THE CLINICAL AND PATHOLOGIC FEATURES OF “NON-HORMONAL” ADRENOCORTICAL TUMORS
Report of Twenty New Cases and Review of the Literature
BERNARD S. LEWINSKY, MD, KENNETH M. GRIGOR, BSC, MB, CHB, THOMAS SYMINGTON, BSC, MD, FRCPATH, AND A. MUNRO NEVILLE, PHD, MD, MRCPATH
The clinicopathologic features of 178 patients with “non-hormonal” or “non- functioning” adrenocortical tumors are presented. Such tumors usually affect patients in the 5th, 6th, and 7th decades and occur in males twice as often as females. The prognosis is poor, most patients succumbing during the 1st year after diagnosis. The most helpful radiographic diagnostic test is the intravenous pyelogram, although arteriography and pre-sacral air insufflation may also aid in the diagnosis. Lymphangiography was found to be of value in assessing the lymph nodes during treatment and at subsequent followup examinations. No reliable, definite indication of the functional or metastatic potential of these tumors can be made from histopathologic examination; all should be viewed as malignant. The tumors are capable of forming precursor steroids without hormonal activity. Hence they are not in fact “non-functioning.” Their treat- ment should be primarily surgical, but postoperative radiotherapy should be administered if there is residual tumor. All chemotherapeutic agents are rela- tively ineffective but some form of combination chemotherapy may be beneficial.
A DRENOCORTICAL CARCINOMAS ARE RARE TU- mors which may be classified as “func- tioning” or “non-hormonal” according to the clinical syndromes with which they are asso- ciated. Hypercorticalism takes the form of the adrenogenital syndrome (virilism or feminiza- tion), Conn’s syndrome (hyperaldosteronism with low plasma renin), or Cushing’s syn- drome; the detailed clinico-pathologic fea- tures of these tumors have been published elsewhere.43-45,64 Adrenocortical tumors are considered to be “non-hormonal” if there is no clinical evidence of endocrine upset. They are very rare; wide experience is difficult to obtain at one institution, as is exemplified by the large number of single case reports in the literature over the past 30 years. An analysis of these cases along with 20 additional new cases seen by us at the Royal Marsden Hos- pital, London, Royal Infirmary, Glasgow, and
From the Institute of Cancer Research and Royal Marsden Hospital, London, SW3 6JB, England; and the Royal Infirmary, Glasgow, C.4., Scotland.
Supported by an American Cancer Society Grant (BSL) and Medical Research Council Grant 970/656/B.
Address for reprints: Professor A. Munro Neville, Institute of Cancer Research, Fulham Road, London, SW3 6JB, England.
The authors wish to thank those physicians and surgeons who made the clinical material available to them for study.
the Institute of Cancer Research, London, was thought to be worthwhile in order to trace some aspects of their behavior and response to treatment.
MATERIALS AND METHODS
Thirteen cases of “non-hormonal” adreno- cortical tumors were seen at the Royal Mars- den Hospital from 1948 to 1972. One case was excluded because the histologic material was not available. The cases were referred primarily to the hospital for treatment rather than diagnosis. Some of the clinical and all of the histologic data are available in a fur- ther 8 cases referred for pathologic diagnosis to the University Department of Pathology, Glasgow Royal Infirmary, from 1960 to 1970. Their inclusion brings the total number of new cases to 20.
Histologic examination was made on paraf- fin-embedded material sectioned at 6 u and stained with hematoxylin and eosin. Some specimens were received as paraffin-embedded blocks or previously stained sections. Surgical material was fixed in 10% neutral formalin and trimmed prior to embedding.
The present series (Table 1) consists of 11 males and 9 females ranging in age from 21/2
to 66 years; 10 of the patients were between 50 and 70 years of age. The right adrenal gland was affected in 9 patients and the left in 10. In one (Case 13), the site was not stated.
Signs and symptoms: The commonest pre- senting features were a palpable mass (11/20) and pain (11/20) (Table 1). Anorexia was present in six patients, while fever was re- corded only once (a child aged 21/2 years). In each of four patients, backache and vague dyspepsia were also observed.
