infrequently observed. These explosions have caused several authors 2 to hypothesize that the primary tumor may have an inhibitory effect on the growth of disseminated tumor cells. Within this theoretic framework, once the primary tumor is removed, rapid growth rates return to disseminated tumor cells. Figure 1 is a roentgenogram of the chest showing multiple pulmonary metastases that appeared 4 months after surgical resection of a primary extremity fibrosarcoma. Immediately prior to surgery, the patient
628
SUGARBAKER
American Journal of Pathology
had undergone full chest tomograms to exclude small metastases and none were found. At the first postoperative roentgenogram, 4 months later, multiple metastases were seen. Despite these extremes in the posttreatment diagnosis of gross metastasis, for most patients who are not cured by initial treatments, metastases become apparent within a 2-3-year time span. Varying Growth Potential of Occult Regional Lymph Node Metastases
Either by study design in randomized, prospective clinical trials, or because differences of opinion existed within the medical community as to the efficacy of regional lymph node dissection, there are interesting comparisons of the incidences of occult (not clinically palpated) metastases in regional lymph nodes with the numbers of gross metastases appearing during clinical follow-up if lymph glands remain intact. As has been recently reviewed,7 less than 10% of the occult metastases identified in papillary carcinoma of the thyroid ever grow to palpable clinical status within a 15-year follow-up interval. Similarly, in carcinoma of the breast, 40% of the axillary surgical specimens were positive for occult metastatic disease. However, in the parallel group of patients in which the axilla was not removed, only 15% have become positive with up to 5 years of observation. Thus, the growth potential of occult lymphatic metastases in carcinoma of the breast can be approximated at 37.5%. On the other hand, in malignant melanoma and squamous cell carcinoma, similar comparisons give an estimate of essentially 100% growth potential for these two different histologic types. Thus, even after metastasis has occurred, there is significant variation in the human model as to the growth potential of micrometastatic regional lymphatic disease. Organ Patterns of Metastasis in Man
As has been recently discussed,8 for malignancies of low or moderate metastatic potential, the organ patterns of metastasis in man are dominantly explained by the anatomic routing of tumor cells from the primary site to the first set of regional lymph nodes or organs. Despite this influence of anatomic routing on initial metastases, subsequent secondary metastases to distant organs demonstrate some specific organ tropisms. For instance, frequent metastases of adenocarcinoma of the gastrointestinal tract to the ovary and of malignant melanoma to the small bowel mucosa and the relatively greater propensity of breast cancer to metastasize to bone are examples of such organ tropism. For tumors of very high metastatic potential, metastases appear widely, early in the disease course, and organ tropism, if present, is masked by this rapid neoplastic progression.
METASTASIS IN MAN
Vol. 97, No. 3 December 1979
629
RL/N ( j34)
100
80 c I
60-
7d
_/n/rans# (NV=3)
t _, 2
,,*--' 4
Sl,semlc (N=18)°
40-
20
84 48 60 96 120 18 24 3036 Time Months After Treatment of Primary TEXT-FIGURE 2-The time of the diagnosis of the first metastasis occuring after wide excision of malignant melanoma of the trunk is seen. Local recurrences (LR) and regional lymph node recurrences (RLN) occur on an earlier time frame than do first metastases in systemic organ sites. In this study, approximately half of the first systemic metastases occurred during the 5-10-year period of observation.
