ECTOPIC HORMONE SYNDROMES ASSOCIATED WITH TUMORS IN CHILDHOOD

(1)

ECTOPIC

HORMONE

SYNDROMES

ASSOCIATED

WITH

TUMORS

IN CHILDHOOD

Gilbert S. Omenn, M.D.

Division of Medical Genetics, University of Washington, Seattle, Washington

Abbreviations

ACTH

: adrenocorticotrophic

hormone

ADH: antidiuretic hormone

DNA: deoxyribonucleic acid

ESF:

erythropoiesis-stimulating factor

FSH:

follicle-stimulating

hormone

ICSH:

interstitial

cell.stimulating

hormone

ILA:

insulin-like

activity LH:

luteinizing

hormone

-MSH:

beta-melanocyte

stimulating

hormone

PTH: parathyroid hormone

TSH: thyrotropin

I

T is vell known that tumors arising in

pi-tuitary, parathyroid, thyroid, adrenal,

gonadal, or pancreatic tissue may produce

excessive amounts of the hormone usually

made in that gland. However, in addition,

tumors arising in nonendocrine tissues

have secreted substances with potent

hor-monal activity, and certain tumors of one

endocrine gland have produced the

hor-mone of a different gland. This

phenome-non, “ectopic hormone production by

tu-mors,” has been demonstrated in hundreds

of tumors, and the tumor substances appear

to be physiologically and immunologically

identical to the corresponding hormone

normally produced in the appropriate

endo-crine

Ectopic hormone syndromes have

three-fold clinica value:

(

1

) these

syndromes

can serve as diagnostic clues to the

pres-ence of unsuspected malignancy;

(

2

)

cor-rection of the metabolic effects of hormone

excess in a patient with known cancer may

produce dramatic clinical improvement and

may permit resection of a tumor whose

sys-temic effects otherwise seem to indicate

metastatic spread; and

(

3

) measurement

of

the ectopic hormone or its effects may be

useful in evaluating therapy and in

detect-ing recurrence.

With the decline of mortality from acute

infectious diseases in this country, cancer

has become a leading cause of death in

children. Reports of probable ectopic

hor-mone syndromes in patients under age 20

are reviewed here with the expectation that

use of appropriate diagnostic tests will

re-veal many more cases and be helpful in the

care of some children with tumors.

ECTOPIC ACTH AND

CUSHING’S SYNDROME

Leyton3’4 deserves the credit for

postulat-ing that a nonpituitary, nonadrenocortical

tumor could duplicate Cushing’s syndrome

by

production of an adrenocorticotrophic

substance. In 1927, he studied an

11-year-old boy with the syndrome of “diabetes of

bearded women”

(

Cushing’s syndrome).

The boy developed abdominal

protuber-ance and glycosuria shortly after a normal

examination at the time of an

appendec-tomy. His facial appearance changed

dras-tically within 3 weeks, due to hirsuteness

and fat deposition. The differential

diagno-sis was presumed to lie between primary

pituitary and primary adrenal disease. At

autopsy, however, bilateral adrenal

hyper-plasia was found in association with an

oat-cell carcinoma of the thvmus. The pituitary

gland was serially sectioned and stained for

basophils and was normal.

(Received October 9; accepted for publication November 4, 1970.)

Supported by National Institute of Child Health and Human Development ( 5 F03 HD43122-02). ADDRESS FOR REPRINTS: Division of Medical Genetics, Departments of Medicine and Genetics,

University of Washington, Seattle, Washington 98105

(2)

Physical

Signs of . liP Case Year Sex, .lye

Syndrome

.4CT!! .ldrenal Pituitary Assay

(ilyco- Ilyper- Basophils of

suria plasia Tumor

. Refer-Tumor Pal/ow-up

ence

Died ( inn) Well (6 mu) after

re-section

Died (1yr)

Died Well (10 mo)

Died

Died Well (I yr)

Died

I)ied (18 mo);

palhia-tion with#{236}

mctyra-pone 3 6 7 8 9 10 10 11 12

614 ECTOPIC HORMONE SYNDROMES

TABLE I

Ecropic ACTH SYNDROMD IN CHILDREN

I 1931 M, 11

l94 F, 8/li

1 1949 M, 14

4 1056 F, 10

1; 1961 F, 1 l/

6 1965 ChilI

7 1965 infant

S 1967 M,22’i

9 1967 M. I 6’l

10 1969 ‘Small Child’ II 1909 M, 16

+ No + + Normal

+ + + ..