Radiologic studies: These investigations were carried out in most but not all patients (Table 1). The intravenous pyelogram was abnormal in 12/13 cases and revealed either
a renal deformity, a suprarenal mass, or dis- placement of the kidney. The barium meal was abnormal in three patients and was inter- preted as a primary gastric tumor in two cases (Cases 6 and 10). Presacral air insufflation and arteriography contributed to the diagnosis in six cases (Cases 6, 8, 10, 13, 19, and 20). A postoperative lymphangiogram (Case 12) re- vealed evidence suggesting left external iliac and para-aortic node involvement.
Steroid investigations: The principal in- vestigations which were carried out are shown in Table 2. In a few instances, minimal aber- ration of cortisol metabolism may have ex- isted but without causing overt clinical mani- festations. In addition, increased excretion of
| Case | Sex | Age | Signs, symptoms, and roentgenographic studies |
|---|---|---|---|
| [ : 1 | M | 2}] | 5 days' history of malaise, drowsiness, backache, right facial weakness, fever. IVP: I11- defined mass right kidney; metastases to right 8th and 10th ribs. |
| [ 2 | M | 38] | Weakness and tiredness for 5 years. 5 months prior to admission, heart failure and hepatomegaly. Pain right upper quadrant, palpable mass, weight loss, ankle edema. Liver palpable 6 cm. IVP: Ptosis right kidney. Arteriogram: Vascular component identified. |
| [ 3 | F | 35] | 8 years left loin pain, 2 years hepatosplenomegaly of unknown etiology, mass left loin, shortness of breath. IVP: Tumor of left suprarenal gland. |
| [ 4 | M | 38] | Swelling of abdomen for 2 years. Pyrosis for 2 years. Mass right upper quadrant. IVP: Large right renal mass. Mass above and larger than the kidney. |
| [ 5 | F | 61] | Abdominal discomfort and increasing girth for 1 month. |
| Ł 6 | F | 56] | Dragging sensation in epigastrium for 1 month, mass palpable, increasing nausea and vomiting, anaemia, weight loss, and pain. Barium meal: Carcinoma of stomach. |
| [ 7 | M | 64] | Pain right side and back. Hematuria. IVP: Enlarged right kidney. |
| [ 8 | F | 53] | 5 week pain left flank, increasing girth, palpable mass, anorexia. IVP: Downward dis- placement of left kidney. Pre-sacral air insufflation: Suprarenal mass. Aortagram: Tumor vessels seen originating from aorta. |
| [ 9 | F | 48] | kidney. Backache, abdominal discomfort, anorexia, palpable mass for 1 month. IVP: Mass left |
| [10 | F | 42] | 7/69: Admitted with pain left hypochondrium radiating to the left iliac fossa, shortness of breath. Neurofibromatosis. 10/71: Tiredness, anorexia, loin pain, nausea and vomiting, pain over 9th and 10th ribs. IVP: Renal pelves elarged, mass left upper quandrant. Barium meal: Mass in left hypochondrium. Spine: Loss of pedicle T9. Pelvis: Right acetabular deposit. |
| [11 | F | 65] | 1966: Right adrenal tumor removed. 1972: Nausea, vomiting, and anorexia. Mass in right loin and a skin nodule found. IVP: Negative. Chest: Multiple metastases in lung. |
| [12 | M | 66] | Indigestion "for many years," 2-week history of lower abdominal pain. 25 1b weight loss and palpable mass in right upper quadrant. Barium meal: Large liver and displacement of stomach to left. IVP: Right kidney displaced downwards. Lymphogram: Deposits left external iliac and left para-aortic nodes. |
| [13 | M | -] | Urinary obstruction and paraplegia due to dorsal vertebral metastases. Roentgenogram: Air insufflation revealed adrenal tumor. |
| [14 | M | 59] | Abdominal swelling in left upper quadrant for 1 year. Abdominal wall recurrence 3} years postoperative. |
| [15 | M | 39] | 1 year "indigestion" and upper abdominal pain. Chest roentgenogram: Lung metastases 2 years postoperative. |
| [16 | F | 45] | Chest roentgenogram: Lung metastases, March 1966. Mild abdominal pain and backache. IVP: Left kidney displaced downwards. Spleen displaced upwards. |
| [17 | F | 57] | Asymptomatic. Chest roentgenogram: Lung metastasis. |
| [18 | M | 50] | Abdominal swelling, proptosis 3 years postoperative. Skull roentgenogram: Retro-orbital tumor confirmed by tomography and arteriography. Chest roentgenogram: Lung metastases. |
| [19 | M | 14] | Chest pain, mass right loin. Chest roentgenogram: Lung metastases. Arteriogram: Blood supply of tumor from aorta. |
| [20 | M | 61] | 42 lb weight loss in 1 year. Left abdominal pain. Chest roentgenogram: Normal. IVP: Left kidney displaced downwards. Arteriogram: Suprarenal tumor confirmed. |
the metabolites of pregnenolone, including pregn-5-ene-3a, 16a, 20a-triol were present in the urine of two patients (Cases 3 and 20).
