Feminizing Adreno-Cortical Carcinoma :
Report of a Case
A. H. SLAVOTINEK, University Department of Surgery, Royal Adelaide Hospital, Adelaide and R. G. EDWARDS,1 Institute of Medical and Veterinary Science, Adelaide
A case of feminizing adreno-cortical carcinoma is reported and features of these tumours are commented on. The differential diagnosis of gynecomastia and its investigation are discussed. The features of adrenal carcinoma are also discussed, the literature is reviewed and treatment is outlined.
REPORTS of feminizing adreno-cortical tumours are relatively rare; the population- frequency of these tumours is approximately 1 :5,000,000. Bittorf (1919) is reported to be the first to describe a case of gynecomastia in a 26-year-old male with a tumour of the adrenal cortex. Higgins et alii (1956) reviewed the existing literature and found 27 cases reported up to that date. Later collective reviews have also been made by Wallach et alii (1957), Stewart et alii (1964) and Gabrilove et alii (1965). The last-mentioned authors reviewed 52 cases and discussed their features in detail.
This case report was stimulated by the rela- tive scarcity of documented cases and the fact that this patient may be one of the oldest in age so far reported. To our knowledge only one other case has been reported in Australian literature (Ferrier et alii, 1960).
CASE REPORT
The patient, a 68-year-old farmer, was admitted to the Royal Adelaide Hospital on August 17, 1967. Six months prior to admission he had consulted his general practitioner because of bilateral gynæco- mastia; three months later his breasts became tender and nodular as well as swollen. On his admission to hospital there were no other symptoms suggestive of feminization. His strength and hair growth remained unchanged, nor did he notice any change in his voice, libido, size of genitalia or distribution of body hair. There was no history of œdema or acneiform eruptions. His alcohol consumption was only moderate, he had stopped smoking 16 years previously and he was not receiving any drug therapy.
’ Medical biochemist.
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There was no family history of gynæcomastia or any other endocrine disorder. He was married and potent, but had no offspring.
On examination the patient was a pleasant plethoric man, weighing 675 kg. The distribution of his body fat and hair was normal. His blood pressure was 180/100 mm. Hg but no other abnormality was detected in the cardiovascular or respiratory system. Both breasts showed a gross diffusely nodular enlargement (Figure 1). They were tender on
palpation, the areola were pink and there was no excessive prominence of Montgomery’s tubercles. No abnormal lymph-nodes were palpable in the axillæ or supraclavicular fossa. Both testes were soft but of normal size, and the prostate gland was normal to palpation. A mass could be readily pal- pated under the left costal margin. It was firm and smooth with a rounded edge and moved on respira- tion. The swelling, although bimanually palpable, was not characteristic of a renal or a splenic enlargement.
FEMINIZING ADRENAL CARCINOMA
The following preoperative investigations were performed. The erythrocyte sedimentation rate was 13 mm. in the first hour and 36 mm. in the second (Westergren). The hemoglobin value was 13.8 grammes per 100 ml. White cells were 8,800 per c.mm. with a normal distribution, and the blood group was () positive. The results of electrolyte determinations, liver function tests, electrocardiogram and chest X-ray examinations were all within normal limits. The bone texture in the radiological skeletal survey and the views of the pituitary fossa were normal. The glucose tolerance curve was mildly diabetic, but there was no glycosuria on routine ward testing of the urine. The chromosomal pattern of the polymorphonuclear leucocytes was that of a normal male. A plain skiagram of the abdomen revealed a space-occupying lesion under the left diaphragm, and an intravenous pyelogram confirmed that the mass was displacing the left kidney. Selec- tive renal angiography revealed a vascular retro- peritoneal tumour, 10 cm. in diameter, situated above the left kidney.
The hormonal studies of urine in this case are summarized in Table 1. Both preoperative and post- operative values are included for comparison.
A transient period of hypotension occurred about four hours postoperatively, which was initially treated by colloid replacement and then with intra- venous hydrocortisone. Further postoperative pro- gress was uneventful except for a brief period of pyrexia caused by postoperative atelectasis of the left lower lobe. Postoperative biochemical investigations were all within normal limits; the urinary steroids and œstrogens (Table I) had reverted to normal values by the fourteenth postoperative day. The breasts became less tender and were decreasing in size. The patient was discharged from hospital 18 days after operation, and when he was examined again four months later, his health was good, he had returned to work and his breasts had continued to decrease in size.