± + + + Normal

+ + + + Normal

+ + + ..

± No No . . ..

± ± + + Normal

+ .. .. ..

± .. + +

No CA thymes No Chromaffinoma

(pheochromocytoma) No Sympathicoblastoma No Alveolar CA thymes

No Renal

ganghioneuro-blastoma

+ “Liver”

+ Ganghioma No l8let Cell CA of

pancreas

. . Adrenal neurobla.stoma

+ Adrenal carcinoma

+ Anaplastic CA (lung)

By comparing four pairs of age-matched

patients, Leyton’ emphasized that the

phys-ical and metabolic effects of adrenal

hyper-plasia were indistinguishable whether the

adrenal were stimulated by the pituitary in

Gushing’s “basophilism” or by another

mechanism when the source was an oat-cell

carcinoma of the thymus

( three

cases ) or

the lung.5

There have been at least 11 cases of

full-blown Cushing’s syndrome due to probable

ectopic production of ACTh by tumors in

childhood

(

Table I

)

. Completely

charac-terized cases of ectopic ACTH syndrome

have l)ilateral adrenal hyperplasia, normal

pituitary basophils, positive assay for

ACTH

in the tumor, and failure of

suppres-sion of elevated plasma ACTH by

dexa-methasone.1

ACTH

has been

demonstrated

immunologically in four of the tumors in

childhood

( Cases

6, 7, 10, and 11

)

. The

tu-mor of Case 9 gave a negative assay after

being stored frozen for 5 years, and the other

tumors were not assayed. In several of these

cases the possibility of a concomitant

pitu-itary adenoma was not excluded, of course.

Nevertheless, good clinical evidence for the

syndrome is ol)tained when successful

resec-tion of the tumor corrects the signs of

Cush-ing’s syndrome, as in 3 of these 11 cases

(

Table I, Cases 2, 5, and 8). In addition,

effective palliation was achieved with

met-yrapone in Case 11, transforming a

mori-bund, edematous, hypokalemic youngster

into a relatively healthy schoolboy for 18

months.1 These tumors were examined

his-tologically to rule out the possibility of

adre-nat cortical cell rests, which would

pro-duce glucocorticoids and be associated with

adrenal hypoplasia.

A

rare example,

pre-senting as a mass in the liver, was reported

in 1952,13 and a similar case was seen in 1963

by Dr. David \V. Smith

( personal

commu-nication).

In adults, more than 100 tumors have

been demonstrated by radioimmunoassay

or bioassay to contain an ACTH-like

sub-stance.1 The tumor substance behaves

iden-tically with pituitary ACTH in a great

many physical, chemical, immunological,

and biological tests,1#{176}and pituitary ACTH content is decreased, indicating suppression

by high plasma cortisol. The majority of

these tumors in adults have been oat-cell

bronchogenic carcinoma, a very uncommon

tumor in childhood.1 Other tumors

fre-quently associated with ectopic ACTH

pro-duction in adults, however, are oat-cell

car-cinoma of the thymus, islet-cell and acinar

carcinoma of the pancreas, medullary

carcinoma of the thyroid, bronchial

(3)

carcinoma,1”0 similar types of neoplasms to

those responsible for the ectopic ACTH

syndrome in children (Table I).

On the basis

of experiences

with

adults,

it

is likely that many other cases go

unrecog-nized in children. The typical physical

fea-tures of Cushing’s syndrome-moon facies,

obesity, edema, osteoporosis, striae, and

hy-perpigmentation-may not have time to

de-velop, if the underlying malignant disease

progresses rapidly. Ectopic ACTH

produc-tion has been suspected in a majority of the

adult cases only because of the presence of

hyperglycemia or hypokalemic alkalosis, the

metabolic effects of hypercortisolism.1

Burkinshaw, et al.h1 raised the possibility

that anabolic effects of rapid growth might

prevent development of hypokalemia in

young children. However, Cases 4 and 9

( Table

I ) had

striking

hypokalemia,

as do

many infants and children with Cushing’s

syndrome of primary pituitary or adrenal

516

ECTOPIC GONADOTROPIN AND

PRECOCIOUS PUBERTY

“True precocious puberty” refers to

in-crease in size of the gonads and the

appear-ance of secondary sexual characteristics

be-fore age 10 in boys and before age 83 in

girls.17 The causes1#{176}include a variety of

en-docrine,

cerebral,

and

idiopathic

syn-dronles, presumably leading to premature

secretion of pituitary gonadotropins.