The results of our studies of steroid metab- olism by some of the tumors in vitro and in monolayer culture will be reported separately.
Treatment: Complete excision of the tumor was achieved surgically in 11 patients (Cases 1, 5, 10-12, 14-16, 18-20). The tumors of 3 (Cases 2, 4, and 8) could only be partially removed, and in a further 3 patients (Cases 6, 7, and 9) a diagnostic biopsy only was taken. The diagnosis was established at au- topsy in 2 patients (Cases 3 and 17), in 1 of whom a prior liver biopsy had revealed “met- astatic tumor.”
Adequate details of therapy are available only for 13 patients (Table 2). Five of the patients received postoperative radiotherapy to the tumor bed; the dose range utilizing megavoltage equipment was between 2040 r and 4800 r over 21 to 52 days (Table 2). There was no significant clinical change in these 5 patients with the exception of Case 11 (vide infra). Two patients (Cases 10 and 12) re- ceived palliative radiotherapy for bone me- tastases with relief of pain. One patient (Case 6) was treated by radioactive-gold pituitary ablation with no measurable tumor response. Four other patients received no radiotherapy (Table 2).
Four patients were treated with chemo- therapeutic agents. Two (Cases 2 and 12) received in addition to radiotherapy, o, p’- DDD (2(2-chlorophenyl)-2-(4-chlorophenyl)-1, 1-dichloroethane), 8-10 gm per day. Case 12 is still alive and has shown good tumor regres- sion in the positive nodes as judged by lymph- angiography. Case 1 received methotrexate, 10 mg per day, and the final patient (Case 11) was treated with cyclophosphamide (0.5-1 mg intravenously) weekly, vincristine sulfate (0.5 mg intravenously), methotrexate (50 mg intravenously), and 5-fluorouracil (5-FU; 300 mg intravenously) singly or in combination at various time intervals after completing a course of radiotherapy. After two doses of 5-FU she developed a duodenocolic fistula which was surgically repaired. No tumor re- mained in the treated area, and while recover- ing from surgery and without receiving fur- ther chemotherapy, her lung metastases also completely disappeared radiologically. This remission, however, was short-lived.
Three patients received neither radio- nor chemotherapy postoperatively and one of
them (Case 4) is still alive 18 years after operation.
SURVIVAL
Adequate data are available in 18 cases (Table 3) one of whom was an autopsy diag- nosis. Six patients died within 6 months of diagnosis. Two patients survived 7 months, one, 13 months and two, 7 years. Two patients are alive and well without evidence of recur- rent disease (Case 4, 18 years; Case 20, 1 month). Four patients are alive but have evidence of remaining or recurrent tumor (Case 12, 5 months; Case 14, 31/2 years; Case 18, 4 years; Case 19, 6 months).
PATHOLOGY
The details of the pathologic features are shown in Table 3. All the tumors are large, lobular, and with cut surfaces which are red- dish-brown in color and show areas of recent and old hemorrhage and evidence of necrosis (Fig. 1). The tumors have a thin capsule which may be adherent to the adjacent tissues. They weighed from 700-4500 gm and measured up to 40 × 33 × 25 cm.
