CONGENITAL METASTASIZING ADRENAL CORTICAL CARCINOMA ASSOCIATED WITH CYTOMEGALY OF THE FETAL ADRENAL CORTEX
FRANK E. SHERMAN, M.D., LEE W. BASS, M.D., AND GEORGE H. FETTERMAN, M.D. Departments of Pathology and Pediatrics, Children’s Hospital of Pittsburgh and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
The finding of numbers of large anaplastic cells in the human fetal adrenal cortex has been reported by Craig and Landing.1 Potter2 described the same phenomenon, and termed it cytomegaly. Craig and Landing found that the anaplastic or cytomegalic cells were present in significant numbers in 37 cases in a series of 1039 adrenal glands. The glands they studied were from stillborn infants and infants up to 2 months of age. Potter observed the cytomegalic change in the fetal adrenal cortex of 10 fetuses and infants, and stated that its incidence was less than 1 per cent. In both reports, it was noted that the change might affect one or both adrenal glands.
Craig and Landing were convinced that the large atypical cells were capable of re- production, and that they did not represent a degenerative phenomenon. Further, these authors suggested that the anaplastic cells might in ”… a small percentage of cases … give rise to the masculinizing adrenal corti- cal carcinomas of childhood.”
This report deals with a newborn infant in whom such anaplastic cells were present in the fetal adrenal cortex proper and in several adrenal cortical nodules. Metastatic nodules of similar cells were present in choroid plexus, lungs, and pancreas.
The atypical cellular change in the fetal adrenal cortex, termed variously as ana- plasia or cytomegaly, will hereinafter in this report be referred to as cytomegaly.
REPORT OF CASE
The patient, a 5-day-old white girl, was delivered by elective low-forceps following an uneventful pregnancy. She was born 2
Dr. Sherman is Pathologist, Dr. Bass is Pediatrician, and Dr. Fetterman is Pathologist.
weeks before estimated date and weighed 3050 Gm. The only abnormality noted at birth was that her tongue was unusually large. She became cyanotic shortly after birth and was placed in an incubator into which oxygen was introduced at the rate of 4 1. per min. When 12 hr. of age, she was taken out of oxygen.
When 46 hr. old, she cried shrilly at in- tervals, and would become cyanotic after crying. Her fists were clenched, her body rigid. She was again placed in an atmosphere of oxygen. She became listless and unrespon- sive. Oxygen was provided continuously from this time on, but there was little or no improvement.
At 52 hr., she became apneic. Resuscita- tion was difficult, requiring 5 min. Her tongue was at this time pulled forward and secured to her lower lip with a towel clip. Cyanosis was practically constant following this episode, and she remained lethargic. There were several more episodes of apnea, and she displayed twitching at intervals. A first feeding was offered on the third day, but the infant was unable to swallow.
At 72 hr., a consultant noted moderate jaundice. Masses thought to represent kidneys were palpated in either flank. The liver was 1 cm. below the costal margin; the spleen was not palpable.
The infant was transferred to Children’s Hospital of Pittsburgh.
Physical examination on admission re- vealed a limp, slightly icteric, acutely ill infant. Her temperature was 95.8 F., her pulse rate 122 per min., and her respirations 11 per min. Respirations were regular. Her large tongue fell back in the pharynx. Scat- tered, moist, coarse rhonchi were heard over both lung fields. Cardiac auscultation was normal. The kidneys were palpable. Deep tendon reflexes were absent.
She was placed in an incubator with an
oxygen-intake of 8 l. per min. Penicillin and streptomycin were administered.
Shortly after the physical examination, the infant became apneic but then she im- proved for a few minutes following intra- muscular administration of caffeine and sodium benzoate. - She stopped breathing again, and an emergency tracheotomy was performed. She remained apneic following this procedure and was sustained by arti- ficial respirations for 1 hr. before spontane- ous respirations were resumed.
