Journal of Surgical Oncology 1 1 : 193-205 (1 979)
Metastases From Carcinoma of Mammary Gland: An Autopsy Study .......................................................................................... .......................................................................................... NESTOR CIFUENTES, MD, and JOHN W. PICKREN, MD Information o n metastases from carcinoma of the mammary gland in an autopsy study of 707 cases occurring in white women over a 15-year period are presented and tabulated. Multiple primary cancers occurred in 19% of the cases. Of the 137 cases that exhibit more than one neoplastic malignancy, 31 (23%) were present in the contralateral mammary gland. Seventy patients had no metastasis from the mammary cancer at the time of death, and 55 of these patients had another cancer. Additional information has been added concerning the frequency of metastasis in parathyroid and thymus. When a parathyroid contains a metastasis, extensive metastases were noted in many organs and thus represents a late stage of the cancer.
..................................................................................... ..................................................................................... Key words: mammary carcinoma, metastases, autopsy study, mammary cancer
INTRODUCTION Cancer of the mammary gland causes more deaths in women than cancer of any other organ. Several authors have published data on the autopsy findings of fatal mammary cancer with the number of cases ranging from 71 to 432 [l-41, and many authors have reported on the metastases to a specific site. We have collected data on consecutive autopsies from 773 mammary cancers in a 15-year period. Our data include information on metastasis to the thymus and parathyroid which has not been reported previously.
From the Department of Pathology, Roswell Park Memorial Institute, Department of Health, New York State, Buffalo. Address reprint requests to John W.Pickren, MD, Department of Pathology, Roswell Park Memorial Institute, Department of Health, New York State, 666 Elm Street, Buffalo, NY 14263. 0022-4790/79/1103-0193$02.90 @ 1979 Alan
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MATERIALS AND METHODS Roswell Park Memorial Institute has a unique and highly successful method of obtaining permission for autopsies on patients who die. At the time of admission to the hospital, the patient (or the legal guardian for minors and incompetents) is requested to sign for a post-mortem examination in the event of death during hospitalization. Such permission is almost always obtained. Autopsies were performed on 97% of patients who died. Thus, for practical purposes, there is no bias in the selection of cases for post-mortem evaluation. During the period of this study, 1959-1974, there were 7,500 autopsies performed. From these autopsies 773 primary cancer of the mammary gland were found. These cancers included epithelial, nonhemopoietic mesenchymal, and hemopoietic neoplasms. Only eight fell into the categories of nonepithelial cancers. Thus, almost all were of epithelial origin. For the purpose of tabulation, the data on men (12 cases) and the nonwhite women (23 cases) were deleted (Table I). For the most part, the cases were identified as adenocarcinoma (duct carcinoma) but five cases were identified as other types of epithelial cancer including squamous cell carcinoma, malignant melanoma, anaplastic carcinoma, and metastatic carcinoma. These five latter cases were excluded from the study. Eighteen cases were excluded because of errors in coding. These deletions left 707 cases of mammary carcinoma occurring in white women for analysis. This information was coded for machine calculation by the resident who performed the autopsy at the time of completion of its histological study. Both the gross and histologic findings were used to determine the appropriate answers t o the questions on the form.
RESULTS The ages of the patients at death are shown in decades in Table 11. The youngest patient was age 25 years and oldest was 87. This distribution of ages is different from the distribution in those reports listing the age of patients at the time of diagnosis showing a shift towards an older population in our study. This older age difference is to be expected since the age was determined at a later time in the course of the disease. In our patients the age was determined at death rather than the age when the tumor was first discovered. However, our data are comparable to the data shown in mortality tables for mammary cancer. Thus, this information suggests this series of cases are comparable t o mammary cancer occurring in patients who have died elsewhere.
TABLE 1. Sex and Race Distribution in Cancer of Mammary Gland Race and sex
Number of cases
Cases (%)
White women Nonwhite women Nonwhite men White men
738 23 1 11
95.4 3 0.1
Total
77 3
100.0
1.5
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TABLE 11. Mammary Gland Carcinoma, Age at Time of Death -
Age/ years
20-29 30-39 40-49 50-59 60-69 70-79 80-89
Patients
Percentage
6 53 160 206 180 95
1 8 23 29 25 13
I
I
From the National Surgical Adjuvant breast project, it was shown that almost 100% of the patients younger than 50 years old had menstruation, and the group older than 50 did not [5]. Two hundred nineteen (31%) of our patients were less than 50 years of age, and 488 (69%) were 50 years and older. Fifteen (2%) of them were 50 at the time of death. No attempt has been made t o correlate clinical hormonal evaluation in our cases, but 261 patients had oophrectomy before death. Table I11 shows the incidence of multiple cancers occurring in this series. Nineteen percent (137 cases) of the cases had more than one cancer. This frequency (19%) of multiple cancers occurring in white women with mammary cancer is significantly higher than the 11% observed in a study of patients with cancer from all sites, including both sexes and all races [6]. In a clinical study of 2,504 patients with gynecological cancer, Buchler found 209 patients who had a second cancer. Fifty-eight (28%) of the 209 second cancers involved the mammary gland. Furthermore, the mammary cancer was detected before the genital cancer in 43 of the 58 cases, and in 2 patients the mammary and genital cancers were detected simultaneously [7]. In 31 of our patients the mammary cancer was bilateral. The tabulated information concerns each of the mammary glands involved by cancer. Thus, the total number of patients in this series of 707 cases of mammary cancers is actually 676. Furthermore, the tables include information on patients who had successful treatment of their mammary cancer and died from other causes including a second cancer of another organ. In addition, patients are included who died from complications of therapy rather than metastases. Seventy of our patients had no metastases from their mammary cancer. They are included in the calculations.
TABLE 111. Number of Rimary Cancers in Patients With Mammary Carcinoma Number of cancers
Number of cases
Percent of cases
570 128 8 1
81 18 1 0.1
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METASTASIS Lymph Nodes Lymph nodes are commonly seeded by secondary cancer by three different routes: a) direct spread, b) blood stream, c) lymphatics. Spread by lymphatics is the most common route [8]. In breast cancer the frequency of metastases to lymph nodes ranges from 71% in Warren and Witham [4] to 64% in Meissner [2]. Thus, lymph nodes are involved by metastatic cancer in about two-thirds of the cases. When subdivided by location of lymph nodes, the mediastinal lymph nodes are the group most frequently involved. In our study the lymph nodes have been subdivided by the following categories: cervical, thoracic, abdominal, pelvic, and others. The breakdown of the affected lymph nodes according to the areas shows thoracic lymph nodes t o be the ones most commonly involved by metastatic cancer from breast cancer. Seventyone percent of the cases had metastasis in one or more of the lymph node groups (Table IV). Bone Practically any malignant tumor can metastasize to bone: it is uncommon for tumors of some organs t o metastasize to bone, eg, the squamous cell carcinoma of the skin, but highly characteristic of other sites, eg, adenocarcinoma of the prostate and mammary gland [9]. Johnston in a study of 653 autopsies on patients with cancer found metastases in bones in 32.5% of the cases [ l o ] . The wide range of reported rates of metastases to bone varying from a low of 20% to a high of 70% depends in part on the duration and stage of the disease at the time of the patient’s death. Metastases to bone occur more frequently from cancer originating in the mammary gland than any other organ. Johnston reported a metastatic rate of 57% to bone from breast cancer and a 55% rate from prostate cancer. Skeletal metastases is obviously underestimated even in necropsy studies [ l 11 . In a comprehensive study, Fornasier [ 121 found vertebral metastases in 61% of 7 0 patients with breast cancer. He removed a slice of the vertebral bodies from T3 to L4. Tissue was selected for histologic study from obvious grossly abnormal bone, but in those cases without such changes, roentgenography, a hand lens, or a dissecting microscope was used to select abnormal tissue. In our 707 cases, 472 patients (67%) had involvement of the vertebrae. Other bones were involved on 401 occasions (57%). TABLE IV. Frequency of Metastases to Lymph Nodes From Mammary Carcinoma Metastases Lymph node group
Negative Number
Cervical Thoracic Abdominal Pelvic Other sites
446 316 418 562 437
Total
204
Unknown
Positive %
Number
%
Number
59 79 62
239 379 276 114 188
34 54 39 16 27
22 12 13 31 82
29
503
71
0
63 4s
%
3 2 2 4 12
Totalcases
107 107 707 707 707 707
Metastases From Mammary Gland Carcinoma
197
In our autopsies, histologic studies are done from sample on bones in all cases. These samples include vertebrae, iliac crest, and rib. The vertebral body bones from the lumbar region t o the upper thoracic area were examined by slicing the vertebral bodies. Metastases occurred in vertebrae more often than in other bones (Table V). This result may be spurious because a large surface of the vertebral bodies were examined grossly for selection of the sample to be studied histologically while samples of other bones were selected in a random fashion. Seventy-one percent of all the patients harbored metastasis in one or more of the skeletal structures. Abrams [ 1 1 quoted a 73.1%in a series of 167 cases. Thus, bone metastases in patients with fatal breast cancer is very common.