A variable histologic pattern is seen not only between tumors but also in the same le- sion. The tumor cells arranged in sheets, large alveoli, or cords which may radiate from the numerous thin-walled vascular sinusoids (Figs. 2 and 3) can vary in size from normal to large bizarre forms, but are generally poly- gonal with abundant eosinophilic lipid-poor cytoplasm, and resemble the cytoplasmic fea- tures of “compact cells” seen in the zona re- ticularis of the normal adrenal gland. Small groups of lipid-laden clear cells are also seen occasionally.
The nuclei are usually large, single, and vesicular with one or more prominent nu- cleoli (Fig. 3); giant bizarre or multinucleate forms are not uncommon. Nuclear and cyto- plasmic pleomorphism may be marked in some tumors and slight in others. Several tu- mors exhibit different degrees of pleomor- phism in adjacent parts (Fig. 4). Mitotic ac- tivity varies from 3 per HP field to less than 1 per 10 HP fields.
We used those histologic features-cellular and nuclear pleomorphism, nuclear vesicu- larity and mitotic activity-of proven value in assessing the malignant potential of endo- crine tumors,45,54 and graded the present se-
| Case | Postoperative radiotherapy* | Postoperative chemotherapy* | Laboratory tests |
|---|---|---|---|
| 1 | None | Methotrexate 10 mg/24 hr | |
| 2 | 2700 r in 35 days to tumor bed | o, p' -DDD 8 gm/day for 2 months. Prednisone 15 mg/day | Urinary Urinary 17-oxogenic+ 17-hydroxysteroids+ 135 mg/24 hr 152 mg/24 hr 66 mg/24 hr 83 mg/24 hr (after o, p' DDD) |
| 3 | None | None | Blood and urine steroids reported slightly abnormal |
| 4 | None | None | Urinary 17-oxosteroids: 4.3 mg/24 hrt |
| 5 | 2740 r in 35 days | None | Urinary 17-oxosteroids: 7.5 mg/24 hrt |
| 6 | Pituitary gold rods 42/mc | None | - |
| 7 | 2340 r in 35 days | None | |
| 8 | None | None | Urinary 17-oxosteroids: 40 mg/24 hr |
| 9 | 2050 r in 21 days | None | Plasma cortisol: 0900-24 µg%; 2400-22 µg%+ Urinary 17-oxosteroids: 23 mg/24 hr Urinary 17-hydroxysteroids: 12 mg/24 hr |
| 10 | Bone metastases. 3900 r in 21 days to T9. 3500 r in 30 days to femur. | None | Plasma cortisol: 33.5 ug%. VMA: normalt Urinary 17-oxosteroids: 5 mg/24 hrt Urinary 17-hydroxysteroids: 5 mg/24 hrt |
| 11 | 4896 r in 52 days to the tumor with minimal change in its size. | 2. Jun. 71. to 11. Dec. 71: Cyclophosphamide and vincristine sulfate 3. Mar. 72. to 26. May. 72: Methotrexate 3. Jun. 72. to 4. Jun. 72: 5-fluorouracil (2 doses only) and o, p' -DDD 8 gm/day; Dexamethasone 2/mg daily from July 1972 onwards | Plasma cortisol 3. Jun. 711. 13. Jun. 72+ 0900 47 ug% 15 µg% 2100 6 µg% Urinary 17-hydroxysteroids: 16 mg/24 hr 37 µg% |
| 12 | 2808 r in 15 days to sacroiliac region. Good relief of pain. | 25. May. 72+ 5. June. 72.+ Plasma cortisol am 25 µg% Urinary 17- 6 mg/24 hr pm 30 µg% 3.3 mg/24 hr oxosteroids Urinary 17- 13 mg/24 hr 5 mg/24 hr hydroxysteroids | |
| 20 | None | None | Urinary 17-oxosteroids: 18 mg/24 hr Urinary 17-oxogenic steroids: 17 mg/24 hr Plasma cortisol: 11, 19 µg% Urinary free cortisol: 220 µg/24 hr |
* For surgical details, see Table 3.
+ Postoperative results.