On the day following admission, feedings by polyethylene tube were begun, given at 3-hr. intervals. The infant received 6 feed- ings altogether, 3 of 5 per cent glucose water followed by 3 of artificial feeding mixture.
She breathed irregularly in an oxygen- rich atmosphere until her final spell of apnea on the fifth day of life, when she failed to respond to resuscitative measures and died.
A chest film was technically unsatisfac- tory. Hemoglobin on admission was 15 Gm. per 100 ml., and the erythrocyte count was 4,300,000 per cu. mm. The leukocyte count was 5000 per cu. mm., with 46 per cent poly- morphonuclear leukocytes, 8 per cent meta- myelocytes, and 46 per cent lymphocytes. There was 3+ albumin in the urine which also contained 3 to 4 red blood cells per high power field.
Autopsy Findings
The cause of death was anoxia, thought to have been initiated by airway obstruction owing to macroglossia. Related gross findings were cerebral softening and edema, and severe pulmonary hemorrhage. Other gross findings were renomegaly and pancreato- megaly.
Gross examination. The macroglossia noted clinically was readily verified (Fig. 1).
The brain weighed 340 Gm. It was con- siderably softer than that of the average newborn infant, both before and after fixation. The brain was also markedly con- gested.
The lungs together weighed 47 Gm. They were partially collapsed, firm, and generally dark purple. A few tan, air-containing areas were scattered throughout the pulmonary substance.
The pancreas was unusually large, weigh- ing 9 Gm. It was not otherwise remarkable.
Both kidneys were large with excessive fetal lobulation. The left kidney weighed 34 Gm., the right, 24 Gm.
The combined weight of the adrenal glands was 5.5 Gm., and they were soft and fragile. The cut surfaces presented coarse yellow and red-brown mottling. Generally the fetal cortex appeared pale yellow, but central portions of it were red-brown. Nodules of both fetal and adult cortex were observed (Fig. 2). A large extracapsular adenoma measuring 7 mm. in its greatest diameter was present at the periphery of one adrenal gland, lying adjacent to a large intracapsular nodule of similar size.
The clitoris was not enlarged.
Other organs and tissues were not grossly remarkable.
Microscopic examination. Adrenal glands. Both adrenal glands presented marked cytomegalie changes in the fetal cortex. These changes were also present in several of a number of small cortical nodules. The 2 largest nodules lay side by side, one within the adrenal capsule, the other completely extracapsular. These larger nodules shared in the cytomegalic alteration.
The cytomegalic change in the fetal cortex was striking and widespread (Fig. 3). At least one-fourth of the fetal cortex was composed of these atypical cells. The dis- tribution of the cytomegalic cells was irregular; they tended to be more numerous in the central portion of the glands, but groups of them extended into the adult layers of cortex. The cytomegalic cells varied in size; the largest ones measured as much as 100 to 130 u in diameter with nuclei measuring up to 40 u in diameter.
The nuclei were often round or oval but frequently assumed irregular and even bizarre shapes. Mitotic figures were not found. The nuclei were often densely hyperchromatic, but at times were vesicular. In a number of the cytomegalic cells, the nuclei contained single or multiple vacuoles (Figs. 4 and 5). The vacuoles often contained a thin-appearing eosinophilic material that seemed to lack the substance of true viral inclusion bodies. Nucleoli, often multiple,
.
1 1 11 121 ‘3’ ’ 4’ ‘5’ ‘6’ ‘7’ ‘8’ ‘9’ ‘10’ Centimeters
ICA
ECA
2
3
were identified. These were more readily seen in those nuclei containing less chromatin.
The cytoplasm of the cytomegalic cells was usually brightly eosinophilic, often foamy or granular and sometimes vacuo- lated.
The largest intracapsular nodule was completely bordered by a strip of adult cortex. Considerably over one-half of its substance consisted of fetal cortex present- ing marked cytomegalic change.