Gona-dotropins have been produced ectopically

in nonpituitary, nonpiacental tumors,

in-cluding nine cases of hepatoblastoma and

four cases of trophoblast-like tumors in

pa-tients under age 20

( Table

II )

. Stimulation

of testicular interstitial cells was found

his-tologically in every case and serves to

dis-tinguish gonadotropin-induced precocious

puberty from pseudoprecocity secondary to

a virilizing lesion of the adrenal or gonad.

Assays for gonadotropins in serum, urine, or

tumor extracts were positive whenever

technically adequate preparations were

used

( Table

II )

. Attempts to characterize

the

tumor gonadotropin suggest similarity

to LH

( ICSH

) or possibly

chorionic

gona-dotropin (which is closely related to LH in

biological and immunological tests

)

, rather

than

to

FSH.25’2#{176}

The

testicular

biopsies

support the laboratory conclusion, since

there has been no FSH effect on the

tu-bules. Since LH alone will have no obvious

effect in girls, it is not surprising that all of the cases of ectopic gonadotropin-induced

precocity have occurred in boys.

Gonadotropin production can be a useful

TABLE II

MALE ISO-SEXUAL PRECOCITY Faon EcTopIc GONADOTIIOPINS

.

Leydig Gonadotropins

Case I ear Age Bone

Age

Cell

Ilyper-.

pla.na

Serum

or

Lirine Tumor

Tumor oiiow-up,

Refer-ence

1 195 I 4/1c2 3 + -. .. 1-lepatoblastoina Died (8 1110) 18

2 1959 8 .. + + + Hepatoma Died (14 mo) 19

3 1960 2 6/142 3 6/12 ₊ ₊ ₊ Ilepatoblastoma Died (9 1110) 20

4 1963 ‘3 7 + + .. Hepatoblastoma Died /17 uso) 21

5 1963 2 6/12 6 + + .. Hepatoblastoma Died (20 mo) 22

6 1964 <8 .. + + .. ilepatoblastoma .. 23

7 1966 4 .. .. + .- Hepatoblastoma .. 24

8 1968 3 4 + + + Ilepatoblastoma Died (1 yr) 25

9 1969 ‘2 1/2 .. + + + Hepatoblastoma .. 26

10 1945 15 .. + + + Intracranial chorioepithelioina Died 27

11 1956 2 .. + + .. Pre-sacral teratoma Well (8 yr) 28

12 1961 7 .. + + + Chorioepithelioma Alive (3 mo) 29

(4)

marker for both diagnosis and follow-up.

Since hepatoblastomas and hepatomas are

very commonly fatal, Liddle1 has

sug-gested that methotrexate, so remarkably

successful in chemotherapy of metastatic

choriocarcinoma, be tried in patients with

gonadotropin-producing hepatic tumors. In

fact, Hung, et al.22 reported in 1963 that

their patient no longer produced

gonado-tropin after a course of methotrexate.

Al-though their patient succumbed to the

tu-mor, he had a prolonged survival

( Case

4,

Table II ). It is possible that the tumor was

functionally heterogeneous

( even

if not

de-monstrably so histologically) and that

go-nadotropin-producing cells were eliminated

by this specific therapy. Three other clues

to diagnosis of hepatoblastomas and

hepa-tomas in childhood also should be noted:

(

1

) hemihypertrophy

has

been

associated

with hepatoblastomas in five cases;35 (2)

cystathioninuria was found in seven of ten

cases of primary liver cancer;31 and

(

3

) a

fetal serum protein, alpha fetoprotein, is

produced by about half of the cases of

hep-atoma ill this country and a higher

per-centage in Africa.32

Gonadotropin production may serve as a

marker of recurrence after successful tumor

tlierap, as well. In Case 11 (Table II),

tu-mor recurrence was marked by recurrence

of positive assay for urinary gonadotropin;

irradiation controlled the tumor again.