NON-HORMONAL ADRENOCORTICAL CARCINOMAS . Lewinsky et al.
| Case no. | Macroscopic features | Histologic features | Histologic degree of malignancy | Survival (years) | |||||
|---|---|---|---|---|---|---|---|---|---|
| Cell pleomorphism | |||||||||
| Size | Surgery | Autopsy | Arrangement | Type | Cellular | Nuclear | |||
| 1 | 10 × 7.5 cm ☒ | Right adrenal tumor removed. | Cerebral hemorrhage; metastasis to brain, ribs. | Lobulated sheets, radiating cords. | Compact | Marked | Marked | High | 2/12 |
| 2 | Not known | Right adrenal tumor infiltrating liver, aorta, surrounding tissues, partially removed. | Not performed. | Lobulated sheets, cords. | Compact | Moderate | Slight | Moderate | 13/12 |
| 3 | 16 cm diam. | Needle biopsy of liver showed metastatic carcinoma. Inoperable left adrenal tumor seen at. laparotomy. | Invasion and obstruc- tion of renal and adrenal veins and inferior vena cava. Metastasis to liver, kidney. | Lobulated sheets, cords. | Mixed compact and clear | Moderate | Moderate | Moderate | 3 days |
| 4 | 25 × 20 cm | Partial removal of cystic tumor filling entire upper right quadrant displacing stomach, duodenum, colon, kidney. | Lobulated sheets, radiat- ing cords. | Compact | Slight | Slight | Low | Alive 18 | |
| 5 | "Fetal skull" | Right adrenal tumor removed from between liver and diaphragm, ruptured during removal. | Metastasis to liver. | Lobulated sheets, few radiating cords. | Mainly compact; few clear cell nests | Moderate | Moderate | Moderate | 7/12 |
| 6 | "Large" | Tumor arising to left of liver and surrounding spleen; metastasis to liver; inoperable. | Sheets, acini, radiating cords. | Compact | Slight | Slight | Low | 3/12 | |
| 7 | 25 × 19 X 15 cm | Inoperable right adrenal tumor extending beyond capsule involving perirenal tissues, liver, lymph nodes. | Metastasis to left kidney and peritoneum. | sheets. Lobulated | Compact | Slight | Slight | Moderate | 3/12 |
| 8 | Not known | Left adrenal tumor involv- ing renal vein removed except for renal vein extension. | Metastasis to lung, liver, vertebral bodies, femur. | Lobulated sheets, radiat- ing cords. | Compact | Marked | Marked | High | 7/12 |
| 9 | 11 cm diam. | Inoperable tumor involving spleen, great vessels, vertebral bodies. | Lobulated sheets. | Mixed compact and clear | Marked | Marked | Moderately high | 3/12 | |
| 10 | 20 X 20 X ☒ ☒ 20 cm | Removal of tumor displacing stomach and pancreas. | Lobulated sheets, few cords. | Compact | Marked | Marked | Moderately high | 6/12 | No. 3 | |
|---|---|---|---|---|---|---|---|---|---|---|
| 11 | 40 × 33 X ☒ ☒ 25 cm | Right adrenal tumor removed. | Sheets, few cords and acini. | Compact | Moderate | Moderate | Moderate | 6 | ||
| 12 | 30 cm 4.5 kg | Removal of right adrenal tumor. | Sheets, radiat- ing cords. | Compact | Slight | Slight | Low | Alive 5/12 | ||
| 13 | Not known | Lobulated sheets, radiat- ing cords. | Spindle | Marked | Marked | High | Not known | NON-HORMONAL | ||
| 14 | 27.5 X 22 ☒ × 12.5 cm ☒ | Removal of left adrenal tumor adherent to adjacent organs. Peripheral fleshy tissue; central necrosis. | Lobulated sheets, few cords. | Compact | Moderate | Moderate | Moderate | Alive 3} | ||
| 15 | 15 × 15 × ☒ ☒ 9 cm | Left adrenal tumor removed with adherent spleen, kidney, tail of pancreas; capsule intact. Central hemorrhagic necrosis. | Lobulated sheet, acini, radiating cords. | Compact | Slight | Slight | Low | 6 | ADRENOCORTICAL | |
| 16 | 23 × 20 X ☒ ☒ 15 cm | Removal of left adrenal tumor. Smooth, encapsulated, fleshy with central necrosis. | Lobulated sheets, radiat- ing cords, acini. | Mainly compact; nests of clear cells | Slight | Slight | Low | Not known | CARCINOMAS | |
| 17 | 1100 g | Right adrenal tumor invading inferior vena cava, metastasis to lung. | Lobulated sheets, few radiating cords, acini. | Mainly compact; few clear | Moderately severe | Moderately severe | Moderate | Autopsy diagnosis | . | |
| 18 | 19 X 17 X ☒ ☒ 9 cm | Removal of lobulated tumor of left adrenal. Left lobectomy for lung metastasis. | Trabeculated sheets, radiating cords. | Mixed compact and clear | Moderate | Moderate | Moderate | Alive 4 | Lewinsky et | |