Spleen In our study, 109 of 707 (15%) patients had metastases to the spleen. The most common cancer giving rise t o splenic involvement are the lymphomas. Robbins states that carcinoma metastasizes t o the spleen rarely and only when generalized carcinomatosis has occurred, with the exception of melanocarcinoma [13]. He offers the explanation that the spleen is an unfavorable soil for the growth of secondary cancer because of the barrier of the thick walled splenic arteries [ 131. Berge found metastasis in the spleen in 65 of 693 patients with breast carcinoma [ 141. Iversen divided 47 patients with mammary carcinoma into groups receiving or not receiving steroid therapy. Although the number of cases is small, 8 of 31 patients receiving steroids had splenic metastases while none of 16 nonsteroid treated patients had metastases [ 151 .We have not analyzed our data for the effect of steroids on metastases. In the old literature the frequency of splenic metastases from mammary cancer varies from 1% to 5%. Paget, as quoted by Iversen, in 1889 found the spleen t o be involved in 17 of 735 mammary cancer autopsies [ 1 5 ] . Dunn as quoted by Iversen reported 16%involvement of spleen in 50 cases after exhaustive histological examination [ 15J .
Lungs Another organ in which metastasis from breast cancer commonly occurs is the lung (Table VI). Viadana et a1 consider this organ a filter that is interposed between primary tumor and other noncontiguous organs [16]. The spread of carcinoma of the breast t o the lung may take multiple patterns. Kane et a1 in autopsy material on cancer patients found 26 cases of microscopic tumor emboli, in the absence of gross lesion in the lung. Of 16 cases analyzed, four were found to have primary mammary gland cancers [ 171 .
TABLE V. Frequency of Metastases to Bones From Mammary Carcinoma Vertebra
Other bones
Vertebra and/ or other bones
Metastasis
Number
%
Number
%
Number
%
Present Absent Unknown
472
67
41
503 204
71
33
40 1 290
57
234 1
16
2
0
0
29
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In our series a total of 472 (67%) patients had metastases in the lung (Table VI). Our figure is comparable t o those of Abrams, 77% of 167 patients [ 11, and Meissner, 57% of 432 patients [2]. In our patients, the pleura was affected in one-half of the cases. The great majority of patients with pleural involved also had metastases in the lungs. However, on 30 occasions the pleura was affected alone without lung involvement. Central Nervous System The brain was removed in 704 of the 707 autopsies. Metastases were present at some site within the central nervous system in 31% of the 707 cases. In Table VII the central nervous system has been divided into 5 areas. Both the dura and brain are frequently involved (1 8%each), but the choroid plexus and leptomeninges are less commonly involved. The number of cases with involvement of the spinal cord is also considered in the calculations to determine the percentages of involvement of the central nervous system. However, the spinal cord was not routinely removed, and metastases were found in the spinal cord cord in 20 cases. In a series of 432 autopsies on patients with mammary carcinoma, Meissner reports a 10%frequency of metastases to the central nervous system but does not further subdivide the system 121. Willis noted the tumors most frequently responsible for cerebral metastases are carcinomas of the breast, lung, and kidney and found in his personal cases that mammary carcinoma accounted for 7 of the 29 cases [ 181 . TABLE VI. Frequency of Metastasis to Lungs From Mammary Carcinoma Metastases Site
Number
%
413 408 39 1 39 42 47 2
58 57 55 6 6 67
Right lung Left lung Both lungs One lung only No specified lung Right and/or left lung
107
Total cases ~
~
~
~~
~
~
~
~
~
TABLE VII. Frequency of Metastasis to the Central Nervous System From Mammary Carcinoma Metastases Negd t ive
Unknown
Positive
Number
Number
Q
Brain Dura mater Choroid Leptomeninges Spinal cord
516 575 690 659 378
81 81 98 93 53
128 129 9 36 20
18 18 1 5 3
3 3 8 12 309
Total
489
69
21 5
31
3
Site
Number
%
%
1 1 1 2 44
Total cases
701 707 707 707 707 707
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Cardiovascular System In our series the heart was involved with metastasis on 83 occasions (12%). The pericardial sac was seeded 132 times (19%) (Table VIII). Both the heart and pericardium were affected 45 times. In 170 cases (24%), either the heart, the pericardium, or both were involved by metastases from the mammary carcinoma. In other words, one out of four patients with carcinoma of the breast had neoplastic involvement to the heart or pericardium. Nakamura reported four of 15 (26%) of patients with breast cancer t o have heart metastases [19]. In summarizing the literature, Nakamura found 104 of 366 cases (28%) of mammary cancers t o have metastasized t o the heart. Kline proposed a route for the neoplastic seeding of the heart as a retrogressive flow of cancer cells along lymphatics channels from mediastinal lymph nodes whose sinuses have been plugged by metastasis, a criterion that is fulfilled in 76% of our cases. The frequency of cardiac metastasis from mammary carcinoma in his 64 cases was 12.5% [20]. Pituitary Of the 707 patients, the pituitary gland was examined in 704 cases. Metastases were found in 117 (1 7%) of patients. Smulders and Smets found metastases in the pituitary gland in 28% of their breast cancer patients [37]. Hogerstrand and Schonebecks’ figure was 15% (46 of 308 cases), and in their review of the literature noted a variation from 1 to 28% [21 J .