Specific assay for gonadotropin in tumor

cx-tracts also permitted precise understanding

of the mechanism of precocious puberty in

Cases 10 and 12. Because of their location

in proximity to the posterior hypothalamus,

where many tumors seem to trigger

preco-ciotIs puberty by mechanical effects,1#{176}

cc-topic gonadotropin production would not

have been suspected, except that the

tu-mors had chorioepithelial histology. Case

13 illustrates an important physiological

difference in the effects of excessive

circu-lating gonadotropins before and after

pu-hertv. Prepubertal boys had greatly

increased plasma testosterone, but

post-pu-bertal males have normal testosterone and

androstenedione levels for their age,

de-spite further Leydig cell hyperplasia.3#{176} In

addition, fluoxymesterone, which

sup-presses pituitary LH secretion, causes a

de-crease in plasma testosterone in these older

patients.3#{176} Thus, adult men with

gonadotro-pin-producing bronchogenic carcinoma or

choriocarcinoma

do not show

enhanced

vir-ilization.

To distinguish

pituitary

from

tu-mor gonadotropin, a short course of high

doses of estrogen may be given : ectopic

go-nadotropin will not decrease in serum or

urine, while pituitary secretion will be

feed-backsuppressed.1 This test is analogous to

the dexamethasone suppression test for

ACTH.

HYPOGLYCEMIA ASSOCIATED

WITH TUMORS

Nine cases of hypoglycemia have been

associated with massive, non-islet-cell,

ab-dominal tumors in children

(

Table III).

These patients met Whipple’s triad of

crite-na for diagnosis of organic hypoglycemia:

(

1

) symptoms

of hypoglycemia

in the

fast-ing state; (2) blood glucose less than 50 mg

/100 ml during the attack; and

(

3) relief

of symptoms in response to intravenous

ad-ministration of glucose as 50% dextrose.

Usu-ally the blood glucose falls slowly, and the

hypoglycemia is protracted. The major

ef-fects are headache, diminished visual acuity,

confusion, and various neurologic and

be-havioral signs. By contrast, reactive

hypo-glycemia tends to be more rapid in onset and

short-lived in duration; its major symptoms

of sweating, tachycardia, and hunger reflect

the compensatory hyperglycemic

media-nisms. All of the patients who survived

oper-ation

( Table

III )

obtained

relief

from

hypoglycemia with partial or complete

re-section of the tumor; four of the nine had

extended survival in relatively good health.

In adults,

more

than

200 abdominal and

thoracic tumors have been associated with

hypoglycemia.1’33 In a review of 100

six were adrenal carcinomas, 21 were

primary hepatic carcinomas, and 64 were

various large mesenchymal

tumors-fibro-sarcomas, mesotheliomas, neurofibromas,

(5)

Case J’ear Sex, lye

Ilypo-ylycemic

Attacks

Fis1iny Blood Sugar

(mg/100 ml)

Tumor

11,_if serum1’ I:, mar

.

Follow-up

Well (S I, 2 yrs post-np)

itcJ’t- -ences

33 1 1943 1.’, 19 + 20 Uterine myosarconia

2 1948 F. 14 + 1.5 Adrenocorthal (‘A

(2,70 gni)

.. l)ied (3 nm) 34

3 11)55 F, 16 + . . Fibrosareoma .. Well for 3 years. Recurrence: lie,!

(5yrs)

35

4 1959 F, 17 + 30 Retroperitoneal liemangiopericytoma

.. Vell for several years. Itecurrerice: lied (10 yrs)

36

5 1964 i\l, 5 + 27 Wilms’ Tumor (80 gin) (Left kidney)

. . Vell (1 yr post-op) 37

6 1966 Sl, Newborn + 18 Congenital Neuroblastoma +/ - l)ied (it) days) 18

7 1966 :i, 14 + 30 Embryonal retroperitoneal rhabdomyosarcoma

-.“ I)ied (1 yr); IV glucose reversed coma and liemiplegia

39

8 1968 F, 19 Chronic effects

31 Retroperitoneal Reticulum-cell sarcoma

-,‘ - Died (4 inn) 40

9 1968 M, 14 + 313 Abdominal lyusphosarcoma -f- Died (at operation) 40

*Symptoms reversed by intravenous glucose.

t II. ‘lnsuliri-like activity, by bioassay.

TABLE III

iIYP()GIY(EMI A ASSO(’IAT ED WITH TIMOIIS I N (‘IlIlnItEN

lymphosarcomas. The tumors averaged

more than 2,000 gm in weight. It is clear

that the types of tumors occurring in the

childhood cases are similar.

