ADRENAL-CORTICAL CARCINOMA AND MELANOCARCINOMA IN A 5-YEAR-OLD NEGRO CHILD
JOHN B. POORE, M.D., * ALAN C. MERMANN, M.D., f AND JULIA S. YU, M.D.#
W E HAVE RECENTLY OBSERVED a 5-year-old Negro boy with an androgenic adrenal- cortical carcinoma and precocious puberty who developed a melanocarcinoma of his buc- cal mucosa and died as a result of its metas- tases. We believe that up to the present time no similar case has been reported. Among the unusual features of this case was an unexpected regression of the buccal-mucosal melanocarci- noma following hormone therapy.
CASE HISTORY
C. R., a 5-year-old Negro boy, was admitted to the Pediatric Service of Memorial Center on June 23, 1953. The patient complained chiefly of a lump in his left cheek and inability to walk. Prenatal and postnatal histories were negative. His early development seemed nor- mal until about the age of 6 months, when the parents first noted progressive enlargement of his penis and testes; by the age of 2 years he had developed a fine growth of pubic hair, and his voice deepened. When the child was about 2 years old the family physician referred him to Mt. Sinai Hospital in New York City. There these features were noted, and, in addition, a mass was palpated in the left upper quadrant of the abdomen. 17-Ketosteroid excretion was studied repeatedly and found to range from 91 to 104 mg. per twenty-four hours.
Late in May, 1951, an encapsulated tumor mass was removed from the left suprarenal area. On histological examination this proved to be an adrenal-cortical carcinoma (see Fig. 2).
From the Pathology Laboratories and the Pediatric Service, Memorial Center for Cancer and Allied Dis- eases, New York, New York.
The authors are indebted to Dr. William G. Bern- hard of the St. Barnabas Hospital of Newark, New Jersey, for use of histological material from the pri- mary melanocarcinoma and to the Department of Pathology of the Mt. Sinai Hospital, New York City, for use of histological material from the adrenal-corti- cal carcinoma.
Mention of this case appears in a footnote reference by Allen and Spitz,2 p. 156.
* Trainee of the National Cancer Institute. Present address: Department of Pathology, University of Vir- ginia Hospital, Charlottesville, Virginia.
+ Present address: 152 Broad Street, Guilford, Con- necticut.
# Present address: Children’s Memorial Hospital, Chicago, Illinois.
Received for publication, April 16, 1954.
Postoperative 17-ketosteroid excretion studies are not mentioned in the records available.
Within two months a pea-sized nodule was noticed in the patient’s left cheek. Little atten- tion was paid to this for more than a year, until the nodule became noticeably larger. On November 22, 1952, this lesion was excised at the Hospital of St. Barnabas for Women and Children in Newark, New Jersey. It was con- sidered to be a metastatic nodule of anaplastic adrenal-cortical carcinoma but was subse- quently shown to be a primary nonpigmented melanocarcinoma (see Fig. 3).
In April, 1953, the 17-ketosteroid-excretion level was reported as 5.4 mg. in twenty-four hours; the 11-oxysteroid excretion, as 0.8 mg. in twenty-four hours; and the total steroids, as 7.0 mg. in twenty-four hours. By June of 1953 a recurrent mass was noted in the left buccal mucosa, and the patient was referred to Me- morial Center.
Pertinent physical findings on admission in- cluded a 3-cm., hard, nontender, movable mass in the left cheek; an enlarged submandibular node; weakness and hypotonia of the lower extremities; temperature of 103.4º F .; evidence of weight loss; and a hemoglobin of 8.6 gm. The external genitalia appeared larger than average for the boy’s age group (Fig. 1). 17- Ketosteroid-excretion studies on admission were recorded as 1.02 mg. in twenty-four hours. Slides from the primary adrenal and buccal-mucosal tumors were reviewed in the Pathology Laboratories of Memorial Center; the adrenal tumor was confirmed as a cortical carcinoma and the buccal-mucosal tumor as a primary melanocarcinoma. Roentgenological examination of the chest revealed negative lung fields. Skeletal survey showed an esti- mated bone age of 7 years; in addition there were lytic lesions in the boares of T-10, L-4, and L-5. Aspiration biopsies proved that these areas contained metastatic melanocarcinoma.
In spite of irradiation therapy to the spine (3300 r), total sensory loss and motor paralysis below the hips developed, as well as loss of bladder and anal sphincter control. Plans to attempt surgical removal of the recurrent le- sion in the mouth were discarded when the bone metastases were found. The 3-cm. mouth lesion was therefore subjected to 3550 r of ir- radiation therapy from July 16 to July 29. No change in the size of the lesion was noted by
the time irradiation therapy was completed or for the subsequent three months. On August 24, the left submandibular node was excised. This was ultimately interpreted as metastatic melanocarcinoma. A trial of therapy with a purine analogue followed irradiation, with no palpable or roentgenological evidence of re- gression of any of the lesions. On November 3, the patient was placed on oral therapy with ethinyl estradiol.
