METASTASIS OF CANCER TO CANCER
S. M. RABSON, M.D., PAUL L. STIER, M.D., JERALDINE C. BAUMGARTNER, M.D.,
AND DAVID ROSENBAUM, M.D.
Departments of Pathology and Medicine, St. Joseph Hospital, Fort Wayne, Indiana, and the
Department of Pathology, Veterans Administration Hospital, Indianapolis, Indiana
Instances of multiple malignant newgrowths in the same person are now numerous. In a review in 1944, Slaughter10 collected 1828 cases from the literature
and added 40 of his own; yet, there was no mention of the spread of one neoplasm to another. In 1953 Watson 15 described 422 instances, proved microscopically; each time without such spread. There are more than 50 cases published of
cancers metastasizing to what the authors considered neoplasms. Most of the
latter fail to meet the criteria of true neoplasia, which Robertson 7 well defined
as "a more or less disorganized and independent hyperplasia of tissues, which
tends to invade and metastasize." In this definition "neoplasia" is synonymous
with "cancer." It is true that a neoplasm at one stage of its development may
not invade or metastasize, but this does not mean that it is not cancerous.
While it is true that there are some lesions that are difficult to classify as neoplastic or nonneoplastic, there are many that most oncologists would reject as
not satisfying Robertson's criteria. These include uterine "myomas," thyroid
and adrenal cortical "adenomas," "cystomas" of ovary and such hamartomatous
conditions as dermal neurofibromas, ovarian dermoids and hepatic hemangiomas.
All of these diagnoses have been applied to tumors to which cancers have metastasized.
In agreement with Walter12 who reported on cancerous tumors that metastasized to other cancers, we have accepted only 19 cases, including the 5 here reported, for enrollment in the category of metastasis of cancer to cancer. Several
other reports are equivocal because the cancerous nature of the second tumor is
debatable or may be challenged. The first of these is that of Ulesko-Stroganowa11
in which an anaplastic uterine newgrowth, termed an "endothelioma" by her,
had extended to 1 ovary; both ovaries had "cystoma papillare proliferum."
Others were reported by Fried, 3 who recognized metastasis of bronchogenic
carcinoma, and by Bernstein, 2 who described spread of mammary cancer to
meningiomas. Jackson and Symmers6 recorded, in a paper with somewhat equivocal title, 3 cases, none of which could be classified as metastasis of cancer to
cancer. In 1 patient "the stroma of the deeper parts of this growth (polypoid
Received for publication November 27, 1953.
This article was reviewed in the Veterans Administration and is published with the
approval of the Chief Medical Director. The statements and conclusions published by the
authors are the result of their own study and do not necessarily reflect the opinion of the
Veterans Administration.
Dr. Rabson is Director, Department of Pathology, and Drs. Stier and Baumgartner
are members of the Department of Medicine, St. Joseph Hospital; Dr. Rosenbaum is Director, Department of Pathology, Veterans Administration Hospital.
572
MAY 1954
METASTASIS TO CANCER
573
adenocarcinoma of sigmoid colon) was invaded by the anaplastic tumour (carcinoma of bronchus), but no transition from one to the other was seen . . . ,"
indicating that collision and not metastasis of newgrowth to newgrowth was the
true state.
The first of the definite examples of metastasis of cancer to cancer was recorded in 1902 by Berent, 1 who described spread of squamous-cell carcinoma of
the lower jaw to a hypernephroma of the right kidney in a 58-year-old houseman. Hammann's 4 patient, a 41-year-old butcher, had muscle lesions classified,
during life, as granulomas. At necropsy, the condition was diagnosed as multiple
sarcomatosis secondary to primary spindle-cell sarcoma of the thyroid gland.
The poor illustrations make it difficult to confirm; on the basis of probability,
carcinoma is more likely. A cancerous deposit was also found in a right renal
hypernephroma, and the author postulated that the endocrine neoplasm might
have been stimulated by the kidney lesion.
A woman of 65 years had endometrial adenocarcinoma, secondary evidence of
which was identified in a hypernephroma of the left kidney; this was largely in
the blood vessels, predominantly arteries, according to Walter.12 In a discussion
of Schneeberg lung cancer, Schmorl8 incidentally mentioned an instance of metastasis to hypernephroma. Simard and Saucier,9 in a man of unstated age,
found metastasis of prostatic adenocarcinoma in a mesenteric newgrowth, the
identity of which was uncertain. "Reticulosarcoma" and rhabdomyosarcoma
were considered; there was unsuccessful search for striations. Willis,16 however,
thought all tumors in this case were carcinomatous, a position which is difficult
to refute; hence, this case is listed here as "doubtful."