| 19 | 18 X 15 X ☒ ☒ 13 cm 1520 g | Removal of right well encapsulated adrenal tumor adherent to liver and invading adrenal vein. | Lobulated sheets, radiating cords. | Compact | Slight | Slight | Low | Alive 6/12 | al. | |
| 20 | 12 cm diam. 700 g | Removal of left adrenal tumor with adherent kidney and spleen. | Lobulated sheets. | Mixed compact and clear | Marked | Marked | High | Alive 1/12 | 783 |
ries of tumors into those of high, moderate, or low malignancy. Those classified as highly malignant died within 7 months, those of moderate malignancy, between 1 month and 6 years, while those of low malignancy sur- vived for up to 18 years postoperatively, al-
though one died within 3 months (Table 3). Thus, as a general rule, using those criteria, the higher the grade of histologic malignancy, the shorter the survival (but exceptions exist).
The adrenal cortex attached or contralat- eral to the tumor was available for study from only four patients (Cases 5, 8, 10, and 17). The appearances were within normal limits (Fig. 5) in both cases (Cases 10 and 17) where the gland was not compressed.
Evidence of tumor spread was noted in many cases. Two of the tumors directly in- vaded local structures, and in six, there was extension along the central adrenal or renal veins, or involvement of the inferior vena cava or aorta (Table 3). The local lymph nodes were involved in only two cases (Table 3); distant metastases were observed initially or developed in 14 patients, the commonest sites being liver (6 cases), bones (6 cases), lung (5 cases), and brain (2 cases).
DISCUSSION
One hundred fifty-eight cases with “non- hormonal” adrenocortical carcinomas have
been collected from the literature (see Refer- ences; articles marked with “R”) and are now reviewed together with the present series, making a total of 178 examples. This tumor, thus, is extremely rare, an observation which is further demonstrated by the fact that we have personally seen and reviewed during the past 12 years the pathology of 112 adrenal tu- mors causing hypercorticalism.43-45,54
Age, sex, incidence, and location of tumors: In 133 of the 178 patients, age data are known and are shown in Fig. 6 and Table 4. There appear to be two distributions, one between 0-10 years and the other between the 5th and 7th decades (Fig. 6).12,52 Males are affected more often than females (Table 4). In 89 of the cases in the literature in which the site is stated, the left adrenal was involved in 55 and the right in 30. In the remaining 4, tumor in- volved both adrenal glands. It is not known if these represent separate primary tumors or whether one is a metastasis of the other.
Signs and symptoms: Table 4 records the four commonest presenting signs and symp- toms. In their discussions, Wood,59 Lipsett,37
and Heinbecker25 stated that the clinical on- set was insidious and it may be months and sometimes years before a diagnosis is made, by which time a mass is palpable or the pain is severe. A left-sided tumor may mimic a gas- tric ulcer or tumor; gastro-intestinal bleeding was a presenting symptom in six cases. The lack of early symptoms allows the tumor to remain undetected. Therefore, patients may present initially in bizarre fashions such as simulating the Budd-Chiari syndrome16 with a right adrenal tumor, acute perforated ap- pendicitis resulting from a metastasis,22 visual problems due to a secondary deposit in the retinal choroid,18 or pelvic complaints due to vaginal metastases.26
Fever was a feature in all of Wood’s59 cases, but in only 16 other cases in the literature. In our series, only one case, a child of 21/2 years, had a fever. Its significance is obscure; fever may decline immediately after surgical re- moval of the tumor,57 and has been related to the presence of marked tumor necrosis.56,57,59
Diagnostic roentgenographic studies: The most valuable diagnostic radiologic test is the
intravenous pyelogram, 22 out of 24 carried out by other workers and 12 out of 13 in our series being positive, and therefore should be the first study performed if the diagnosis is suspected. Arteriography is helpful in outlin- ing its vascular supply and may detect in- volvement of the contralateral gland. Presacral air insufflation can outline the mass more clearly but gives no further information as to its nature.
