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[CANCER RESEARCH 34, 2088-2091, August 1974]
Ectopie Synthesis and Paraneoplastic Syndromes1
Thomas C. Hall2
Los Angeles County-University of Southern California Cancer Hospital and Research Center, Los Angeles, California 90033
Summary
Paraneoplastic syndromes are clinically important dis
turbances of function in distant organs of the human cancer
patient. They appear to arise because partially differenti
ated cells in specific tissues, when transformed, retain some
specialized synthetic capacities of their tissues of origin,
while expressing others which result in rapid growth,
mobility, broaching of the basement membrane, and lack of
feedback inhibition. The result is the production and release
into circulation of unusual amounts and/or varieties of
macromolecules, which may result in unphysiological overor underactivity of a number of distant host target organs.
The products involved should be studied as possible ontogenic-phase-specific tissue macromolecules.
Introduction
The "paraneoplastic syndromes" are disease entities
found in cancer patients, in whom clinical disorders of
function are found in host organs at a distance from the
cancer (7). It has been calculated that, at any one time, 15%
of cancer patients will be suffering from such distant
metabolic effects of the cancer, as opposed to the symptoms
and signs that the cancer causes by direct invasion of host
organs. The incidence and severity of such systemic mani
festations increase with the severity of the neoplastic
process; it is believed that three-fourths of all uncured
cancer patients will suffer from such a syndrome during the
course of their disease.
The second major histological anlägefrom which tu
mors arise to produce "ectopie" products is the foregut.
Here we find hepatoblastomas producing gonadotrophins
and pancreatic tumors producing gastrin and insulin. Not
all glandular foregut cancers are functioning, however. The
stomach and lining epithelium have rarely been described as
involved in such syndromes, although cancer of the lower
gastrointestinal tract may be associated with distant effects
upon the skin, such as acanthosis nigricans. The nephrogenic ridge "cancers," e.g., of kidney, ovary, and uterus,
commonly produce erythropoietic substances which resem
ble those normally produced by the anoxic normal kidney.
Occasionally, a kidney tumor will be associated with
hypercalcemia in the absence of bone métastases,or a
prostatic cancer will produce Cushing's syndrome, or
hypokalemic alkalosis, suggesting the synthesis of parathy
roid hormone or ACTH of pituitary type. This emphasizes
that the tumor product is usually, but not invariably, similar
to a normal product of a tissue derived from the same
embryogénieanlägeas the tumor.
The neuroectodermal tumors do not often give rise to
metabolic derangements of other host organs. This may be
because most brain tumors are of connective tissue or glial
origin, or because the material "ectopically" produced
would resemble that of normal neurons, which do not have
endocrine functions and, accordingly, would be difficult to
detect. However, certain cells of neuroectodermal origin do
wander into other areas during embryogenesis and come to
represent an "organ" which is widely dispersed throughout
the other parenchymatous organs. These cells are neuroClassification
secretory, commonly producing one or more amines with
The tumors that are found to be associated with distant powerful systemic effects. Such cells include the Kulschitsky cell of the lung, and the argentaffin cells of the
host effects can be grouped into 4 major types, character
ized by the embryological origin of the tissue from which the gastrointestinal tract. Because of their characteristic histotumors arise. The commonest cancer of branchial cleft chemical staining properties, they have been called by
origin is that of the lung. Such tumors give rise to many Pearse (8) the "amine precursor uptake and decarboxylatsyndromes caused by the cancer producing the polypeptide ing (APUD) cells." Tumors derived from this 3rd embryohormones which are normally produced by other branchial logical anlägeinclude carcinoids of the gastrointestinal
cleft derivatives such as the parathyroid and the anterior tract, lung, and pheochromocytomas, which may produce
pituitary. Parathyroid cancers continue to produce their a wide spectrum of catechols and polypeptide hormones.
The final embryological anlägefrom which physiologi
own normal product, parathyroid hormone, but in excessive
amounts; this is true of both adenocarcinomas and medul cally active cancers arise is the chorion itself; choriocarlary tumors. The neoplastic synthesis of hormones is not cinomas of the placenta and those of the gonads commonly
complete, however, since lung cancers rarely make TSH.3 produce large amounts of chorionic gonadotrophins and, in
some cases, TSH.