Adrenal Glands The adrenal gland is a common site for metastatic neoplastic growth from breast cancer. The adrenal gland contained metastases in 27% of all malignant growths [ 11 . In breast cancer, metastases in adrenal glands have been reported to occur in 55% of cases by Taylor and 25% by Huggins as quoted by Aldrete and Bohrod [22]. In a study of adrenal glands removed as treatment of advanced breast cancer, Aldrete and Bohrod found 18 of 46 (39%) surgical specimens t o contain metastases from breast cancer. Tho’se patients with bilateral metastases had a 50% mortality rate. Adrenalectomy in patients with unilateral involvement resulted in subjective improvement in most patients. Patients with periadrenal fat involvement showed objective improvement. In our patients the frequency of adrenal metastases was 41% (Table IX). The right and left adrenal glands were involved almost equally and the metastases were most often bilateral (Table IX). In an occasional case unilateral involvement was noted (Table IX). Those cases noted as “side not specified” indicated a microscopic finding without involvement noted on the gross examination. TABLE VIII. Frequency of Metastases to Cardiovascular System From Mammary Carcinoma ~~
Number
Number
%
%
~~~
Present Absent Unknown
83 62 3 1
Total
I01
Heart and/or pericardium
Pericardium
Heart Site
~
12 88
Number
%
170 531
24 76
~
132 573 2
I07
19 81
I01
200
Cifuentes and Pickren
TABLE IX. Frequency of Metastasis to Adrenal Glands From Mammary Carcinoma ~
~~
~
Metastases Site
Number
%
30 32 26
Right gland Left gland Both adrenals Unilateral adrenal Adrenal side not specified Right and/or left adrenal
136 144 120 35 30 185
41
Total examined Number not examined
448 259
63 31
Total cases
101
8
7
Examination of the adrenal glands was not performed at post-mortem study on 269 occasions. This lack of examination was the result of a prior bilateral adrenalectomy performed during life. Thus, the adrenals were not present for postmortem examination.
Thyroid Secondary cancer in the thyroid occurs more frequently than primary thyroid cancer [21]. Of the various cancers, malignant melanoma give rise t o the highest incidence of thyroid metastases. Shimaoka et a1 found that 39% of their patients with malignant melanoma had thyroid metastases [23] . Carcinoma of the mammary gland is the second most frequent tumor to metastasize t o thyroid. Meissner and Warren reported a frequency of 9.5% of metastases in the thyroid from mammary cancer [24]. Shimaoka et al reported a frequency of 21% [23]. In our study (which includes Shimaoka cases) the frequency of thyroid metastases from mammary cancer is 20%.
Parathyroid In our study the parathyroid glands were involved with neoplastic disease in 28 (4%) patients. When a parathyroid was involved many other organs were also involved. An average of 18 other sites contained metastases when the parathyroid glands were demonstrated to be involved. The number of sites involved ranged from 6 t o 38, but only one patient had less than 10 sites. Thus, the demonstration of parathyroid metastases from mammary cancer is indicative of a cancer that has disseminated widely. Thymus The tumors most frequently responsible for secondary involvement of the thymus are carcinoma of the breast, lung, and thyroid. Thymus involvement generally results from secondary extension from foci of metastases t o the mediastinal lymph nodes [25]. In our study, we found metastatic seeding of the thymus in 75 cases (1 1%). Ovaries In 261 cases the ovaries were not examined, because they had been excised previously by a surgical procedure. Thus, the data on metastases to ovaries are limited to 446 autopsies. In 11 patients, a unilateral oophorectomy had been previously performed leaving only one ovary to be examined at autopsy.
Metastases From Mammary Gland Carcinoma
20 1
Twenty-one percent of the 446 cases had metastases in one or both ovaries. The metastases were bilateral in 58 cases, unilateral in 37 cases which include the 18 cases where the side of involvement was unknown. However, when the side was known, the right and left ovaries were involved equally, 70 right side and 69 left side (Table X). Compel and Silverberg found secondary involvement of the ovary by mammary cancer in 10% of the patients examined at autopsy [26]. In an autopsy study Turksoy [27] found ovarian metastases from breast cancer in 42 percent of 19 cases. In a surgical study of mammary cancer patients undergoing prophylactic oophrectomy, he found 31% Of 26 cases t o have ovarian metastases. The tumors most frequently responsible for secondary tumors of the ovaries are the gastrointestinal carcinoma, breast cancer, and endometrial carcinoma [18] . Israel noted in a study of 33 cases of metastases to the ovaries that cancer of the mammary gland was primary source in 13 cases [28] . In a study of 120 cases of metastases to the ovary, Woodruff found that 12% originated in the mammary gland [29].
Liver Metastases to the liver are noted frequently from most cancers regardless of the venous drainage of the organ in which the primary tumor arises [30]. Mammary cancer frequently metastasizes to the liver (Table XI). This datum is similar to those reported by others [3].
Stomach Metastases in the stomach from mammary cancer occurred in 69 of our 707 patients (10%).Metastases to the serosa of the stomach is not included in this figure. Metastases t o the peritoneum is placed in another category. In our study, t o be classified as metastases
TABLE X. Frequency of Metastasis t o Ovaries From Mammary Carcinoma Metastases Site
Number
%
-
70 69 58 19 18 95
16 16 13 4 4
Total examined Total not examined
446 26 1
63 37
Total cases
701
Right ovary Left ovary Both ovaries Unilateral ovary Side not specified Right and/or left ovary
21
TABLE XI. Frequency of Metastases to Liver and BiUiary Tract From Mammary Carcinoma Positive
Negative Site of metastasis Liver Biliary tract Liver and/or biliary tract
Number 261 627 255
%
38 88 36
Number
%
440
62 11 64
16
452
202
Cifuentes and Pickren
t o stomach the muscularis or mucosa had t o be involved. Hartmann and Sherlock strongly entertained steroid therapy as a cause for development of metastatic lesions in the stomach from breast cancer [31]. In a series of 204 patients who received steroid treatment, they noted a rate of 21%of metastasis in the gastroduodenal area, as compared t o the rate of 13% in nontreated pateints [31]. They collected four papers published before 1949 in which the data showed 14 of 439 (3%) breast cancer patients to have gastric metastasis [31]. Their conclusions were that metastasis to the mucosa and submucosa of the stomach is six times as frequent in the steroid treated group, as compared with the control patients. Iversen proposed that treatment with cortisone or related drugs predispose t o metatasis because of the effect of the drugs on permeability of blood vessel and lymphatics [ 151. Choi et a1 in an autopsy study of 341 patients with breast cancer found 28 patients with stomach metastasis. These cases are also included in our study, except for their one case which occurred in a man [32]. Choi et a1 evaluated the clinical findings and found half not having gastric syniptomatology [32]. In the Abrams series the metastatic rate t o stomach from breast carcinoma in 167 cases was 14%,but he noted the majority of the cases exhibit serosal implants only [ 1 ] . Ash reported on 337 patients with carcinoma of breast and found 57 (1 6%) t o have metastasis in the stomach [33].
The Gastrointestinal Tract In our analysis of these organs, we have separated the gastrointestinal tract into three parts: 1) stomach, 2) small intestine, and 3) large intestine. Further, we excluded cases with only serosal implants on these structures. When the muscular wall, submucosa, or mucosa contain foci of secondary cancer, then the organ was listed as containing metastases. The gastrointestinal tract can be affected by metastatic lesion by three different pathways: 1) transperitoneal, 2) blood stream, and 3) lymphatic. Almost all of the previous quoted reports reflect a higher percent of involvement of serosa than the muscular or mucosal walls of these tubular abdominal organs. In our series, the stomach was involved in 10% of cases, small intestine in 9%, and large intestine in 8%.The peritoneum was involved in 25% of cases. In 112 cases one or more of the above segments of the gastrointestinal tract were involved (a rate of 16%). In 92 cases ( 1 3%) the peritoneum was seeded with neoplastic tissue without involvement of muscular or mucosal walls of these tubular organs. The present findings are in accordance with those of Abrams, who quotes 24.6% for the peritoneum and 14.4% for the gastrointestinal tract (Table XII).
Kidneys Our study revealed that the right and left kidneys are equally involved by metastases from mammary cancer (Table XIII). Usually, the involvement is bilateral but occasionally only one kidney contains metastasis from the mammary cancer. Klinger reported similar findings in his cases [34]. In our study, metastasis to kidney from mammary cancer occurred in 97 of the 707 patients (14%). This figure is similar to that reported by others; Walther 9% [37] and Sproul 17% [3]. Brennington noted that one-fourth of the metastases in kidneys represent mammary carcinoma [35].