In 1948 Walther,13 a Swiss radiologist, published his exhaustive study of cancerous metastasis which extensively supplements Willis' "The Spread of Tumours
in the Human Body." In the last edition of the latter, incidentally, the author
has no example of his own of metastasis of cancer to cancer. Walther recorded
4 cases, in the first of which there was the finding of a pinhead extension of
bronchial carcinoma in a nonmetastasizing left hj'pernephroma; the patient was
a 4.7-year-old gardener. In a 64-year-old housewife, breast carcinoma had secondarily deposited in a malignant "parastruma." Another housewife of 66 years
hai'boi'ed a hypernephroma of the left kidney to which gastric adenocarcinoma
had spread. The fourth patient, a 58-year-old crane operator, also had a left
hypernephroma with metastases from a noncornifying carcinoma of the piriform
sinus.
In a recent personal communication Walther14 added 3 more hitherto unreported instances, in the first of which a 58-year-old housewife died with a thyroid carcinoma. At necropsy, a prepyloric gastric adenocarcinoma harbored
metastases of the thyroid microfollicular adenocarcinoma. A 67-year-old cabinetmaker had bronchial squamous-cell carcinoma which had spread to a prostatic
adenocarcinoma, while the third case was that of a 55-year-old merchant who
had a fatal "small-celled" carcinoma of the bronchus with secondary deposits
in a pancreatic adenocarcinoma found at autopsy.
The recent report of Ortega6 and his co-workers included 3 definite examples
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RABSON ET
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of the spread of cancer to cancer. In the first, there was extension of left choroidal
melanoma to left hypernephroma; the patient was a 64-year-old woman. The
second patient was a 43-year-old woman who had lymph nodes, already involved by lymphatic leukemia, to which squamous-cell carcinoma of the tongue
had spread. The last instance was that of a man of 67 years who had lymphatic
leukemia for 9 months when admitted to a hospital about 3 months ante mortem.
At that time there was general enlargement of lymph nodes and hepatomegaly.
The left breast was the seat of obvious neoplasm, as were the adjacent axillary
nodes. One of the latter was removed and demonstrated highly immature epithelial cancer as well as the changes of lymphatic leukemia. The breast tumor
was not examined by biopsy and there was no autopsy; the authors assumed that
the breast lesion was primary and made the diagnosis of "adenocarcinoma."
REPORT OF CASES
Cose 1
A 72-year-old white woman, who had previously been a bakery worker, was a d m i t t e d
for the first time to t h e St. Joseph Hospital, F o r t Wayne, Indiana, in M a y 1951, complaining
of dyspnea, radiating chest pain, anorexia, weight loss and weakness. T h e illness apparently
began with a " c o l d " the previous September (treated with antibiotics and sulfa drugs)
and was aggravated in February when, for 36 hours, there was abdominal pain with nausea
and vomiting. Following this, the p a t i e n t was no longer able to work. Dullness with bronchial breathing and rales was noted over the lower half of the left lung. T h e anterior border
of the liver was palpable beneath the right costal margin and was tender. A radiologic report
noted t h a t consolidation along the left cardiac border, apex of right lung and base of left
lung was unchanged from a former examintion (October, 1950). Two weeks later the first
two areas were said to have enlarged.
T h e diagnoses were coronary arterial disease, old pulmonary tuberculosis (right) and
unresolved pneumonia (left). I t was thought t h a t the last condition may have been exaggerated by changes secondary to aspiration of oil; the patient had taken oily nose drops each
winter for several years. I t was doubted t h a t there was pulmonary neoplasia, although
t h a t condition could not be ruled out.
The woman's general s t a t u s , as well as the dyspnea, improved and she was discharged
after 3 weeks in t h e hospital. The terminal admission followed 5 months later and was
ended by death after 10 days. Severe pains in the back and in the liver area were additional
complaints. T h e radiologic areas of consolidation had further enlarged and there were
several foci of destruction in the skull, suggestive of cancerous metastasis. I t was now
surmised t h a t the condition in the left lung was probably neoplastic and responsible for
t h e cranial findings.
At necropsy, performed an hour after death, t h e findings were largely unexpected.
Gross examination. T h e left lung (410 grams) was removed together with parietal pleura
and p a r t of t h e mediastinum because these structures could not be separated. T h e entire
lower lobe was extremely firm, and on the cut surface presented an almost homogeneous,
firm, gray-mottled background against which the numerous air passages and vessels stood
out. T h e main bronchus disappeared in t h e solid portion of the lung and its course could
not be traced for more than 3 cm.