1Presented at the Third Conference on Embryonic and Fetal Antigens
In addition to classification by the tissue of tumor origin,
in Cancer, November 4 to 7, 1973, Knoxville, Tenn.
syndromes can also be grouped pathophysiologically ac
2American Cancer Society Research Professor PRP-47.
3The abbreviations used are: TSH, thyroid-stimulating hormone; cording to the mediators which are produced by the tumors
ACTH, adrenocorticotrophic hormone.
and which then alter the function of noncancer tissues of the
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Ectopie Synthesis and Paraneoplastic Syndromes
host. These can be considered as short-range substances
which act only upon the cells quite close to the cancer cell,
and long-range mediators which have their major action
upon an organ other than that in which the tumor originates
or is found as a metastatic deposit. We shall pay little at
tention to the short-range effectors here, except for the few
cases in which a direct effect so alters the function of an
organ that a "secondary" paraneoplastic syndrome re
sults. Examples of short-range mediator effects include the
intravascular coagulation produced around small tumor
emboli by direct activation of clotting factors, proliferation
of endothelium by angiogenesis factors, and osteoblastic
and osteolytic changes immediately around the tumor. Each
of these can, in some instances, also produce distant system
effects. In the cases cited above they produce, respectively,
disseminated intravascular coagulation, "clubbing," and
hypocalcemia or hypercalcemia.
The long-range factors include: (a) normal active secre
tory endocrine products of the tissue from which the tumor
derived, e.g., steroids produced by ovarian, testicular, and
adrenal tumors, in excess of physiological need, apparently
because of an inoperative negative-feedback loop. a-Fetoglobulin fits this class, although it is a normal product of the
embryogénieor fetal liver, rather than of the adult tissue. In
this case an ontogenetic repressor seems to be lost; (b)
cytoplasmic constituents of the tumor, some of which are
shared with the normal adult tissue of origin, e.g., prostatic
acid phosphatase, or are shared with fetal cells of the
corresponding tissue, e.g., fetal hemoglobin production in
acute childhood leukemia (?); (c) immunologically active
membrane or cytoplasmic tumor cell constituents which
produce antibody or cellular immune reactions in the host,
e.g., dermatomyositis, nephrosis, and ulcerative colitis; (d)
tumor-produced excesses of trophic hormones which in turn
produce overfunction of a target organ, whose products then
produce systemic effects, e.g., a thymoma secreting ACTH
which induces Cushing's syndrome.
The clinical manifestations seen ultimately involve overfunction or underfunction of certain organs that are affected
by these tumor-produced substances. Not all organs are
involved and, usually, malfunction of a single organ system
predominates clinically. The skin as an overreactive target
organ is represented by the occurrence of acanthosis
nigricans, and atrophie dysfunction is suggested by sclero
derma. The nervous system can be overstimulated, as
manifested by the mania and psychosis induced by some
cancers, principally of the lung. Underfunction of the
central nervous system appears to be involved in the
peripheral neuropathy and myasthenia-like syndromes ob
served with many cancers. Depression of the gustatory
functions of the brain or cranial nerves is apparently
involved in the loss of appetite and taste so common in
patients with advanced cancer and results in cachexia of an
extreme degree due to poor nutrition of organs not directly
involved by tumor. The kidney is an organ that can be
stimulated to produce angiotensin and hypertensin by
renin-producing tumors, and erythropoietin by cerebellar
tumors with resulting erythrocytosis. Lung tumors com
monly produce antidiuretic hormone, with resulting
Schwartz-Bartter syndrome. Renal function can deteriorate
AUGUST
because of the production by distant tumors of amyloid
(myeloma), excess uric acid (leukemia), or antigen-antibody
complexes (lymphoma, colon cancer). The bone matrix can
be stimulated to produce osteoid by the local action of
métastasesfrom mucus- and phosphatase-secreting tumors,
with resulting increased density of bone cortex, crowding
out of marrow, and leukoerythroblastic anemia. Increased
cortical calcification of bone can also be induced by the
distant production of thyrocalcitonin by medullary parathy
roid cancer. Analogously, decreased bone matrix can be
induced by local tumor cell osteolysis, with resulting
hypercalcemia; this is the usual mechanism by which breast
cancer causes hypercalcemia. Parathormone-like
sub
stances produced by lung cancer can also produce hypercal
cemia by acting to dissolve bone. It is interesting to note
that although we have considered these syndromes as
manifestations of over- and underactivity of the bone
matrix, if one focuses on the action of the mediators at a
cellular level, both osteolysis and osteoblastosis may be
produced by a tumor mediator stimulating to physiological
overactivity the osteoclasts and the osteoblasts, respectively.