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TABLE XII. Metastases to Gastrointestinal Tract From Mammary Carcinoma Metastases Negative Site Stomach Small intestine Large intestine Stomach, small intestine and/or large intestine Peritoneum
Positive
Number
Number
%
637 643 647 5 95
69 64 57 112
10 9 8 16
528
178
25
TABLE XIII. Frequency of Metastasis to Kidneys From Mammary Carcinoma Metastases Site Right kidney Left kidney Both kidneys Unilateral kidney Side not specified Right and/or left kidney Total cases
Number
%
13 73 64 18 15 91
10 10 9 3 2 14
I07
Excretory System of the Kidney In a series of 99 metastatic lesions t o the ureter, 9 had the primary neoplasms arising in the mammary glands [35]. In an autopsy review of 181 cases of carcinoma of the breast, the ureters were affected in 15 cases (8.3%) [36]. The majority of these metastatic lesions were bilateral [36]. In our study we have included the urethra, bladder, and ureters together. Sixty-one of our 707 (9%) patients had one or more of these organs involved. Abrams found the ureteral metastases in 7.8% of these patients and bladder metastases in 2.4% [ l ] . A summary of our findings is shown in Table XIV. Metastases are found in multiple organs in women dying from mammary carcinoma.
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TABLE XIV. Summation of Metastases From Carcinoma of Mammary Gland Metastatic sites Lymph nodes All bones Lungs Liver Pleura Adrenals Central nervous system Muscular system Peritoneum Ovaries Thyroid Pericardiu m Pituitary Gastrointestinal tract Spleen Kidney Genital tract Pancreas Heart Periadrenal fat Extra hep. biliary tract Thymus Urinary excretory system Upper digestive tract Upper respiratory tract Great vessels Parathyroids Pineal gland
Percent of cases
71 71 67 62 50 41 31 29 25 21 20 19 17 16 15 14 14 13 11 12 11 11 9 7 6 6 4 2
REFERENCES 1. Abrams HL Spiro R, Goldstein N : Metastasis in carcinoma. Cancer 3:74-85, 1950. 2. Meissner W, Warren S: In Oxley DK, Nuclear diagnosis of disseminated cancer of the breast. Am J Clin Pathol 64:780-785, 1975. 3. Sproul EE: In Haagensen CD: “Disease of the Breast.’’ Philadelphia: Saunders, 1973, 2nd Ed, p 426. 4. Warren S, Witham EM: Studies on tumor metastases. Surg Obst Gynecol57:81-85, 1933. 5 . Viadana E, Cotter R, Pickren JW, Bross IDJ: An autopsy study of metastatic sites of breast cancer. Cancer Res. 33:179-181, 1973. 6. Pickren JW: Cancer often strikes twice. NYSJ Med 95-99, 1963. 7. Buchler D: Multiple primaries and gynecological malignancies. Am J Obs Cynecol 123:376-381, 1975. 8. Ostacio JN: In Pelayo Correa (ed): “Texto de Pathologia.” Prensa Medica Mexicana, 1970, p 885. 9. Aegert and Kirkpatrick: “Orthopedic Disease.” Philadelphia: Saunders, 1975,4th Ed, p 470. 10. Johnston AD: Pathology of metastatic tumors in bone. Clin Orthop Relat Res. 73:8-32, 1970. 11. Jaffe HL: “Tumor and Tumorous Conditions of Bone and Joints.” Philadelphia: Lea and Febiger, 1958, p 589. 12. Fornasier VL, Horne JB: Metastasis to the vertebral column. Cancer 36:SYO-594, 1975. 13. Robbins S: “Pathological Basis of Disease.” Philadelphia: Saunders, 1974, p 778. 14. Berge T : Spleen metastasis. Acta Pathol Microb Scand 82:499-506, 1974. 15. lversen HG, Hjort GH: The influence of steroids in spleen, metastases in breast cancer. Acta Pathol Microb Scand 44:205-212, 1958.
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16. Viadana E, Kwai Ling: Pattern of metastasis in adenocarcinoma of man. J Med 6: 1- 14, 1975. 17. Kane RD, Hawkins HK, Miller AJA, Noce PS: Microscopic pulmonary tumor emboli associate with dyspnea. Cancer 36:1473-1482, 1975. 18. Willis RA: “Spread of Tumors in Human Body.” St. Louis: Mosby, 1952, 2nd Ed, p 255. 19. Nakamura A, Suchi T, Mizuno Y: The effect of malignant neoplasms on the heart. Jpn Circ J 39~531-542, 1975. 20. Kline 1K: Cardiac lymphatic involvement by metastatic tumor. Cancer 29:799-807, 1972. 21. Hagestrand, Schonebeck: Metastasis to the pituitary gland. Acta Pathol Microbiol Scand 75:64-70, 1969. 22. Aldrete LS, Bohrod MD: Adrenal metastasis in carcinoma of the breast. Am Surg 33:174-178, 1967. 23. Shimaoka K, Sokal JE, Pickren JW: Metastatic neoplasms of the thyroid gland. Cancer 15557565,1962. 24. Meissner W, Warren S: “Tumors of the Thyroid Gland.” Washington, DC: Armed Forces Institute of Pathology, 1968, 2nd Series, p 127. 25. Rosai J, Levine GD: “Tumors of the Thymus.” Washington, DC: Armed Forces Institute of Pathology, 1975, 2nd Series, p 206. 26. Compel C, Silverberg S: “Pathology in Gynecology and Obstetrics.” Philadelphia: Lippincott, 1977, 2nd Ed, p 352. 27. Turksoy N: Ovarian metastases of breast carcinoma. Obst Gynecol 15:573-578, 1960. 28. Israel LS, Helser EV, Hausman DH: The challenge of metastatic ovarian carcinoma. Am J Obst Gynecol 93:1094-1101, 1965. 29. Woodruff‘ LJ, Murthy YS,Bhaskar TN, Bordbar F, Tseng SS: Metastatic ovarian tumors. Am J Obst Gynecol 107:202-209.1970. 30. Sherlock S: “Disease of Liver and Biliary System.” London: Blackwell, 1975,5th M,p 684. 31. Hartmann WP, Sherlock P: Gastroduodenal metastasis from carcinoma of the breast. Cancer 14:426-431, 1961. 32. Choi SH, Sheehan FR, Pickren JW: Metastatic involvement of the stomach by breast cancer. Cancer 17:791-797, 1964. 33. Ash M, Wiedel PD, Habif DV: Gastrointestinal metastasis from carcinoma of the breast. Arch Surg 961840-843,1968. 34. Klinger ME: In “Campbell Urology.” Philadelphia: Saunders, 1963,2nd Ed, p 987. 35. Bennington and Bitwing: “Tumor of Kidney, Pelvis and Ureter.” Washington, DC: Armed Forces Institute of Pathology, 1975,2nd series, p 320. 36. Geller SA, Lin CS: Ureteral obstruction from carcinoma of breast. Arch Pathol99:476-478, 1975. 37. Smulders J, Smets W: Les metastases des carcinomes mammaire frequence des metastases hypophysaires. Bull Assoc Franc P L‘etudd du Cancer 47:434-456, 1960. 38. Walther HE: In Haagensen CD: “Disease of the Breast.” Philadelphia: Saunders, 1973,2nd Ed, p 426.