The histopathology (Figures 2 and 3) of the adrenal tumour was as follows.
The cut surface is golden brown in colour with large areas of hæmorrhage and necrosis. Several spherical tumours up to 1 cm. in diameter are present in the attached fatty tissue. The tumour Iras a fibrous tissue capsule of varying thickness,
| TABLE I | ||||
|---|---|---|---|---|
| Date | Urinary Volume (MI./24 hrs.) | 17-Ketosteroids (Mg./24 hrs.) | 17- Ketogenic Steroids (Mg./24 hrs.) | Œstrone (p.g./24 hrs.) |
| August, 1967 : | ||||
| 18/19 | 2,820 | 63 | 67 .2 | 357 |
| 19/20 | 2,205 | 63 .8 | 65 .9 | 296 |
| 20/2I | 2,635 | 56.3 | 73.7 | 360 |
| 21/22 | 2,330 | 61 .0 | 58 .4 | 330 |
| Operation August 22, 1967 | ||||
| September, 1967 : | ||||
| 3/ 4 | 1,580 | 7 .I | 1.6 | 2.6 |
| 4/ 5 | 2,215 | 7.5 | 10*0 | 3.7 |
| 5/ 6 | 1,900 | 7.0 | 7*5 | 3*2 |
| 6/ 7 | 1,820 | 5 .5 | 7.I | 3 .I |
| Normal values | 0.5-7 | 3:5-14.5 | 0-II | |
| Mean 3 | Mean 7 | Mean 5 *4 | ||
The preoperative urinary 17-ketosteroids, 17-keto- genic steroids and œstrone values were all markedly elevated; the urinary œstrone values were found to be 35 times greater than normal. Urinary preg- nanetriol and related steroids were also estimated and showed higher preoperative values. All hormonal valute levels showed a postoperative return towards normal. Fractionation of the urinary steroids in cases of adrenal carcinomata will be reported else- where.
A diagnosis of a feminizing tumour of the left adrenal cortex was made, and on August 22 the abdomen was explored. A firm encapsulated tumour of the left adrenal weighing 680 grammes was found, which was displacing the left kidney downwards. The right adrenal gland, liver and regional lymph-nodes were normal to inspection and palpation. Removal of the tumour was relatively easy except for the medial aspect, where it was tethered by tough fibrous adhesions and by its vascular pedicle. Testicular and breast biopsies were then performed.
beneath which the growth tends to retain the pattern of the zona glomerulosa in some areas. Elsewhere the pattern is very variable, many cells have abundant vacuolated lipoid-laden cytoplasm, and groups of cells with a very eosin- ophilic and often granular cytoplasm also occur. Much of the tumour consists of cells showing marked nuclear pleomorphism and hyper- chromasia. Giant bizarre nuclei and not infre- quent multinucleate cells are seen in such areas, but mitoses are not numerous. There is exten- sive necrosis and hæmorrhage throughout the tumour and the nodules in the attached fatty tissue show the features of a cortical adenoma, and while some are encapsulated, others are not so confined. No tumour has been demonstrated in blood vessels, but there is tumour invasion through the capsule into the adjacent fatty tissue, and the growth is considered to be malignant.
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The testicular biopsy shows seminiferous tubules of normal structure with evidence of spermatogenesis. There is no evidence of tes- ticular atrophy. Breast biopsy shows features of gynæcomastia.
COMMENT
In a recent publication, Hutter and Kayhoe (1966) reviewed 186 patients with carcinoma of the adrenal cortex. The overall population incidence was reported as two per million for all primary adreno-cortical carcinomas. Tumours manifesting themselves by producing feminizing features in males comprised 11% of the cases these authors reviewed.