0
6
12
Other anecdotal clinical observations demonstrate that the dominant pattern of metastasis can be altered by acute tissue trauma or inflammation.4 Additionally, corticosteroid therapy and/or chemotherapy have been observed to alter a typical pattern of metastasis in man." Apparent Host Resistance to Primary Tumor and Metastasis May Vary
Regression zones are not uncommonly seen in a primary malignant melanoma (Figure 2). Histologic examination of such regression zones usually reveals an area of dermal atrophy with some free melanin pigment or macrophage-contained pigment. At the interface of such a zone with melanoma cells, an intense host mononuclear cell reaction is usually seen. In Figure 3 is shown a patient whose primary lesion was apparently completely destroyed by the host reactive process; yet regional nodal metastasis occurred and required surgical extirpation. Some 3-5% of all malignant melanomas present with regional nodal metastasis; yet a primary malignancy cannot be identified. It seems likely that host reactivity has eliminated the primary tumor in such patients; yet metastases occur. This evidence suggests a variation in the responsiveness in primary tumors and metastases to host reactive (possibly immune) mechanisms. Such a phenomenon is also demonstrable experimentally.9 Cellular Heterogeneity of Primary Malignancies in Man
Metastasis presumably represents a clone developing from a single cell (or small clump of tumor cells). Characteristics of the metastasis, there-
630
SUGARBAKER
American Journal of Pathology
fore, must correlate with the characteristics of possibly heterogeneous subpopulations of cells within the primary tumor. In Figure 4 is seen multiple in-transit metastases occurring in a patient who had undergone resection of a primary tumor near the ankle. Of interest is the marked variation in pigment production in these metastases. Some are black and others are unpigmented, supporting the hypothesis that the primary tumor contained a heterogeneous cell population with respect to pigment production. References 1. Everson TC: Spontaneous regression of cancer. Ann NY Acad Sci 114:721-735, 1964 2. Sugarbaker EV, Thornthwaite J, Ketcham AS: Inhibitory effect of a primary tumor on metastasis, Cancer Invasion and Metastasis: Biologic Mechanisms and Therapy. Edited by SB Day, WP Laird, Myers, P Stansly, S Garattini, MG Lewis. New York, Raven Press, 1977, p 227 3. Sugarbaker EV, Ketcham AS, Cohen AM: Studies of dormant tumor cells. Cancer 28:545, 1971 4. DerHagopian RP, Sugarbaker EV, Ketcham AS: Inflammatory oncotaxis. JAMA 240:374-375, 1978 5. Lindberg R: Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 29:1446-1449, 1972 6. Sugarbaker EV, McBride CM: Melanoma of the trunk: The results of surgical excision and anatomic guidelines for predicting nodal metastasis. Surgery 80:22-30, 1976 7. Sugarbaker EV: Cancer metastasis: A product of tumor-host interactions. Year Book Medical Publishers. 3(7), 1979 8. Sugarbaker EV: Patterns of metastasis in human malignancies, Cancer Metastasis. Edited by Fidler IJ. New York, Marcel Dekker, 1977 9. Sugarbaker EV, Cohen AM: Altered antigenicity in spontaneous pulmonary metastases from an antigenic murine sarcoma. Surgery 72:155-161, 1972
Figure 1--Multiple pulmonary metas tases are seen. Four months pre viously this patient had undergone full chest tomograms, which were unremarkable. A large primary sarcoma of the extremity was resected. The first postoperative chest roentgenogra showed extensive metastatic disease, which is consistent with the hypothe sis that the primary tumor can exhibit an inhibitory effect over dissemi nated-but occult-tumor cells.
Figure 2-Large, malignant mela
noma of the sole of the foot. In the central portion of this lesion is a white regression zone. Pathologic evalua tion through this area revealed dermal atrophy and free pigment or macro phage-contained pigment. At the bor der with viable tumor an intense mononuclear cell infiltrate was observed.
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Figure 3-Two years previously, a black mole, which intermittently bled, gradually disappeared. About 18 months after its disappearance, a mass appeared in the right groin, which, on biopsy, proved to be metastatic malignant melanoma. This observation suggests that host defense to malignant melanoma can vary between primary tumor and metastasis. Figure 4-Multiple in-transit satellites are seen in this extremity several years after wide excision of a malignant melanoma of the ankle region and approximately 18 months after inguinal node dissection for metastatic disease. Of interest is the fact that many of the "clones" are amelanotic and some deeply pigmented. Since these metastases can be viewed as "clones" growing from single cells, this observation is consistent with the hypothesis that the primary tumor contains a heterogeneous population of tumor cells, at least with respect to pigment production.