Unlike tumor production of ACTH,

gona-dotropins, parathyroid hormone,

erythro-poietin, or thyrotropin, the mechanism of

tumor-associated hypoglycemia remains a

perplexing issue. Only rarely has insulin

been detectable by immunoassay in the

tu-mors, though a number of tumor extracts

have had “insulin-like activity” in the rat

diaphragm or epididymal fat pad

bioas-says.23 Some of the very large tumors,

espe-cially those which compromise capacity for

gluconeogenesis by involvement of the liver,

may cause hypoglycemia by consumption of

glucose.4#{176} Stimulation of pancreatic insulin

output is unlikely, both because of the

neg-ative immunoassays for insulin and because

of the uselessness of pancreatectomy.23 It is

possible that some tumors synthesize

prom-sulin, just as the beta cells of the pancreatic

islets do, but then lack the specific enzyme

to cleave this polypeptide to the two-chain

structure of insulin.41 Less specific cleavage

might yield an “insulin-like” product which

is biologically active, but which is negative

on immunoassay. Case 6 (Table III ) had a

pattern of blood glucose unresponsiveness

and decrease in free fatty acids after

epi-nephrine injection, which is compatible

with high circulating insulin-like activity,

despite a negative immunoassay.38 In sum,

although several mechanisms may be at play

with the various tumors, the tumor is

re-sponsible for the hypoglycemia and should

be the focus of therapy.

Hypoglycemia, especially in childhood,

can be elusive to diagnose,1#{176} and a high

in-dcx of suspicion is essential. Upon

encoun-tering children with large tumors of the

types listed in Table III, we should be alert

to the possibility that a variety of symptoms

may be due to tumor-associated

hypoglyce-mia.

ECTOPIC PARATHYROID HORMONE

AND HYPERCALCEMIA

Hypercalcemia can cause nausea,

vomit-ing, anorexia, constipation, polyuria, weight

loss, weakness, and mental confusion.

Sc-vere hypercalcemia may progress to oliguria,

azotemia, stupor, and coma.

Nonparathy-roid, malignant tumors may cause hypercal.

cemia by two mechanisms : (1) producing a

parathyroid-hormone-like substance, or (2)

(6)

618 ECTOPIC hORMONE SYNDROMES

at a rate sufficient to cause hypercalciuria

and hypercalcemia. So long as renal

func-tion is normal, the serum phosphorus will

be low in the first case ( ectopic parathyroid

hormone production ) and normal or high

in the second, permitting differential

diag-nosis.

In a recent review,42 73 cases in adults

met the criteria of hypercalcemia,

hypo-phosphatemia, normal parathyroid glands,

and lack of significant osseous metastases

for recognition as ectopic parathyroid

hor-mone syndrome. Fifteen of the tumors had

been shown by immunoassays to contain a

substance indistinguishable from the

hor-mone of the parathyroid glands. The

physi-ological effects and clinical complications of

the excessive levels of ectopic hormone

were identical to those associated with

pri-mary hyperparathyroidism, except for

con-comitant effects of the neoplasm itself.2

The major types of tumors were renal cell

carcinomas and squamous cell carcinomas

of the lung and of other tissues, plus several

cases of hepatic, pancreatic, and ovarian

carcinoma.

This syndrome was thought to be a rarity

in adults, and only a few cases appeared in

the literature between 1936 and 1956.

How-ever, the demonstration that resection of

the tumor ( nephrectomy, for example )

cor-rected the hypercalcemia’3 and the

realiza-tion that hypercalcemia is a clue to

under-lying resectable tumors have stimulated

internists to screen patients with symptoms

compatible with hypercalcemia for elevated

seruni calcium levels. More than 30 cases

have now been reported in which

parathy-roid hormone-producing nonparathyroid

tumors have been treated successfully.2

Thus far, only two cases have been

recog-nized in children.4’45 The first is one of the

best studied of all the cases, occurring in a

2-year-old boy with hepatoblastoma and

as-cites, hypercalcemia and

hypophosphate-mia. Tashjian’t was able to grow tumor

cells from the ascites fluid in tissue culture

and prove that the malignant cells were

producing immunologically active

para-thyroid hormone. The other patient was a

7-year-old boy with anaplastic carcinoma of

the testis, who had a plasma calcium of 12.8

mg/ 100 ml, low serum phosphorus, and

hy-percalciuria. Excessive parathyroid

hor-mone secretion was suspected because of

subperiosteal erosions at the metaphyses of

both femoral necks and at the distal ends of

the radial and ulnar bones, but tumor tissue

was not assayed for ectopic parathyroid

hormone and autopsy examination was not

permitted.