T h e liver (1850 grams) contained numerous gray neoplastic nodules measuring up to 5
cm. in diameter. Occupying most of the cecum was a large ulcerated newgrowth extending
through the serosal surface and involving adjacent structures, including the appendix.
T h e lymph nodes about the p o r t a hepatis and the head of the pancreas were much enlarged
by cancer.
Microscopic examination. A section of the left pulmonary lobe (Fig. 1) had as the only
recognizable respiratory element a bar of hyaline cartilage, probably t h a t of a bronchus,
MAY 1954
METASTASIS TO CANCER
07D
F I G . 1 (upper). Composite photomicrograph of 2 adjacent areas of lung, both lymphosarcomatous. On the right, bronchial cartilage alone identifies the organ: on the left,
secondary deposit of cecal adenocarcinoma. Hematoxylin and eosin. X 190.
F I G . 2 (lower). Clear-cell carcinoma of kidney harboring secondarily invasive bronchogenic carcinoma. Hematoxylin and eosin. X 360.
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RABSON ET
AL.
VOL. 24
although small areas of carbon pigmentation in arterial adventitia were suggestive of lung.
The rest of the section consisted entirely of neoplasm of 2 easily distinguished varieties,
with the second invading the first. The first type of cancer was of dense lymphoid tissues
with well-defined reticulum. The lymphoid cells were fairly regular in size and had large
hyperchromic nuclei. There were also cells of the reticulum-cell type, some with mitotic
figures. Vascular mural invasion from without was also identified. The other, an epithelial
newgrowth, occupied a rounded area in the lymphoma and was made up of ill-defined acini,
columns and festoons of cells that tended to be polygonal. Mitosis was not obvious.
The liver and pancreas had areas of both lymphosarcoma and adenocarcinoma, as did
the lymph nodes at the head of the pancreas. All adenocarcinomatous foci resembled the
cecal newgrowth. There was no evidence of the coexistence of lymphosarcoma in the latter
or in its skull metastases.
The final diagnoses, then, included cecal adenocarcinoma with local spread directly to
the peritoneum and metastases to the abdominal lymph nodes, left lung, liver, pancreas
and skull. Except in the peritoneum and skull, these secondary neoplasms involved preexistent lymphosarcoma at the metastatic sites.
Case 2
A 58-year-old white man was admitted to the Veterans Administration Hospital, Indianapolis, March 21, 1951, because of productive cough, chest pain, generalized muscle
ache and weight loss. He had a draining sinus of the right flank of suspected brucellotic
origin; he had been a meat inspector working with cattle infected with brucellosis and
tuberculosis. X-ray films demonstrated a massive shadow of the right lung. On a previous
occasion acid-fast bacilli had been found on smear only, but subsequent examinations were
negative. Tuberculosis and fungus infection were included in the differential diagnosis;
it seemed possible to rule out primary pulmonary cancer. The man died on April 17, 1951.
At necropsy (A51-46), the base of the right upper pulmonary lobe had a firm greenmottled neoplasm (3 cm. in diameter) that had extended directly and by metastasis to the
remainder of the lung. There were macroscopic secondary tumors in the heart, liver, adrenal
glands and bones. The left kidney harbored, deep to the cortex, a gray to brown newgrowth
(1.5 cm. in diameter).
Microscopic examination. In the lung the entire thickness of a bronchus was involved
by cancer. Cartilage was spared, as were some of the glands and muscle bundles. The tumor
was composed of small round and spindle cells, without particular arrangement. They were
closely packed and had hyperchromic nuclei and very little cytoplasm. There were many
mitotic figures.
The renal nodule was made up of large round and polyhedral cells with well-defined cell
borders and small nuclei. The cytoplasm was extremely poorly stained and appeared to have
contained large amounts of lipoid material. In some places the neoplasm was trabeculated
by well-vascularized connective-tissue septums. In one focus of cancer (Fig. 2) there were
small groups of markedly hyperchromatic cells that were moderately elongated and had
deep-staining nuclei and but little cytoplasm. These were well differentiated from the largo
clear cells of the host tumor and appeared identical with the cells of the bronchogenic carcinoma.
Bronchogenic carcinoma of the right lung had metastasized to many places, one of which
was an area of clear-cell carcinoma of the left kidney.
FIG. 3 (upper). Clear-cell carcinoma of kidney with emboli of pulmonary adenocarcinoma. Hematoxylin and eosin. X 275.