In general, there appear to be more syndromes recognized
in conjunction with mediators that stimulate organs to
overactivity than with mediators that are inhibitory. This
may be more apparent than real, since in many instances
tumor-induced underfunctions of a host organ would be
hard to detect clinically.
An example of tumor-induced hypofunction of bone
marrow is the pure red cell aplasia that is sometimes seen in
conjunction with thymomas. Here there is evidence of a
circulating immunoglobulin (1). Another, short-range effect
may be the inhibition of normal hematopoiesis by products
of nearby cells of myelogenous leukemia. Generally, how
ever, the bone marrow is stimulated, in the case of
erythropoietin-secreting tumors of kidney and ovary, to
produce red cells, as is true in the case of the hemolytic
anemias of breast cancer and lymphoma. The leukocytosis
seen in lung cancers may in time be found to be due to the
effect of a lung cancer-produced mediator.
When the immunological system is "depressed" by
tumors, the depression is usually either the result of local
replacement of the immune system by a tumor of those
organs, i.e., a lymphoma, or is due to circulating products
by a distant tumor. In the 1st instance, the effects must be
considered to be due to the short-range factors which permit
tumor cells to compete successfully with the normal cellular
inhabitants of node or spleen. In the 2nd case, immune
hypofunction is seen as depressed reactivity to recall and
neoantigens. This is commonly and erroneously attributed
to a generally depressed state of immune reactivity whereas,
in fact, it is usually due to selective impairment of immune
response by the production of excess amounts of tumorassociated tissue antigens. This is a long-range type of
effect. Overactivity of the immune system is much more
common, and is most frequently seen with epithelial can
cers, presumably secondary to their release during invasiveness of epithelial material into the mesenchymal immunocompetency system. The frequency of hyperergic
autoimmune syndromes seems proportional to the fre
quency of incidence of tumors—lung, colon, and breast
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T. C. Hall
being most frequent. The secondary target organs of
autoimmune damage include connective tissue (dermatomyositis), epithelia (ulcerative colitis and regional
enteritis), brain (cerebellar degeneration), and kidney
(glomerulopathic nephrosis).
The term "oncocognitive autoimmunity" has been coined
to suggest that many other "autoimmune" diseases may
occur as the unavoidable yet undesirable consequences of
immune recognition of small cancer foci and their successful
rejection by the host. Many tissue-specific antigenic mate
rials have been shown to be present in tumors derived from
those tissues (6), whereas no convincing evidence for human
tumor-specific antigens exists. Thus, immunological surveil
lance directed toward small foci of epithelial cancer could
well result in destructive lesions in the nearby normal tissue.
This is suggested by the high frequency of reactivity of
lymphocytes from patients with ulcerative colitis against
normal colon tissue. Other antigens shared between tumor
and normal epithelia have been described for nervous tissue
by Caspari and Field (4) and reactivity of multiple sclerosis
sera against human malignant tissues by Burns et al. (3).
Thus, cancer can be likened to infections or trauma which
disrupt the basement membrane and release antigenic
epithelial material into the mesenchyme, giving rise to, for
example, thyroiditis or sympathetic ophthalmitis, respec
tively. Since the initiation of tumor growth is not a clinically
noted event, a minute colonie tumor could go through many
years of antigenic warfare with the host, resulting in
prolonged ulcerative colitis before the tumor finally broke
through. Seen this way, the high incidence of autoimmune
diseases preceding cancer may have been the first evidence
of carcinomatous transformation.
The endocrine organs are the commonest sites of sympto
matic paraneoplastic functional alterations. In most in
stances, there are, clinically, overactivity syndromes. Thus,
sexual precocity can occur secondary to gonadotrophin
production by lung or liver cancer, and occasionally by
stimulation of the gonads by a direct metastasis.