Metastases From Carcinoma of Mammary Gland: An Autopsy Study .......................................................................................... .......................................................................................... NESTOR CIFUENTES, MD, and JOHN W. PICKREN, MD Information o n metastases from carcinoma of the mammary gland in an autopsy study of 707 cases occurring in white women over a 15-year period are presented and tabulated. Multiple primary cancers occurred in 19% of the cases. Of the 137 cases that exhibit more than one neoplastic malignancy, 31 (23%) were present in the contralateral mammary gland. Seventy patients had no metastasis from the mammary cancer at the time of death, and 55 of these patients had another cancer. Additional information has been added concerning the frequency of metastasis in parathyroid and thymus. When a parathyroid contains a metastasis, extensive metastases were noted in many organs and thus represents a late stage of the cancer.
..................................................................................... ..................................................................................... Key words: mammary carcinoma, metastases, autopsy study, mammary cancer
INTRODUCTION Cancer of the mammary gland causes more deaths in women than cancer of any other organ. Several authors have published data on the autopsy findings of fatal mammary cancer with the number of cases ranging from 71 to 432 [l-41, and many authors have reported on the metastases to a specific site. We have collected data on consecutive autopsies from 773 mammary cancers in a 15-year period. Our data include information on metastasis to the thymus and parathyroid which has not been reported previously.
From the Department of Pathology, Roswell Park Memorial Institute, Department of Health, New York State, Buffalo. Address reprint requests to John W.Pickren, MD, Department of Pathology, Roswell Park Memorial Institute, Department of Health, New York State, 666 Elm Street, Buffalo, NY 14263. 0022-4790/79/1103-0193$02.90 @ 1979 Alan
R. Liss, Inc.
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MATERIALS AND METHODS Roswell Park Memorial Institute has a unique and highly successful method of obtaining permission for autopsies on patients who die. At the time of admission to the hospital, the patient (or the legal guardian for minors and incompetents) is requested to sign for a post-mortem examination in the event of death during hospitalization. Such permission is almost always obtained. Autopsies were performed on 97% of patients who died. Thus, for practical purposes, there is no bias in the selection of cases for post-mortem evaluation. During the period of this study, 1959-1974, there were 7,500 autopsies performed. From these autopsies 773 primary cancer of the mammary gland were found. These cancers included epithelial, nonhemopoietic mesenchymal, and hemopoietic neoplasms. Only eight fell into the categories of nonepithelial cancers. Thus, almost all were of epithelial origin. For the purpose of tabulation, the data on men (12 cases) and the nonwhite women (23 cases) were deleted (Table I). For the most part, the cases were identified as adenocarcinoma (duct carcinoma) but five cases were identified as other types of epithelial cancer including squamous cell carcinoma, malignant melanoma, anaplastic carcinoma, and metastatic carcinoma. These five latter cases were excluded from the study. Eighteen cases were excluded because of errors in coding. These deletions left 707 cases of mammary carcinoma occurring in white women for analysis. This information was coded for machine calculation by the resident who performed the autopsy at the time of completion of its histological study. Both the gross and histologic findings were used to determine the appropriate answers t o the questions on the form.
RESULTS The ages of the patients at death are shown in decades in Table 11. The youngest patient was age 25 years and oldest was 87. This distribution of ages is different from the distribution in those reports listing the age of patients at the time of diagnosis showing a shift towards an older population in our study. This older age difference is to be expected since the age was determined at a later time in the course of the disease. In our patients the age was determined at death rather than the age when the tumor was first discovered. However, our data are comparable to the data shown in mortality tables for mammary cancer. Thus, this information suggests this series of cases are comparable t o mammary cancer occurring in patients who have died elsewhere.
TABLE 1. Sex and Race Distribution in Cancer of Mammary Gland Race and sex
Number of cases
Cases (%)
White women Nonwhite women Nonwhite men White men
738 23 1 11
95.4 3 0.1
Total
77 3
100.0
1.5
Metastases From Mammary Gland Carcinoma
195
TABLE 11. Mammary Gland Carcinoma, Age at Time of Death -
Age/ years
20-29 30-39 40-49 50-59 60-69 70-79 80-89
Patients
Percentage
6 53 160 206 180 95
1 8 23 29 25 13
I
I
From the National Surgical Adjuvant breast project, it was shown that almost 100% of the patients younger than 50 years old had menstruation, and the group older than 50 did not [5]. Two hundred nineteen (31%) of our patients were less than 50 years of age, and 488 (69%) were 50 years and older. Fifteen (2%) of them were 50 at the time of death. No attempt has been made t o correlate clinical hormonal evaluation in our cases, but 261 patients had oophrectomy before death. Table I11 shows the incidence of multiple cancers occurring in this series. Nineteen percent (137 cases) of the cases had more than one cancer. This frequency (19%) of multiple cancers occurring in white women with mammary cancer is significantly higher than the 11% observed in a study of patients with cancer from all sites, including both sexes and all races [6]. In a clinical study of 2,504 patients with gynecological cancer, Buchler found 209 patients who had a second cancer. Fifty-eight (28%) of the 209 second cancers involved the mammary gland. Furthermore, the mammary cancer was detected before the genital cancer in 43 of the 58 cases, and in 2 patients the mammary and genital cancers were detected simultaneously [7]. In 31 of our patients the mammary cancer was bilateral. The tabulated information concerns each of the mammary glands involved by cancer. Thus, the total number of patients in this series of 707 cases of mammary cancers is actually 676. Furthermore, the tables include information on patients who had successful treatment of their mammary cancer and died from other causes including a second cancer of another organ. In addition, patients are included who died from complications of therapy rather than metastases. Seventy of our patients had no metastases from their mammary cancer. They are included in the calculations.
TABLE 111. Number of Rimary Cancers in Patients With Mammary Carcinoma Number of cancers
Number of cases
Percent of cases
570 128 8 1
81 18 1 0.1
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METASTASIS Lymph Nodes Lymph nodes are commonly seeded by secondary cancer by three different routes: a) direct spread, b) blood stream, c) lymphatics. Spread by lymphatics is the most common route [8]. In breast cancer the frequency of metastases to lymph nodes ranges from 71% in Warren and Witham [4] to 64% in Meissner [2]. Thus, lymph nodes are involved by metastatic cancer in about two-thirds of the cases. When subdivided by location of lymph nodes, the mediastinal lymph nodes are the group most frequently involved. In our study the lymph nodes have been subdivided by the following categories: cervical, thoracic, abdominal, pelvic, and others. The breakdown of the affected lymph nodes according to the areas shows thoracic lymph nodes t o be the ones most commonly involved by metastatic cancer from breast cancer. Seventyone percent of the cases had metastasis in one or more of the lymph node groups (Table IV). Bone Practically any malignant tumor can metastasize to bone: it is uncommon for tumors of some organs t o metastasize to bone, eg, the squamous cell carcinoma of the skin, but highly characteristic of other sites, eg, adenocarcinoma of the prostate and mammary gland [9]. Johnston in a study of 653 autopsies on patients with cancer found metastases in bones in 32.5% of the cases [ l o ] . The wide range of reported rates of metastases to bone varying from a low of 20% to a high of 70% depends in part on the duration and stage of the disease at the time of the patient’s death. Metastases to bone occur more frequently from cancer originating in the mammary gland than any other organ. Johnston reported a metastatic rate of 57% to bone from breast cancer and a 55% rate from prostate cancer. Skeletal metastases is obviously underestimated even in necropsy studies [ l 11 . In a comprehensive study, Fornasier [ 121 found vertebral metastases in 61% of 7 0 patients with breast cancer. He removed a slice of the vertebral bodies from T3 to L4. Tissue was selected for histologic study from obvious grossly abnormal bone, but in those cases without such changes, roentgenography, a hand lens, or a dissecting microscope was used to select abnormal tissue. In our 707 cases, 472 patients (67%) had involvement of the vertebrae. Other bones were involved on 401 occasions (57%). TABLE IV. Frequency of Metastases to Lymph Nodes From Mammary Carcinoma Metastases Lymph node group
Negative Number
Cervical Thoracic Abdominal Pelvic Other sites
446 316 418 562 437
Total
204
Unknown
Positive %
Number
%
Number
59 79 62
239 379 276 114 188
34 54 39 16 27
22 12 13 31 82
29
503
71
0
63 4s
%
3 2 2 4 12
Totalcases
107 107 707 707 707 707
Metastases From Mammary Gland Carcinoma
197
In our autopsies, histologic studies are done from sample on bones in all cases. These samples include vertebrae, iliac crest, and rib. The vertebral body bones from the lumbar region t o the upper thoracic area were examined by slicing the vertebral bodies. Metastases occurred in vertebrae more often than in other bones (Table V). This result may be spurious because a large surface of the vertebral bodies were examined grossly for selection of the sample to be studied histologically while samples of other bones were selected in a random fashion. Seventy-one percent of all the patients harbored metastasis in one or more of the skeletal structures. Abrams [ 1 1 quoted a 73.1%in a series of 167 cases. Thus, bone metastases in patients with fatal breast cancer is very common.