In spite of all therapy, new metastatic le- sions appeared in the femora, humeri, ribs, scalp, and lungs. The liver became enlarged and nodular. The patient’s condition deterio- rated inexorably until death occurred on Janu- ary 10, 1953, his 199th hospital day. During his entire stay at Memorial Hospital, urinary 17-ketosteroid-excretion levels were within normal limits, none measuring higher than 2.3 mg. per twenty-four hours. At the time of death, the lesion in the left buccal mucosa, which had remained 3 cm. in diameter up until the time ethinyl estradiol therapy was instituted, was palpable only as an area of in- definite thickening in the soft tissues of the cheek, measuring about 1 cm. in diameter. Complete autopsy was performed.
PATHOLOGICAL FINDINGS
Surgical Specimens. ADRENAL TUMOR. Histo- logical examination of the surgical specimens removed from this boy leaves no room for doubt that two separate primary malignant neoplasms existed. Histological sections (Fig. 2) from the tumor removed from the left suprarenal area in 1951 showed typical adre- nal-cortical carcinoma of a low-grade malig- nancy. Large, irregularly shaped, roughly
polyhedral cells were arranged in broad sheets and in cordlike and alveolar groups, separated by thin strands of connective tissue bearing small blood vessels. These latter areas are par- ticularly reminiscent of the zona fasciculata of the normal adrenal cortex. The cells con- tained considerable pale-pink cytoplasm in which numerous vacuoles appeared. No pig- ment granules could be identified in hema- toxylin and eosin sections. The nuclei were predominantly centrally located, small, and round, with a distinct chromatin network and a single, usually eccentric nucleus. Occasional bizarre forms were seen with large club-shaped or oval hyperchromatic nuclei and double nucleoli. A few pyknotic nuclear forms were found, mitotic figures were rare, and very little stromal tissue was present.
MELANOCARCINOMA. Microscopic examina- tion of the tumor removed from the buccal mucosa in May of 1952 disclosed the character- istic features of a primary melanocarcinoma. The tumor was described grossly as being ulcerated over most of its surface, and this was borne out by the histological sections. At the edges of the ulcerated area (Fig. 3), however, foci of distinct malignant junctional change were present in the basal epithelial layers of the intact mucous membrane. The remainder of the tumor (Fig. 4) was composed of sheets of closely packed spindle-shaped cells growing into the soft tissue of the cheek. The nuclei were of uniform size and round or ovoid and contained from one to three light-purplish nucleoli of varying sizes. Mitotic figures were plentiful, large mononuclear bizarre forms were rare, and no pigment could be found in any portion of the tumor. Demonstration of melanin pigment by the DOPA reaction was not attempted. Arthur C. Allen, in the autopsy protocol, has said of this tumor “the cellularity and pattern of the primary melanocarcinoma is quite different from that of juvenile mela- nomas and in accord with the patterns seen in fatal melanocarcinomas in children by Dr. Spitz and myself.”
Autopsy Findings. At autopsy the body was that of an emaciated Negro male child who ap- peared to be about 5 years old. The genitalia were normal for his age; the penis measured 5.2 cm. in length and the testes were soft and measured 2.2 cm. in greatest dimensions. Sub- cutaneous tumor nodules, which measured as much as 5 cm. in diameter, were present under the skin of the scalp. Examination of the vis- cera revealed widespread metastatic disease,
the most striking accumulations of which oc- curred in the liver and in the lungs. The liver weighed 2310 gm. and practically filled the abdomen, elevating the diaphragm and crowd- ing the intestines into the pelvis below. Multi- ple, soft, grayish-white, well-demarcated tumor deposits, which measured from 1 to 13 cm. in diameter, occupied most of the parenchyma of the liver. Several of these showed central hem- orrhage and necrosis. The lungs weighed 265 gm. and 300 gm. and were likewise filled with round, grayish-white, well-defined tumor nod- ules that tended to bulge above the parenchy- ma of the cut surface. These measured from 1 to 2.3 cm. and appeared in all lobes and on pleural surfaces. The intervening lung paren- chyma was sparse but showed no evidence of consolidation. One 3-cm. metastatic nodule was growing from the myocardium of the right ventricle and bulged above epicardial surfaces. Other metastases were found in the right adre- nal gland, pancreas, thymus, peritoneal sur- faces, dura mater, lymph nodes in all areas, and marrow cavity of all bones examined. The body of T-10 was collapsed at the site of tumor metastasis, and the spinal cord was compressed at this level. A 1-cm. area of thickening in the left buccal mucosa was all that remained of the residual tumor at the site of the primary melanoma. Tumor could not be grossly iden- tified in what appeared to be dense fibrous tis- sue.