Overfunction of the adrenal cortex secondary to ACTH
production by lungs, liver, prostate, and other tumors has
been described. Excess thyroid hormone secondary to TSH
production has been noted in patients with choriocarcinoma, but actual clinical hyperthyroidism is uncommon.
Pathogenesis
The histological basis for the paraneoplastic syndromes
seems based upon the fact that tumor cells are invasive, and
thus epithelial cancers carry usually forbidden cell compo
nents to beneath the basement membrane and into the
mesenchyme. When in the mesenchyme, the tumor vessel
displays a faulty and discontinuous endothelium which
permits ready access to the bloodstream of tumor-derived
steroids, amines, polypeptides, and antigens. This is com
pounded by the fact that many tumor daughter cells die
while in the mesenchyme and release more foreign mate
rials. Epithelial cells normally are prevented from entering
the mesenchyme by an impenetrable barrier; when they die
they are shed onto a surface and conveyed to the environ
ment, their antigens never being seen by the mesenchyme.
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Biochemically, many of the tumor-associated mediators
are comparable or identical to normal products of normal
tissues. Their production by tumors has been called "ec
topie," "inappropriate," and "derepressed." The first sug
gests that some materials produced are ectopie in place
(since, for example, a lung cell should not be making
ACTH) or are ectopie in time, since a liver cell should not
be making a-fetoglobulin after fetal life. From the point of
view of the partially differentiated lung or liver cell that is
producing the product, however, such functions may not
be ectopie to that cell; nevertheless, the lack of turnoff of
synthesis in the presence of lack of need for the product
suggests "irresponsible" production. Similarly, it may ap
pear inappropriate for a lung tumor cell to make serotonin,
but not if the cell is a Kulschitsky cell; it is still an irrespon
sive tumor, however. Derepressed synthesis has also been
used to describe the function of such cells. To date, return
of previous functions to a previously repressed mature cell
has not been shown to occur. A more reasonable hypothesis
to explain the syndromes that induce excess production
of a recognizable trophic product is to consider them
to result from tumefaction of those histological ele
ments which are usually in prolonged partial ontogenic
diapause. Repair after injury is always organ specific:
the damaged fingernail does not grow a liver back,
and liver regeneration does not result in bone marrow
islands in the portal spaces. There are, accordingly,
resting cells in each organ which are undifferentiated
enough to be able to respond to growth and repair stimuli,
but differentiated sufficiently to develop into functioning
mature cells of the organ in which they lie. These cells
should also be those within each tissue, with DNA most
easily available to the carcinogenic action of viruses,
radiation, and chemicals. However, in humans they are
much more like their normal tissue counterparts than they
are like the immature cancer cells of other tissues. This fact
was not properly appreciated by Greenstein (5), who
worked with a narrow special group of rodent tumors.
When such cells, which are reasonably well differentiated,
become transformed, they can express many normal tissue
functions but are nonresponsive to the negative physiologi
cal controls for rates of growth and secretory capacities.
Therefore, tumors that are uncontrolled for growth and
product synthesis result in local masses and distant endo
crine syndromes. In most instances of carcinogenesis,
the ease of transforming a more immature cell should be
greater, hence most cancers should arise in diapausal cells
too undifferentiated to make physiologically active pro
ducts, so that we find paraneoplastic endocrinopathics in
a minority of cancer patients. Although not differentiated
enough to produce a physiological product, most tumor
cells can be differentiated morphologically by tissue of
origin microscopically. It is interesting that the major dif
ferences between fully normal trophic hormones and those
produced by tumors are in the state of differentiation of
the hormones themselves. Thus, it appears that there are
many more cancer patients who have circulating proinsulin, big gastrin (5), or big ACTH than have tumors making
the final hormone. This suggests that the immature tumor
cell lacks the steps by which the final differentiated product
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Ectopie Synthesis and Paraneoplastic Syndromes
is made by cleaving the precursor polypeptide. In the case study of the progress and pitfalls involved in differentiation
of glycoprotein hormones such as the gonadotrophins, there of the somatic cell.
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and antigenicity may provide an important tool for the
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1974
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2091
Ectopic Synthesis and Paraneoplastic Syndromes
Thomas C. Hall
Cancer Res 1974;34:2088-2091.
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