Spleen In our study, 109 of 707 (15%) patients had metastases to the spleen. The most common cancer giving rise t o splenic involvement are the lymphomas. Robbins states that carcinoma metastasizes t o the spleen rarely and only when generalized carcinomatosis has occurred, with the exception of melanocarcinoma [13]. He offers the explanation that the spleen is an unfavorable soil for the growth of secondary cancer because of the barrier of the thick walled splenic arteries [ 131. Berge found metastasis in the spleen in 65 of 693 patients with breast carcinoma [ 141. Iversen divided 47 patients with mammary carcinoma into groups receiving or not receiving steroid therapy. Although the number of cases is small, 8 of 31 patients receiving steroids had splenic metastases while none of 16 nonsteroid treated patients had metastases [ 151 .We have not analyzed our data for the effect of steroids on metastases. In the old literature the frequency of splenic metastases from mammary cancer varies from 1% to 5%. Paget, as quoted by Iversen, in 1889 found the spleen t o be involved in 17 of 735 mammary cancer autopsies [ 1 5 ] . Dunn as quoted by Iversen reported 16%involvement of spleen in 50 cases after exhaustive histological examination [ 15J .
Lungs Another organ in which metastasis from breast cancer commonly occurs is the lung (Table VI). Viadana et a1 consider this organ a filter that is interposed between primary tumor and other noncontiguous organs [16]. The spread of carcinoma of the breast t o the lung may take multiple patterns. Kane et a1 in autopsy material on cancer patients found 26 cases of microscopic tumor emboli, in the absence of gross lesion in the lung. Of 16 cases analyzed, four were found to have primary mammary gland cancers [ 171 .
TABLE V. Frequency of Metastases to Bones From Mammary Carcinoma Vertebra
Other bones
Vertebra and/ or other bones
Metastasis
Number
%
Number
%
Number
%
Present Absent Unknown
472
67
41
503 204
71
33
40 1 290
57
234 1
16
2
0
0
29
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Cifuentes and Pickren
In our series a total of 472 (67%) patients had metastases in the lung (Table VI). Our figure is comparable t o those of Abrams, 77% of 167 patients [ 11, and Meissner, 57% of 432 patients [2]. In our patients, the pleura was affected in one-half of the cases. The great majority of patients with pleural involved also had metastases in the lungs. However, on 30 occasions the pleura was affected alone without lung involvement. Central Nervous System The brain was removed in 704 of the 707 autopsies. Metastases were present at some site within the central nervous system in 31% of the 707 cases. In Table VII the central nervous system has been divided into 5 areas. Both the dura and brain are frequently involved (1 8%each), but the choroid plexus and leptomeninges are less commonly involved. The number of cases with involvement of the spinal cord is also considered in the calculations to determine the percentages of involvement of the central nervous system. However, the spinal cord was not routinely removed, and metastases were found in the spinal cord cord in 20 cases. In a series of 432 autopsies on patients with mammary carcinoma, Meissner reports a 10%frequency of metastases to the central nervous system but does not further subdivide the system 121. Willis noted the tumors most frequently responsible for cerebral metastases are carcinomas of the breast, lung, and kidney and found in his personal cases that mammary carcinoma accounted for 7 of the 29 cases [ 181 . TABLE VI. Frequency of Metastasis to Lungs From Mammary Carcinoma Metastases Site
Number
%
413 408 39 1 39 42 47 2
58 57 55 6 6 67
Right lung Left lung Both lungs One lung only No specified lung Right and/or left lung
107
Total cases ~
~
~
~~
~
~
~
~
~
TABLE VII. Frequency of Metastasis to the Central Nervous System From Mammary Carcinoma Metastases Negd t ive
Unknown
Positive
Number
Number
Q
Brain Dura mater Choroid Leptomeninges Spinal cord
516 575 690 659 378
81 81 98 93 53
128 129 9 36 20
18 18 1 5 3
3 3 8 12 309
Total
489
69
21 5
31
3
Site
Number
%
%
1 1 1 2 44
Total cases
701 707 707 707 707 707
Metastases From Mammary Gland Carcinoma
199
Cardiovascular System In our series the heart was involved with metastasis on 83 occasions (12%). The pericardial sac was seeded 132 times (19%) (Table VIII). Both the heart and pericardium were affected 45 times. In 170 cases (24%), either the heart, the pericardium, or both were involved by metastases from the mammary carcinoma. In other words, one out of four patients with carcinoma of the breast had neoplastic involvement to the heart or pericardium. Nakamura reported four of 15 (26%) of patients with breast cancer t o have heart metastases [19]. In summarizing the literature, Nakamura found 104 of 366 cases (28%) of mammary cancers t o have metastasized t o the heart. Kline proposed a route for the neoplastic seeding of the heart as a retrogressive flow of cancer cells along lymphatics channels from mediastinal lymph nodes whose sinuses have been plugged by metastasis, a criterion that is fulfilled in 76% of our cases. The frequency of cardiac metastasis from mammary carcinoma in his 64 cases was 12.5% [20]. Pituitary Of the 707 patients, the pituitary gland was examined in 704 cases. Metastases were found in 117 (1 7%) of patients. Smulders and Smets found metastases in the pituitary gland in 28% of their breast cancer patients [37]. Hogerstrand and Schonebecks’ figure was 15% (46 of 308 cases), and in their review of the literature noted a variation from 1 to 28% [21 J .