Gabrilove et alii (1965) reviewed 52 cases of feminizing adrenocortical tumours, and found that gynecomastia was the presenting symptom in 98% of these. Approximately 50% had an associated palpable tumour, atrophy of the testes, or loss of libido, while pain at the
site of the tumour or in the breasts occurred in about 40% of the cases. Seventy-eight per cent. of the feminizing tumours were found to be malignant and 22% benign. The ages of patients varied considerably, ranging from five to 66 years, but the majority were between the
second and fifth decades. The tumours occurred in either adrenal with approximately equal frequency. The findings in the contralateral adrenal were included in 14 cases only ; bilateral involvement by tumour, metastasis or hyper- plasia was found in four of these. An interest- ing feature was the average length of time between the onset of symptoms and the diag- nosis, which was 31 months for a benign tumour and 22 months for patients with carcinoma. Sixty per cent. of cases were found to have secondary deposits at the time of operation or at autopsy, the common sites of metastases
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being liver, lungs and regional lymph nodes, less frequently bones, mediastinum and brain. The average size of the tumour at operation was quite large, the greatest recorded weight being 2650 grammes.
The microscopic features of these tumours vary. Most cells show nuclear pleomorphism and hyperchromasia, and the cytoplasm may be eosinophilic. Multinucleate cells and mitoses are found in both benign and malignant tumours, and it is often quite difficult to differ- entiate between carcinoma and adenoma on cellular morphology alone. Willis ( 1960) classifies a tumour as malignant in the presence of capsular invasion or intravascular spread. In the absence of these findings a diagnosis of adenoma is usually made. Figure 3 shows an area of capsular invasion in a section of tumour removed from our patient. Wallach et alii (1957) and Stewart et alii (1964) felt that every tumour of the adrenal cortex causing feminization should be regarded as malignant. The latter authors found that the average course and prognosis were approximately the same as in other carcinomas of the adrenal cortex, but that the mean life span might be a little shorter in the feminizing type of lesion. Gabrilove et alii found that only 20% of their patients survived for longer than three years from the time of diagnosis.
DISCUSSION
Stewart et alii (1964) and Gabrilove et alii ( 1965) claim that approximately one-half of the cases of feminizing adreno-cortical carcin- omas can be diagnosed clinically by palpation of a subcostal mass in the presence of gynæco- mastia. In the remaining 50%, where the tumour is not palpable, gynæcomastia may be the only presenting symptom or sign. Further- more, the great incidence of secondary deposits found at laparotomy, the large recorded sizes of the lesion, and the relatively poor prognosis, suggest that many of these feminizing adreno- cortical tumours are diagnosed late in the course of their growth. Gynecomastia thus should be regarded as a symptom and not as a clinical entity, and when it is encountered, particularly within the active reproductive life- span, adenoma or carcinoma of the adrenal cortex, although exceedingly rare, should be
considered among the possible causes. It is in this type of a case where estimation of urinary œstrogens is of particular value.
Levy et alii (1964) recognize three main ætiological groups in patients with gynæco- mastia. These are :
1. Gynecomastia caused by alteration of hormonal balance due to a normal physiological process, such as neonatal period or puberty. Only two cases in the series of adrenal tumours reported by Gabrilove et alii (1965) occurred around puberty; both, however, were found to be inoperable.
2. Gynæcomastia due to a pathological process which results either in excess production of hormones, or in alteration of hormonal balance to which the acinar tissue of the breast is sensitive.
A large and varied number of conditions are included in this group. Hyper- and hypo- thyroidism, recovery from starvation, ulcera- tive colitis, rheumatic fever, glomerulo- nephritis and chronic renal diseases treated by dialysis, as well as diseases of the central nervous system such as paraplegia, Friedreich’s ataxia, syringomyelia and dystrophia myo- tonica, are all quoted as possible causes. Tes- ticular atrophy or hypoplasia due to orchitis, irradiation cryptorchism or trauma, varicocele, hydrocele and spermatocele, as well as granulo- matous involvement of the testis in leprosy or tuberculosis, have all been known to be asso- ciated with gynæcomastia. About 10% of patients suffering from neoplastic lesions of the testis have concomitant gynecomastia, which is bilateral in 76%.
Liver disease, pituitary tumours, Kline- felter’s syndrome and underlying lung patho- logy, such as carcinoma of the lung, empyema, bronchiectasis, lung abscess and pneumothorax, may also be added to the list.
3. Finally, gynæcomastia may be caused by direct hormonal therapy. Androgens, œstrogens and occasionally steroids have been known to cause gynæcomastia as well as digoxin, amphetamine, rauwolfia alkaloids, and isonicotinic acid and other drugs.