The large extracapsular adenoma was of special interest. Its composition was similar to that of the cytomegalic areas of fetal cortex proper, except that there were fewer of the typical cytomegalic cells (Figs. 6 and 7). The cytomegalic cells in this adenoma usually contained large dense hyperchro- matic nuclei and appeared in poorly defined groups, intermingled with groups of non- cytomegalic cells. The cytomegalic cells tended to have brightly eosinophilic cyto- plasm which along with the nuclear changes caused them to be conspicuous. In general, this adenoma was rimmed with smaller, less atypical appearing cells. No cells definitely identifiable as representative of zona glo- merulosa or fasciculata were present in this adenoma. The adenoma was bordered by a very thin capsule of its own.
Degenerative changes in the cells of the fetal cortex proper or in the cortical nodules were slight ..
Brain. Many scattered petechial hemor- rhages were present in cerebral white matter, basal ganglia, and brain stem. There were also edema and congestion. In a section including choroid plexus of fourth ventricle, 2 miniature metastatic nodules composed of cells resembling those in the fetal adrenal cortex were seen (Fig. 8). Each nodule measured considerably less than 1 mm. in diameter. The central cells in these nodular collections tended to be larger than those at
periphery. There was a scattering of cyto- megalic cells within each nodule.
Lungs. Four tiny metastatic nodules were found in 12 sections of lung. Each nodule was composed of cells which were unquestion- ably of adrenal origin, and included at least a few cells indistinguishable from the cytomegalic cells in the fetal adrenal cortex (Fig. 9). Smaller, more mature cells occupied the peripheral portions of each nodule. All 4 nodules were interstitial; 1 lay in a lym- phatic channel attached to the lining. There was patchy but severe and widespread hemorrhage in respiratory bronchioles and alveoli. Edema fluid was present in some alveoli. Squamae appeared in all sections. Small, patchy areas of atelectasis were noted.
Pancreas. Present in 2 sections were 8 nodules of tumor. These appeared to be of adrenal origin and included cytomegalic cells such as were seen in adrenal fetal cortex. The nodule that is illustrated con- tained many cytomegalic cells (Fig. 10). Terminal ducts were prominent, appearing to have proliferated, in some instances forming small nodules (Fig. 11). The reason for the increase in bulk of the pancreas was not readily apparent.
Kidneys. Sections of both kidneys pre- sented unusually wide subcapsular nephro- genic zones.
Tongue. Many scattered muscle fibers were swollen and hypertrophied, but at least 90 per cent of the fibers were of normal size.
Sections of other organs and tissues were not remarkable.
The pituitary had been contributed to a special study series and was unfortunately not available for microscopic examination.
Microscopic diagnosis. Carcinoma of fetal adrenal cortex; metastatic carcinoma in brain (choroid plexus), lungs, and pancreas; cytomegaly of the fetal adrenal cortex and
FIG. 3 (upper left). Photomicrograph to illustrate conspicuous cytomegaly of the fetal cortex of the adrenal gland. Large hyperchromatic nuclei may be noted. Hematoxylin and eosin. X 140. FIG. 4 (upper right). Photomicrograph of a portion of the fetal cortex of the adrenal gland in a region of cytomegaly. A single vacuole may be noted in the large hyperchromatic nucleus near the center of the field. Hematoxylin and eosin. X 900.
FIG. 5 (lower left). Photomicrograph to illustrate large cytomegalic cells in the fetal cortex of the adrenal gland. The nucleus of one of the larger cells contains several vacuoles. Hematoxylin and eosin. × 900. FIG. 6 (lower right). Photomicrograph of a portion of the large extracapsular adenoma. Note the patchy distribution of the cytomegalic cells. Hematoxylin and eosin. X 140.
cortical adenoma; focal hyperplasia of small pancreatic ducts.