Adrenal Glands The adrenal gland is a common site for metastatic neoplastic growth from breast cancer. The adrenal gland contained metastases in 27% of all malignant growths [ 11 . In breast cancer, metastases in adrenal glands have been reported to occur in 55% of cases by Taylor and 25% by Huggins as quoted by Aldrete and Bohrod [22]. In a study of adrenal glands removed as treatment of advanced breast cancer, Aldrete and Bohrod found 18 of 46 (39%) surgical specimens t o contain metastases from breast cancer. Tho’se patients with bilateral metastases had a 50% mortality rate. Adrenalectomy in patients with unilateral involvement resulted in subjective improvement in most patients. Patients with periadrenal fat involvement showed objective improvement. In our patients the frequency of adrenal metastases was 41% (Table IX). The right and left adrenal glands were involved almost equally and the metastases were most often bilateral (Table IX). In an occasional case unilateral involvement was noted (Table IX). Those cases noted as “side not specified” indicated a microscopic finding without involvement noted on the gross examination. TABLE VIII. Frequency of Metastases to Cardiovascular System From Mammary Carcinoma ~~
Number
Number
%
%
~~~
Present Absent Unknown
83 62 3 1
Total
I01
Heart and/or pericardium
Pericardium
Heart Site
~
12 88
Number
%
170 531
24 76
~
132 573 2
I07
19 81
I01
200
Cifuentes and Pickren
TABLE IX. Frequency of Metastasis to Adrenal Glands From Mammary Carcinoma ~
~~
~
Metastases Site
Number
%
30 32 26
Right gland Left gland Both adrenals Unilateral adrenal Adrenal side not specified Right and/or left adrenal
136 144 120 35 30 185
41
Total examined Number not examined
448 259
63 31
Total cases
101
8
7
Examination of the adrenal glands was not performed at post-mortem study on 269 occasions. This lack of examination was the result of a prior bilateral adrenalectomy performed during life. Thus, the adrenals were not present for postmortem examination.
Thyroid Secondary cancer in the thyroid occurs more frequently than primary thyroid cancer [21]. Of the various cancers, malignant melanoma give rise t o the highest incidence of thyroid metastases. Shimaoka et a1 found that 39% of their patients with malignant melanoma had thyroid metastases [23] . Carcinoma of the mammary gland is the second most frequent tumor to metastasize t o thyroid. Meissner and Warren reported a frequency of 9.5% of metastases in the thyroid from mammary cancer [24]. Shimaoka et al reported a frequency of 21% [23]. In our study (which includes Shimaoka cases) the frequency of thyroid metastases from mammary cancer is 20%.
Parathyroid In our study the parathyroid glands were involved with neoplastic disease in 28 (4%) patients. When a parathyroid was involved many other organs were also involved. An average of 18 other sites contained metastases when the parathyroid glands were demonstrated to be involved. The number of sites involved ranged from 6 t o 38, but only one patient had less than 10 sites. Thus, the demonstration of parathyroid metastases from mammary cancer is indicative of a cancer that has disseminated widely. Thymus The tumors most frequently responsible for secondary involvement of the thymus are carcinoma of the breast, lung, and thyroid. Thymus involvement generally results from secondary extension from foci of metastases t o the mediastinal lymph nodes [25]. In our study, we found metastatic seeding of the thymus in 75 cases (1 1%). Ovaries In 261 cases the ovaries were not examined, because they had been excised previously by a surgical procedure. Thus, the data on metastases to ovaries are limited to 446 autopsies. In 11 patients, a unilateral oophorectomy had been previously performed leaving only one ovary to be examined at autopsy.
Metastases From Mammary Gland Carcinoma
20 1
Twenty-one percent of the 446 cases had metastases in one or both ovaries. The metastases were bilateral in 58 cases, unilateral in 37 cases which include the 18 cases where the side of involvement was unknown. However, when the side was known, the right and left ovaries were involved equally, 70 right side and 69 left side (Table X). Compel and Silverberg found secondary involvement of the ovary by mammary cancer in 10% of the patients examined at autopsy [26]. In an autopsy study Turksoy [27] found ovarian metastases from breast cancer in 42 percent of 19 cases. In a surgical study of mammary cancer patients undergoing prophylactic oophrectomy, he found 31% Of 26 cases t o have ovarian metastases. The tumors most frequently responsible for secondary tumors of the ovaries are the gastrointestinal carcinoma, breast cancer, and endometrial carcinoma [18] . Israel noted in a study of 33 cases of metastases to the ovaries that cancer of the mammary gland was primary source in 13 cases [28] . In a study of 120 cases of metastases to the ovary, Woodruff found that 12% originated in the mammary gland [29].
Liver Metastases to the liver are noted frequently from most cancers regardless of the venous drainage of the organ in which the primary tumor arises [30]. Mammary cancer frequently metastasizes to the liver (Table XI). This datum is similar to those reported by others [3].
Stomach Metastases in the stomach from mammary cancer occurred in 69 of our 707 patients (10%).Metastases to the serosa of the stomach is not included in this figure. Metastases t o the peritoneum is placed in another category. In our study, t o be classified as metastases
TABLE X. Frequency of Metastasis t o Ovaries From Mammary Carcinoma Metastases Site
Number
%
-
70 69 58 19 18 95
16 16 13 4 4
Total examined Total not examined
446 26 1
63 37
Total cases
701
Right ovary Left ovary Both ovaries Unilateral ovary Side not specified Right and/or left ovary
21
TABLE XI. Frequency of Metastases to Liver and BiUiary Tract From Mammary Carcinoma Positive
Negative Site of metastasis Liver Biliary tract Liver and/or biliary tract
Number 261 627 255
%
38 88 36
Number
%
440
62 11 64
16
452
202
Cifuentes and Pickren
t o stomach the muscularis or mucosa had t o be involved. Hartmann and Sherlock strongly entertained steroid therapy as a cause for development of metastatic lesions in the stomach from breast cancer [31]. In a series of 204 patients who received steroid treatment, they noted a rate of 21%of metastasis in the gastroduodenal area, as compared t o the rate of 13% in nontreated pateints [31]. They collected four papers published before 1949 in which the data showed 14 of 439 (3%) breast cancer patients to have gastric metastasis [31]. Their conclusions were that metastasis to the mucosa and submucosa of the stomach is six times as frequent in the steroid treated group, as compared with the control patients. Iversen proposed that treatment with cortisone or related drugs predispose t o metatasis because of the effect of the drugs on permeability of blood vessel and lymphatics [ 151. Choi et a1 in an autopsy study of 341 patients with breast cancer found 28 patients with stomach metastasis. These cases are also included in our study, except for their one case which occurred in a man [32]. Choi et a1 evaluated the clinical findings and found half not having gastric syniptomatology [32]. In the Abrams series the metastatic rate t o stomach from breast carcinoma in 167 cases was 14%,but he noted the majority of the cases exhibit serosal implants only [ 1 ] . Ash reported on 337 patients with carcinoma of breast and found 57 (1 6%) t o have metastasis in the stomach [33].
The Gastrointestinal Tract In our analysis of these organs, we have separated the gastrointestinal tract into three parts: 1) stomach, 2) small intestine, and 3) large intestine. Further, we excluded cases with only serosal implants on these structures. When the muscular wall, submucosa, or mucosa contain foci of secondary cancer, then the organ was listed as containing metastases. The gastrointestinal tract can be affected by metastatic lesion by three different pathways: 1) transperitoneal, 2) blood stream, and 3) lymphatic. Almost all of the previous quoted reports reflect a higher percent of involvement of serosa than the muscular or mucosal walls of these tubular abdominal organs. In our series, the stomach was involved in 10% of cases, small intestine in 9%, and large intestine in 8%.The peritoneum was involved in 25% of cases. In 112 cases one or more of the above segments of the gastrointestinal tract were involved (a rate of 16%). In 92 cases ( 1 3%) the peritoneum was seeded with neoplastic tissue without involvement of muscular or mucosal walls of these tubular organs. The present findings are in accordance with those of Abrams, who quotes 24.6% for the peritoneum and 14.4% for the gastrointestinal tract (Table XII).
Kidneys Our study revealed that the right and left kidneys are equally involved by metastases from mammary cancer (Table XIII). Usually, the involvement is bilateral but occasionally only one kidney contains metastasis from the mammary cancer. Klinger reported similar findings in his cases [34]. In our study, metastasis to kidney from mammary cancer occurred in 97 of the 707 patients (14%). This figure is similar to that reported by others; Walther 9% [37] and Sproul 17% [3]. Brennington noted that one-fourth of the metastases in kidneys represent mammary carcinoma [35].