The left adrenal gland was missing, and no tumor was found in the scar tissue over the left kidney.
Histological examination of the lesions re- vealed them all to be malignant melanoma. No metastatic adrenal-cortical carcinoma could be found. The pattern seen in most sec- tions studied (Fig. 5) consisted of sheets of spindle-shaped melanoma cells without pig- ment, similar to the primary lesion. Some areas were composed of poorly defined nests of polygonal cells with large nuclei and scanty cytoplasm. Numerous mitoses occurred in all sections; rare large bizarre forms were present. Microscopic study of the thickened left buccal mucosa from the site of the primary melano- carcinoma (Fig. 6) showed a few scattered nests of spindle-shaped tumor cells embedded in pale-pink, almost anuclear, hyaline fibrous tis- sue. There was no evidence of residual junc- tional alteration of the surface epithelium. Tissue was saved for DOPA determination but was lost owing to a refrigeration failure before this could be done.
COMMENT
Multiple Primary Cancers. The case is un- usual for various reasons. First, it represents another example of two separate primary ma- lignant tumors occurring in one person-in this instance, a child. Numerous double pri- mary malignant lesions are documented in the literature and, in fact, are part of the experi- ence of many present-day pathologists. Few, however, have been recorded in children. At least five cases of double primary cancers of different organs have been observed in adults in the Pathology Laboratories of the Memo- rial Center during the past nine months. Per- haps the concept that the individual with can- cer in one site may develop a cancer elsewhere sooner than someone in the noncancerous population is not altogether inapt. It is not our purpose here, however, to belabor further this facet of the tumor problem.
Melanomas in Negroes. The occurrence of a malignant melanoma in a member of the col- ored race is less of a rarity than it was thought to be a decade ago. Earlier presentations of series of cases of melanocarcinoma in this country report a great preponderance of white subjects. Hewer, in 1935, studied Geschickter’s material at Johns Hopkins Hospital and stated that of 60,000 surgical specimens seen, 353 were melanomas and of these only ten were in Negroes. Six of 162 melanomas seen by Web- ster, Stevenson, and Stout were in Negroes. A more recent review of the literature by Morris and Horn in 1951 indicates that up to that time 439 cases of melanoma in Negroes had been recorded, 158 in the North American Negro, 280 in African Negroes, and one in a Parisian Negro. It is our impression, in accord with Morris and Horn, that as more statistics accumulate and are properly extrapolated to account for hospital-population differences, melanoma will not be found to occur signifi- cantly more frequently in white than in col- ored subjects.
Melanocarcinoma in Children. The prepu- bertal age group is very sparsely represented in the world literature dealing with malignant melanomas of skin and mucous membranes. Allen and Spitz, in recording five cases of melanocarcinoma in children from their ex- perience, have estimated the incidence of these tumors in children to be as low as 0.3 per cent of all melanocarcinomas. This is exclusive of ocular lesions and malignant blue nevi. Spitz, in 1948, first outlined the histological criteria
for differentiating the juvenile melanomas from melanocarcinoma. This contribution, which we regard as a significant milestone in the understanding of the nevus-melanoma problem, for the first time clearly separated the childhood melanomas that had a malig- nant appearance but a benign course from those rare instances in prepubertal subjects of melanocarcinoma fully capable of metastasiz- ing and terminating fatally. Our case shows none of the hallmarks of juvenile melanomas. Its histological patterns, the widespread lym- phatic and hematogenous metastases, and the course of the disease are fully in keeping with the findings of other observers, particularly the description by Allen and Spitz of their five cases.
Endocrine Factors. Finally, this case seems to be unique, up to the time of its reporting, with regard to the endocrine factors involved. We refer to the development of a malignant melanoma in a child of prepubertal age, who, at the same time was under the influence of an androgenic adrenal-cortical carcinoma. The repeated finding of elevated urinary 17-keto- steroids in the presence of obvious precocious puberty linked with the finding of primary melanocarcinoma within two months of the removal of the adrenal tumor clearly estab- lished this temporal relationship. Whether this is a result of pure chance or is a causal relationship is a matter that must await ac- cumulation of more material before final reso- lution. We prefer to consider this the first ex- ample of a situation that some observers of the melanoma problem have been expecting might occur. The background for the concept that there may be a hormonal factor in the genesis or activation of some malignant melanomas includes several facets. Recent analyses of the life history of nevi picture a maturing and ageing process in which junctional nevi pre- dominate in children, compound nevi are more common in adolescents and young adults, and intradermal lesions make up most of the nevi seen in older subjects. Significant alterations have been observed in nevi at the time of puberty and of pregnancy, both peri- ods accompanied by measurable increase in hormone activity. Pack has noted accelerated growth and dissemination of melanomas at the time of puberty and has postulated that an endocrine stimulus might have been respon- sible for their increased virulence. In a more recent report covering 1190 cases of melanoma, Pack, Gerber, and Scharnagel found no signifi-
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cant difference in five-year survival between pubertal and adult groups. Three of Mc- Whorter and Woolner’s cases occurred in younger children who died of their disease rather promptly, although a fourth, whose tu- mor appeared at the age of 10, did not die of metastases until the age of 16. In this regard Spitz has stated that “There is a precipitous rise in the capacity of melanomas to metasta- size after puberty.” Pack and Scharnagel felt that hormonal influences may have had some part in the genesis or activation of melanomas in thirty-two women whose tumors were asso- ciated with pregnancy, but incomplete follow- ups leave inconclusive a final interpretation of the behavior of this group compared with other melanomas.