Quite a large proportion of the above- mentioned conditions can be excluded by routine clinical history and examination, while others may require further biochemical, chromosomal, radiological or hormonal studies. The last two investigations were found to be of particular value in this case.
Lang ( 1966) obtained a positive preoperative radiological diagnosis in 135 out of 161 cases of adrenal tumour. Meyers (1966) described the “wedge sign” which may be seen in retro- peritoneal air studies, or in the capillary phase of angiography. This consists of dispropor-
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tionate tumefaction within the upper third of the generally enlarged gland, which should be pathognomonic of a cortical adenoma, and occurs in 50% of their cases. The same author also described an “apical sign” where the visualization of an uninvolved apex in the presence of a mass within the remaining adrenal tissue is thought to be specific of a pheo- chromocytoma.
Various authors differ as regards quanti- tative and qualitative aspects of hormonal analysis of urine. In almost all cases of femin- izing tumour of the adrenal cortex values for 17-ketosteroids, 17-ketogenic steroids, and urinary œstrogens or their fractions, are elevated. Œstrone is most commonly the elevated fraction as in this case, but other workers (Stewart et alii, 1965) found that the cestriol fraction was elevated in their case. Chorionic urinary gonadotrophins, which are almost always elevated in cases of chorion- epithelioma of the testis, are as a rule normal in adreno-cortical tumours.
Excessively high values of urinary steroids and œstrogens are more likely to indicate an adrenal carcinoma than an adenoma, although a certain overlap may occur, particularly in the case of a large adenoma.
Gabrilove et alii (1965) state that if the urinary 17-ketosteroid excretion exceeds 100 mg. in 24 hours, the tumour is almost certainly a carcinoma. Low urinary œstrogen values favour a benign condition, while high values such as in this case, where the urinary œstrone level was 35 times the accepted normal. would indicate a malignancy. Following a successful and complete removal of the tumour these abnormally high values return to normal, and any subsequent elevation should be considered to be pathognomonic of a recurrence or a dis- tant metastasis (Lipsett, 1963). Periodic estimations of urinary steroid and cestrogen fractions are therefore of value as a part of the postoperative follow-up of these patients.
An interesting feature in these types of tumours of the adrenal cortex is first. the rela- tive lack of Cushingoid features in spite of elevated 17-hydroxy-steroids, and second, the presence of gynæcomastia, in the absence of other feminizing features in spite of the abnormally high œstrogen value found in the urine. Cushing’s syndrome results from the
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overproduction of cortisol, rather than its precursor-substances.
Both these fractions and their metabolites are included in the routine estimation of 17-hydroxy-steroids. The excessively high value of urinary 17-hydroxy-steroids thus does not necessarily signify an increased urinary content of cortisol (Gabrilove et alii, 1965 : Harrison et alii, 1966). The above authors also found that fully developed Cushing’s syn- drome is uncommon in cases of feminizing tumours of the adrenal cortex, although some of the features may be encountered, particularly in the presence of a malignant lesion,
Stewart et alii (1964) feel that the lack of feminizing signs in males other than gynæco- mastia may be explained by the variation of œstrogen-androgen halance, which is a function of cestrogen-androgen conversion efficiency.
The treatment of choice for these tumours is still early diagnosis and surgery, because as a rule they are not radiosensitive. As a diag- nostic aid, the urinary estimation of œstrone is a relatively easy technical procedure, and raised values are often present, some time prior to the onset of other symptoms and signs, in patients with gynæcomastia due to neoplastic lesions of the adrenal cortex. The insecticide “Orthopara DDD” (o,p’-DDD) has been shown to produce regression of adreno-cortical carcinomas in man. It is administered by the oral route, and a prolonged course of adminis- tration is recommended (Lipsett, 1966). Occa- sionally severe nausea occurs, and the dosage schedule has to be altered or antiemetic therapy employed. It seems to be the only agent which at the present time is relatively tissue-type specific, and would be of use in the management of inoperable cases or metastases.