ERYTHROCYTOSIS

The renal erythropoiesis-stimulating

fac-tor (ESF ) may be secreted in excess in a

variety of cystic and neoplastic conditions

affecting the kidney. In addition, however,

10 to 20% of cerebellar hemangioblastomas

and some pheochromocytomas have

se-creted ESF ectopically, with resulting

dc-vation of the hematocrit.2 Since white cells

and platelets are normal, this moderate

ele-vation of the hematocrit is usually

asymp-tomatic, but may serve as a clue to the

tu-mor. The frequency of this phenomenon in

children is unknown, since many reports of

cerebellar hemangioblastomas and a report

of 100 cases of pheochromocytoma under

age 1646 did not mention hemoglobin levels.

Nevertheless, one carefully studied case47

was a 10-year-old boy with

pheochromocy-tomata, hematocrit 65%, hemoglobin 21 gin

I

100 ml, erythroid hyperplasia of the bone

marrow, plethora, and a blood pressure of

170/ 140. After resection of four tumor

mass-es, the blood pressure, catecholamine

ex-cretion and hematocrit were all normal.

ESF was demonstrated by bioassay in the

tumor extracts.

It is striking that the tumors which may

be associated with ESF production (

cere-bellar hemangioblastoma,

pheochromocy-toma, and renal cyst or carcinoma ) may all

occur in the same patient with the von

Hip-pel-Lindau syndrome, an autosomal

domi-nant condition.23

COMMENT

The cases summarized in this review

(7)

TABLE IV

Tt-loIt TYPFS ASSOCIATED WITH Ec’roeic IIOIIMONE SYNDROM ES

Syndrome Ectopic hormone Childhood ldults

Cushing’s AC’I’lI Neuroblastoma, pheo

Oat cell CA (tlsynius)

Islet cell CA (pancreas)

Oat cell (‘A (lung, thynius) Pancreas, thyroid,

pheochromocy-toina

Precocious Puherty Gonadotropin ilepatoblastoma

Chorionepithelioma

CA of lung

l-Iypoglyceiiiia ? (Insulin-like

activity ill some)

Iarge mesenchyinal tuntors Large niesenchyirsal tumors

Hepatoluas; adrenal CA

Hypercalcemia Parathormone (PTH)

Hepatoblastoma

Testicular CA

Renal Cell CA

Squamous cell CA (lung; many other sites)

Pancreatic, ovarian CA

Erythrocytosis Erythropoietin Pheochromocytoma Cerebellar henlallgioblastonla

Pheochromocytoma

Inappropriate

Antidiuresis

Arginine-Vasopressin (ADII)

(none) Oat cell CA (lung)

Duodenal, pancreatic (‘A

hormone syndromes in the diagnosis and

management of children with cancer. They

also add a significant dimension to the

dif-ferential diagnosis of endocrine disorders,

especially because of the urgency to

diag-nose tumors at an early stage.

Hypercorti-solism, hypercalcemia, and hypoglycemia

present many nonspecific symptoms, so

their recognition depends upon a high

in-dcx of suspicion.

Since the types of tumors associated with

each syndrome are similar in children and

adults ( Table

IV

), these unusual tumor

products may represent a general

phenome-non in neoplastic cells. The most likely

mechanism for cctopic hormone production

is activation ( derepression ) of the

struc-tural gene coding for the particular

hor-2 10,48 This genetic information is

present in the DNA of all cells, but

acti-vated during development only in the

par-ticular tissue which normally synthesizes

the hormone.

The hypothesis of genetic derepression

leads to three predictions : (1) The ectopic

hormone substance should have precisely

the same amino acid sequence as the

nor-mal hormone. The data are incomplete, for

normal as well as ectopic hormones, but the

results to date are consistent with identity

of ectopic and normal hormones. One

cx-ception seemed to be the production of

thy-rotropin-like activity by choriocarcinomas,

including one in an 18-year-old girl.9 This

substance differed from pituitary TSH, but

cross-reacted on immunoassay with a newly

recognized chorionic

Func-tioning choriocarcinomas can be expected

to produce this normal placental hormone.