Cases of melanocarcinoma in newborn in- fants (one of Russo’s; the case of Dargeon, Eversole, and Del Duca; and that of Sweet and Connerty) suggest that, owing to maternal and placental influences, the more adult endocrine status of this age group may have played a part in the virulence of their disease. In the case reported by Dargeon et al., the disease was metastatic to the infant through the pla- centa, the mother dying within a few days after delivery as a result of melanoma metas- tases.
A fertile field for the study of this concept is afforded the modern observer by the increas- ing number of patients at present receiving steroid-hormone therapy for numerous other conditions. Carefully controlled observations of new and old nevi in patients treated with ACTH and cortisone might contribute con- crete information to what is now a matter of strong but unproved suspicion. Goldman and Richfield, in 1951, reported that five of forty- one patients on ACTH were observed to de- velop “new junctional nevi” that did not regress when therapy was stopped. More such work and larger series of cases obviously must be presented before conclusive deductions can be drawn. In none of the cases of melanocarci- noma in children previously reported has there been evidence presented of biochemical hormone imbalance. Some have shown overt changes associated with the onset of puberty; three cases could be considered as being under the influence of maternal endocrine effects.
Concerning therapy of melanomas along hormonal lines, it has been stated by Pack12 that “the problems or factors influential in the induction of tumors is a thing apart from the problems of their continued growth.” So far
this has been the general finding of those who have treated melanomas, and other malignant tumors, by introducing hormones thought to be antagonistic or by ablation of hormone- producing organs. Castration, adrenalectomy, and hypophysectomy, either singly, in combi- nation, or all three together, have not as yet been reported to produce consistently any sig- nificant alteration in the course of the malig- nant disease. The rare instances in which some apparent therapeutic effect has been achieved by these means stimulates renewed efforts to understand the relationship of hormone stimuli to the origin and growth maintenance of neoplasms. We cite pertinent examples.
Wigby and Metz, in 1939, observed com- plete regression of a melanoma of the cheek and its subcutaneous and pulmonary metas- tases in a 43-year-old man following irradia- tion of the pituitary. The case was reported only eight months after treatment and so can- not be considered a cure; the same workers subsequently treated four more cases of mela- nocarcinoma in the same fashion and noted no effect on the course of the disease in any of the four. It may be significant that their first case was thought to have hematogenous metastases only, while their other four had evidence of spread by lymphatic routes. Shimkin et al., in 1952, reported the case of a 32-year-old man with metastatic melanoma who was subjected to hypophysectomy (99 per cent) and who at autopsy sixty-seven days later was found to have unusual fibrosis and necrosis of liver and spleen metastases, though there was no appar- ent effect on the rate of growth of pulmonary and brain metastases.
Our case presents a similar tantalizing but inconclusive finding. The melanoma recurrent at the site of the primary tumor shrank from a 3-cm. nodule to an elusive 1-cm. area of thickening in the buccal mucosa while being treated with ethinyl estradiol. Histologically it showed marked fibrosis without evidence of radiation reaction and with small, widely spaced nests of small, viable, orderly appear- ing tumor cells in which no mitoses could be found. The area involved had early been in a field of radiation therapy but did not begin to regress until three months later after treat- ment with ethinyl estradiol was started. No other focus of tumor found at autopsy showed this change.
We want to repeat that we cannot prove that this regression was the result of hormone therapy; it is highly suggestive that ethinyl
estradiol might have been the factor involved and is of the same order of evidence as pre- sented for the two cases cited.
SUMMARY
1. A case combining an androgenic adrenal- cortical carcinoma and a melanocarcinoma of the buccal mucosa in a 5-year-old Negro boy is presented.
2. An unusual regression of tumor residual
at the primary site following endocrine ther- apy is described.
3. An endocrine stimulus to the genesis of this melanocarcinoma, which metastasized and terminated fatally, is suggested.
4. A carefully controlled study of the rela- tionship between endocrine factors and the natural history of nevi and melanomas is de- sirable in order to clarify the validity and scope of this concept with regard to the genesis of melanomas and possibly other neoplasms.
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