SUMMARY AND CONCLUSIONS
A case of feminizing carcinoma of the adrenal cortex is reported, and the literature is reviewed. The population incidence of these tumours is about one in 5,000,000, and in almost half of the reported cases gynecomastia was the only presenting symptom or sign. Feminizing tumours of the adrenal cortex are often diagnosed late, and their prognosis is relatively poor. Selective angiography or retro- peritoneal contrast studies are helpful in diag- nosing the site of the lesion. The estimation of
MULTIPLE SYNCHRONOUS COLONIC CARCINOMA
urinary œstrogens together with urinary steroids and their fractions is a valuable diag- nostic aid, not only in investigation of suspected cases of gynæcomastia but also in the post- operative follow-up. “Orthopara DDD” is a valuable tumour-specific agent in the manage- ment of inoperable and recurrent cases.
ACKNOWLEDGEMENTS
The authors wish to thank Professor R. P. Jepson for his advice and permission to report on his case, and Dr. E. G. Hardy, Senior Pathologist of the Institute of Medical and Veterinary Science, who very kindly reported on the histopathology and provided the photo- micrographs.
REFERENCES
BITTORF, A. (1919), Berl. klin. Wschr., 56: 776.
FERRIER, T., Row, P. and Cox, R. (1960), Med. J. Aust., I : 337.
GABRILOVE, J. L., SHARMA, D. C., WOTIZ, H. H. and DORFMAN, R. I. (1965), Medicine, 44: 37.
HARRISON, M. T., BRUSH, M. G. and McFARLANE, M. (1966), J. Endocr., 34:61.
HIGGINS, G. A., BROWNLEE, W. E. and MANTZ, F. A. Jr. (1956), Amer. Surg., 22: 56.
HUTTER, A. M. and KAYHOE, D. E. (1966), Amer. J. Med., 41 : 572.
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LANG, E. K. (1966), Radiology, 87 : 35.
LEVY, D. M., ERICH, J. B. and HAYLES, A. B. (1964), Postgrad. Med., 36:234.
LIPSETT, M. B. (1966), Mod. Treatm., 3: 1377.
LIPSETT, M. B., HERTZ, R. and Ross, G. T. (1963) ; Amer. J. Med., 35 : 374.
MEYERS, M. A. (1966), Radiology, 87 : 889.
SLAUNWHITE, W. R. and BUCHWALD, K. W. (1960), J. clin. Endocr., 20 : 786.
WOTIZ, H. H., STEWART, W. K. and FLEMING, L. W. (1964), Amer. J. Med., 37 : 455.
WALLACH, S., BROWN, H., ENGLERT, E. Jr. and EIKNES, K. (1957), J. clin. Endocr., 17 : 945.
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Multiple Synchronous Primary Carcinoma of the Colon
S. R. CHOWDHURY, Hawera Hospital, Hawera, Taranaki, New Zealand
A case of multiple synchronous primary carcinoma of the colon in association with extensive diverticulitis of the descending and pelvic colon is described, and the incidence and possible @tiology of this condition are reviewed.
MULTIPLE synchronous primary carcinoma has aroused interest from time to time because of its relatively rare incidence. Recent litera- ture draws attention to the chance finding of this condition, and it is therefore important to bear the possibility in mind when dealing with a case of carcinoma of the colon. It is of further importance to recognize the presence of a carcinoma or carcinomata in association with extensive diverticulitis of the colon. An illus- trative case is presented.
CASE HISTORY
The patient, a female aged 73 years, was admitted to hospital as an emergency on June 6, 1967, with a history of pain in the left iliac fossa for three weeks, and passage of blood and mucus per anum for one
week. The pain was dull and aching in nature, but became severe and colicky at times. There was no associated nausea or vomiting. The patient had had anorexia and loss of weight since the onset of symptoms.
She gave a past history of recurrent attacks of pain in the left iliac fossa for six years, of short duration, and associated with constipation. There was no previous history of the passage of blood and mucus, or of diarrhoea. There was no history of familial multiple polyposis, or any other colonic disorder.
On examination the patient was pyrexial. Abdo- minal examination showed slight guarding and marked tenderness in the left iliac fossa. The pelvic and descending colon were palpable, thickened and tender. On rectal examination no abnormality was detected. Blood examination showed polymorpho- nuclear leucocytosis and a raised erythrocyte sedi- mentation rate.
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