(2) Polypeptide hormones should be

produced ectopically, since every cell has

the ribosomes and protein synthetic

en-zymes to translate the message from the

DNA code into the polypeptide hormone.

However, steroid and thyroid hormones,

which require whole sets of enzymes for

specialized biosynthetic pathways, should

not be made ectopically. So far, all cases of

excess gonadal or adrenal steroids have

been secondary to ectopic production of

go-nadotropin or ACTH, respectively ( Tables

(8)

(

3) Although certain hormones are

readily detected because of their systemic

clinical effects in low concentration, synthe.

sis of other polypeptides may be

dere-pressed similarly. In fact, such gene

prod-ucts have been detected antigenically or

enzymatically. Antigenic detection of

alpha-fetoprotein has become a useful diagnostic

test for hepatoma.3 Another embryonic

an-tigen has been associated with carcinoma of

the colon51 and could prove a useful

screen-ing test in such genetic conditions as

poly-posis coli and Gardner’s syndrome. Just as

certain placental hormones have been

pro-duced ectopically, some tumors have

syn-thesized a placental isoenzyme of alkaline

52 Tumors may have elevated

serum alkaline phosphatase without bone or

liver involvement if this ectopic isoenzyme

is produced. Ectopic production of a single

enzyme, tryptophan hydroxylase, can

ac-count for the atypical carcinoid syndrome

associated with certain tumors of the

fore-54 These patients have vivid, red,

patchy flushing rather than the violaceous,

cyanotic flush of the typical carcinoid

syn-drome. Only 5-hydroxytryptophan is made

by these tumors, without being converted

to 5-hydroxytryptamine ( serotonin ) as in

typical carcinoids. Other polypeptide

hor-mones may be detected, also.48 Ectopic

an-tidiuretic hormone with a syndrome of

edema and hypoatremia, ectopic secretin

with watery diarrhea,56 and ectopic growth

hormone with acromegalic changes57 have

been noted in adults. 3-MSH has been

dem-onstrated in every tumor producing ACTH,

1,10,58 and corticotropin-releasing factor-like

peptides have been reported in one case.5#{176}

Also, asymptomatic patients with ectopic

somatomammotropin or placental lactogen

( including a 2-year-old girl)60 and

thyro-calcitonin6l have been found by screening vith specific radioimmunoassays.

In these

tumors,

the concentration

of

ec-topic hormone is much lower than in the

corresponding endocrine gland. Significant

amounts of hormone are produced because

of the greater mass of the tumor. It is not

clear whether all the tumor cells produce a

little hormone or whether only a few cells

produce hormone as efficiently as does the

normal endocrine tissue.

Immunofluores-cent staining of tumor sections with

hor-mone-specific antibody may allow

distinc-tion between these two possibilities.

The ectopic hormones associated with

tu-mors of particular tissues or with particular

types of tumors within a certain tissue#{176}2

in-dicate a nonrandom pattern of

derepres-sion. Such a nonrandom pattern could be

due to differing mechanisms of neoplastic

transformation or to developmental

rela-tionships between tissues that ectopically

produce the same hormones. The study of

ectopic tumor products not only may prove

useful in caring for children with tumors,

but also may yield insight into genetic

regu-latory mechanisms in mammalian cells.

SUMMARY

Ectopic production of hormones by

tu-mors can serve as a clue to diagnosis of the

tumor and as a focus for management of

the patient.

Impressive numbers of cases of

hypercor-tisolism, hypoglycemia, precocious puberty,

and hypercalcemia due to tumors of

nonen-docrine tissues have been reported in

chil-dren already, and it is likely that many

oth-ers go unrecognized.

The types of tumors and the effects of

cc-topic hormones in children are quite similar

to those in adults, though the tumors most

commonly associated reflect the relative

frequencies of those tumors in the different

age groups.

The unifying hypothesis of genetic

dere-pression accounts for the ectopic hormone

syndromes and predicts that additional

un-usual tumor products can be detected.

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1971;47;613

Pediatrics

Gilbert S. Omenn

CHILDHOOD

ECTOPIC HORMONE SYNDROMES ASSOCIATED WITH TUMORS IN

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