DISCUSSION
The cytomegaly found in the fetal adrenal cortex in the present case corresponded to that described by other authors.1, 2 The change was quite striking within the adrenals proper, but was also present in several cortical nodules, 2 of which lay out- side the adrenal capsule.
The nodules found in choroid plexus, lungs, and pancreas were unmistakably of adrenal origin. Each of them contained at least a few cytomegalic cells. These nodules qualified as metastases on several counts. The position of the nodules in choroid plexus and in a pulmonary lymphatic channel conformed to this concept. The attachment
of the nodules to adjacent tissue, demon- strable in several instances, discounted the possibility of traumatic dissemination or of artifact. The histologic resemblance of the nodules to the cytomegalic portions of adrenal and the large extracapsular adenoma was striking. The small masses of tissue resembling fetal adrenal cortex which Potter3 has found in infant lungs do not seem to represent a comparable situation. In Potter’s material no cytomegalic changes were described, and there was no mention of ectopic adrenal tissue in other organs.
It seems likely that the metastases in brain, lung, and pancreas arose from the large extracapsular cortical adrenal ade- noma. We think it less probable that the metastases might have arisen directly from cytomegalie cells in the adrenal proper. We
FIG. 7 (upper left). High-power photomicrograph of a portion of the extracapsular adenoma illus- trated in Figure 6. Several of the cytomegalic cells contained large dense hyperchromatic nuclei. Hema- toxylin and eosin. X 280.
FIG. 8 (upper right). Photomicrograph of one of the metastatic nodules in the choroid plexus. Hema- toxylin and eosin. X 140.
FIG. 9 (lower left). Photomicrograph of one of the metastatic nodules in the interstitial tissue of the lung. Hematoxylin and eosin. X 140.
FIG. 10 (lower right). Photomicrograph of a metastatic nodule in the pancreas. Many of the cells were cytomegalic. Hematoxylin and eosin. × 280.
would suggest, however, that the large adenoma, that we regard as the primary tumor, is itself directly related to the cytomegaly of fetal adrenal cortex, probably having arisen by proliferation of such cytomegalic cells.
The train of events, as reconstructed in this case, appears to support the contention of Craig and Landing that the cytomegalic cells of the fetal adrenal cortex may upon occasion be precursors of adrenal cortical carcinomas of early life.
We are tempted to speculate concerning the possibility that the visceromegaly in this case was related to adrenal hormonal activity. The possibility exists, although we know of no secretion of the adrenal cortex which has been proven to act in this fashion.
SUMMARY
1. A case of metastasizing adrenal cortical carcinoma is reported in a 5-day-old infant in whom there was also extensive cytomegaly of the fetal adrenal cortex.
2. The findings in this case may supply an important link in the pathogenesis or biologic progression of adrenal cortical carcinomas of infancy and childhood.
3. Some support is furnished for the theory of Craig and Landing regarding the oncogenic potential of the cytomegalic cells of the fetal adrenal cortex.
SUMMARIO IN INTERLINGUA
1. Es reportate un caso de carcinoma adreno-cortical a tendentia metastatic, oc- currente in un infante de 5 dies de etate qui etiam exhibiva extense cytomegalia del fetal cortice adrenal.
2. Il es possible que le constationes in iste caso representa un phase importante in le pathogenese o le progression biologic de carcinomas adreno-cortical del infantia e pueritia.
3. Un certe supporto es fornite al theoria de Craig e Landing con respecto al potential oncogene del cellulas cytomegalic in le fetal cortice adrenal.
REFERENCES
1. CRAIG, J. M., AND LANDING, B. H .: Anaplastic cells of fetal adrenal cortex. Am. J. Clin. Path., 21: 940-949, 1951.
2. POTTER, E. L .: Pathology of the Fetus and the Newborn. Chicago: Year Book Publishers, Inc., 1952, p. 284.
3. POTTER, E. L .: Pathology of the Fetus and the Newborn. Chicago: Year Book Publishers, Inc., 1952, p. 267.
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 6, 2016