FIG. 4 (middle). Clear-cell carcinoma of kidney with emboli of prostatic adenocarcinoma.
Hematoxylin and eosin. X 275.
FIG. 5 (lower). Clear-cell carcinoma of kidney with emboli of prostatic adenocarcinoma
Hematoxylin and eosin. X 275.
METASTASIS TO CANCER
FIGS. 3-5
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RABSON ET AL.
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Case S
The third case is the first of a series of 3 that were provided by the Armed Forces Institute of Pathology. A 65-year-old white man (AFIP Accession No. 309025) had a mucoid
adenocarcinoma of the lung that had metastasized to a clear-cell carcinoma (6.5 by 6 by 4
cm.) of the left kidney as well as to the epicardium. Microscopically (Fig. 3), the chief
renal tumor was made up of cuboidal clear cells with single, small, round, dark nuclei.
Adjacent to a focus of necrosis were several solid as well as acinar units, similar to the pulmonary cancer, of tall cuboidal, moderately deep-staining epithelium. Occasional multinucleated forms of the latter had nuclei similar to those of cells with solitary nuclei. In both
types nucleoli were prominent.
Case 4
A 72-year-old white man (AFIP Accession No. 318010) was found to harbor a clinically
silent prostatic adenocarcinoma with spread to an equally silent clear-cell carcinoma
(10 by 8 by 5 cm.) of the right kidney. The latter had given rise to bilateral multiple pulmonary growths. The microscopic section of kidney (Fig. 4) demonstrated heterogeneous
tumor emboli in the vessels of the hypernephroid cancer. The emboli, some of which invaded and destroyed the original newgrowth, were made up of closely packed, hyperchromatic large cuboidal cells with large single nuclei containing prominent nucleoli.
Prostatic cancer also was present elsewhere in the renal tissues.
Case 5
The last case (AFIP Accession No. 562583) is that of a 56-year-old white man who also
manifested spread of prostatic adenocarcinoma to various organs (lymph nodes, liver,
peritoneum, pleura, lungs, skeleton and dura) as well as to a clear-cell carcinoma (1.2 by 0.8
cm.) of the right kidney. Microscopically (Fig. 5), the picture was not unlike that seen in
the previous case.
COMMENT
The striking paucity of recorded examples of the metastasis of cancer to cancer
cannot be readily explained by failure of observation or of publication, especially
since about 2500 cases of multiple cancer already have been reported. The rarity
may be biologic; it is as if, having staked out its claim in an organ or area of an
organ, a cancer is thus protected from invasion by a rival. Just as it destroys the
tissues of the host, so it may destroy any cells that come within its reach, regardless of their character. May it be that neoplasms produce substances locally
antagonistic to other newgrowths, thus militating against the settlement of an
already cancerous locus by another tumor? Disturbance of the entire organism
may indeed be overwhelming for cancer to metastasize to cancer. A corollary is
the suggestion that substances produced by neoplasms be introduced into and
about an alien type of newgrowth to learn whether the latter undergoes regressive
changes.
Also of interest is the fact, already pointed out by Ortega,6 that, of the accepted cases, all but 5 failed to demonstrate metastasis of the host newgrowth.
Incidentally, the reverse was not true of the first or invading neoplasm. Only the
2 instances with lymphatic leukemia and our first, fourth and fifth cases manifested spread of the second cancer in the body. Also remarkable is the role of
hypernephroma serving as host in more than two-thirds of the patients. Its
prominently rich vascular supply may serve to increase the probability of the
settlement of other cancer in it, once its inviolability has been broken.
MAY 1 9 5 4
METASTASIS TO CANCER
579
Opposed to the one assumption of biologic resistance of cancer to cancer is
the other that the rarity of metastasis of neoplasm to neoplasm is pure chance.
A biostatistic consultant concluded that variables were too numerous and illdefined to risk an estimate of the probability of spread to an organ or part of an
organ if another newgrowth was already there.
SUMMARY
Five examples of metastasis of cancer to cancer are reported. Adenocarcinoma,
primary in the cecum, was found in lymphosarcomatous areas of lung, liver,
pancreas and abdominal lymph nodes. Two instances are included of pulmonary
carcinoma spreading to clear-cell carcinoma of the kidney. In 2 others, adenocarcinoma of the prostate also invaded renal clear-cell cancer. No conclusion was
reached concerning the cause of the rarity of instances of metastasis of cancer to
cancer. Antagonism of one newgrowth to another and a low rate of probability
of the meeting of 2 neoplasms in the same portion of an organ were considered.
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