Metastases From Mammary Gland Carcinoma
203
TABLE XII. Metastases to Gastrointestinal Tract From Mammary Carcinoma Metastases Negative Site Stomach Small intestine Large intestine Stomach, small intestine and/or large intestine Peritoneum
Positive
Number
Number
%
637 643 647 5 95
69 64 57 112
10 9 8 16
528
178
25
TABLE XIII. Frequency of Metastasis to Kidneys From Mammary Carcinoma Metastases Site Right kidney Left kidney Both kidneys Unilateral kidney Side not specified Right and/or left kidney Total cases
Number
%
13 73 64 18 15 91
10 10 9 3 2 14
I07
Excretory System of the Kidney In a series of 99 metastatic lesions t o the ureter, 9 had the primary neoplasms arising in the mammary glands [35]. In an autopsy review of 181 cases of carcinoma of the breast, the ureters were affected in 15 cases (8.3%) [36]. The majority of these metastatic lesions were bilateral [36]. In our study we have included the urethra, bladder, and ureters together. Sixty-one of our 707 (9%) patients had one or more of these organs involved. Abrams found the ureteral metastases in 7.8% of these patients and bladder metastases in 2.4% [ l ] . A summary of our findings is shown in Table XIV. Metastases are found in multiple organs in women dying from mammary carcinoma.
204
Cifuentes a n d Pickren
TABLE XIV. Summation of Metastases From Carcinoma of Mammary Gland Metastatic sites Lymph nodes All bones Lungs Liver Pleura Adrenals Central nervous system Muscular system Peritoneum Ovaries Thyroid Pericardiu m Pituitary Gastrointestinal tract Spleen Kidney Genital tract Pancreas Heart Periadrenal fat Extra hep. biliary tract Thymus Urinary excretory system Upper digestive tract Upper respiratory tract Great vessels Parathyroids Pineal gland
Percent of cases
71 71 67 62 50 41 31 29 25 21 20 19 17 16 15 14 14 13 11 12 11 11 9 7 6 6 4 2
REFERENCES 1. Abrams HL Spiro R, Goldstein N : Metastasis in carcinoma. Cancer 3:74-85, 1950. 2. Meissner W, Warren S: In Oxley DK, Nuclear diagnosis of disseminated cancer of the breast. Am J Clin Pathol 64:780-785, 1975. 3. Sproul EE: In Haagensen CD: “Disease of the Breast.’’ Philadelphia: Saunders, 1973, 2nd Ed, p 426. 4. Warren S, Witham EM: Studies on tumor metastases. Surg Obst Gynecol57:81-85, 1933. 5 . Viadana E, Cotter R, Pickren JW, Bross IDJ: An autopsy study of metastatic sites of breast cancer. Cancer Res. 33:179-181, 1973. 6. Pickren JW: Cancer often strikes twice. NYSJ Med 95-99, 1963. 7. Buchler D: Multiple primaries and gynecological malignancies. Am J Obs Cynecol 123:376-381, 1975. 8. Ostacio JN: In Pelayo Correa (ed): “Texto de Pathologia.” Prensa Medica Mexicana, 1970, p 885. 9. Aegert and Kirkpatrick: “Orthopedic Disease.” Philadelphia: Saunders, 1975,4th Ed, p 470. 10. Johnston AD: Pathology of metastatic tumors in bone. Clin Orthop Relat Res. 73:8-32, 1970. 11. Jaffe HL: “Tumor and Tumorous Conditions of Bone and Joints.” Philadelphia: Lea and Febiger, 1958, p 589. 12. Fornasier VL, Horne JB: Metastasis to the vertebral column. Cancer 36:SYO-594, 1975. 13. Robbins S: “Pathological Basis of Disease.” Philadelphia: Saunders, 1974, p 778. 14. Berge T : Spleen metastasis. Acta Pathol Microb Scand 82:499-506, 1974. 15. lversen HG, Hjort GH: The influence of steroids in spleen, metastases in breast cancer. Acta Pathol Microb Scand 44:205-212, 1958.
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16. Viadana E, Kwai Ling: Pattern of metastasis in adenocarcinoma of man. J Med 6: 1- 14, 1975. 17. Kane RD, Hawkins HK, Miller AJA, Noce PS: Microscopic pulmonary tumor emboli associate with dyspnea. Cancer 36:1473-1482, 1975. 18. Willis RA: “Spread of Tumors in Human Body.” St. Louis: Mosby, 1952, 2nd Ed, p 255. 19. Nakamura A, Suchi T, Mizuno Y: The effect of malignant neoplasms on the heart. Jpn Circ J 39~531-542, 1975. 20. Kline 1K: Cardiac lymphatic involvement by metastatic tumor. Cancer 29:799-807, 1972. 21. Hagestrand, Schonebeck: Metastasis to the pituitary gland. Acta Pathol Microbiol Scand 75:64-70, 1969. 22. Aldrete LS, Bohrod MD: Adrenal metastasis in carcinoma of the breast. Am Surg 33:174-178, 1967. 23. Shimaoka K, Sokal JE, Pickren JW: Metastatic neoplasms of the thyroid gland. Cancer 15557565,1962. 24. Meissner W, Warren S: “Tumors of the Thyroid Gland.” Washington, DC: Armed Forces Institute of Pathology, 1968, 2nd Series, p 127. 25. Rosai J, Levine GD: “Tumors of the Thymus.” Washington, DC: Armed Forces Institute of Pathology, 1975, 2nd Series, p 206. 26. Compel C, Silverberg S: “Pathology in Gynecology and Obstetrics.” Philadelphia: Lippincott, 1977, 2nd Ed, p 352. 27. Turksoy N: Ovarian metastases of breast carcinoma. Obst Gynecol 15:573-578, 1960. 28. Israel LS, Helser EV, Hausman DH: The challenge of metastatic ovarian carcinoma. Am J Obst Gynecol 93:1094-1101, 1965. 29. Woodruff‘ LJ, Murthy YS,Bhaskar TN, Bordbar F, Tseng SS: Metastatic ovarian tumors. Am J Obst Gynecol 107:202-209.1970. 30. Sherlock S: “Disease of Liver and Biliary System.” London: Blackwell, 1975,5th M,p 684. 31. Hartmann WP, Sherlock P: Gastroduodenal metastasis from carcinoma of the breast. Cancer 14:426-431, 1961. 32. Choi SH, Sheehan FR, Pickren JW: Metastatic involvement of the stomach by breast cancer. Cancer 17:791-797, 1964. 33. Ash M, Wiedel PD, Habif DV: Gastrointestinal metastasis from carcinoma of the breast. Arch Surg 961840-843,1968. 34. Klinger ME: In “Campbell Urology.” Philadelphia: Saunders, 1963,2nd Ed, p 987. 35. Bennington and Bitwing: “Tumor of Kidney, Pelvis and Ureter.” Washington, DC: Armed Forces Institute of Pathology, 1975,2nd series, p 320. 36. Geller SA, Lin CS: Ureteral obstruction from carcinoma of breast. Arch Pathol99:476-478, 1975. 37. Smulders J, Smets W: Les metastases des carcinomes mammaire frequence des metastases hypophysaires. Bull Assoc Franc P L‘etudd du Cancer 47:434-456, 1960. 38. Walther HE: In Haagensen CD: “Disease of the Breast.” Philadelphia: Saunders, 1973,2nd Ed, p 426.