Due to the rarity of this type of tumor, the role of lymphangiography remains to be estab- lished. The adrenal gland is rich in lym- phatics which drain to the para-aortic nodes.1 Following adequate surgery, a lymphangio- gram may not only detect occult disease in the lymph node chains but may also provide a visual guideline for further radio- or chemo- therapy.
Pathology: The tumors of the present series have macroscopic appearances similar to those of most functioning adrenocortical carcinomas described in the literature,40,43-45,54 but are generally much larger, probably because they do not produce clinical symptoms at an early stage.
The predominant cell is compact in type, a feature not emphasized by other authors. In- deed most tumors described in the literature have been purported to have had more clear than compact cells, a feature which is also at variance with our experience of all other large adrenal tumors which cause hypercorticalism with the exception of those causing hyper- aldosteronism. A possible reason for the cyto- plasmic differences is discussed later.
Heinbecker,25 Huvos,31 and Birke7 have suggested that “non-hormonal” tumors have peculiar features not shared by functioning tumors. We failed to detect any single histo- logic feature, or group of features, which en- abled definitive histologic assessment of the functional capacity of those adrenocortical carcinomas, and their differentiation from other compact cell carcinomas causing hyper- corticalism. However, examination of the at- tached or contralateral cortex will give some clue to the secretory potential of a tumor causing Cushing’s syndrome when it shows cortisol-induced atrophy44 or Conn’s syndrome when the zona glomerulosa is hyperplastic in association with a gland of normal width.45
While the presence of distinct tumor spread, e.g. to the lymph nodes or kidney, is pathog- nomonic of a malignant tumor, such criteria may not be present at the time of initial treat- ment. Consequently, reliance often has to be placed upon the gross pathology and mor- phology.
It seems that the largest tumors in this series are associated with a better prognosis (Cases 4, 11, 14, 15, and 18) (Table 3). However, this criterion is not a reliable guide to manage- ment as is shown by Cases 7 and 10 (Table 3) who died within 6 months with large tumors. The histologic features of capsular invasion or tumor cells in vascular spaces are also quite independent of the potential behavior of the tumor and reaffirm our previous conclusions that these criteria occur with benign and ma-
lignant tumors.43,45,54 While other features, such as nuclear pleomorphism and vesicular- ity, which have proved of value in other stud-
20
20
MALE
17
16
FEMALE
16
15
13
NUMBER
12
12
10
8
8
5
6
4
2
2
2 2
3
O
0-10
11 - 20
21-30
31-40
41-50
51-60
61-70
71-80
DECADE (YEARS)
| Literature | Present series | TOTAL | ||
|---|---|---|---|---|
| Sex distribution | Male | 100 | 11 | 111 |
| Female | 52 | 9 | 61 | |
| No information | 6 | 6 | ||
| Pain | 49 | 11 | 60 | |
| Mass | 68 | 11 | 79 | |
| Signs and symptoms | Weakness/anorexia | 38 | 9 | 47 |
| Fever | 24 | 1 | 25 |
ies of endocrine tumors, did give some indica- tion of the “malignant” potential, such criteria were by no means absolute. Conse- quently, all such tumors are best viewed as carcinomas and the patient followed up ac- cordingly at frequent intervals when suitable steroid assays should be conducted (vide infra).
Metastases: Inadequate data with regard to sites of metastases are recorded in the litera- ture. In his series of 55 examples of “function- ing” and “non-functioning” tumors, Macfar- lane39 reported a 31% over-all incidence of local invasion with local lymph node involve- ment in 44% and metastases to the liver in 68%, lungs in 47%, and bones in 18%. In our series, the local lymph nodes were in- volved in 10% of patients and osseous metas- tases (30%) were as frequent as those in liver. We found two cases (Cases 1 and 18) of veri- fied brain lesions; five other cases were found in the literature.2,14,18,27,52 Previous authors29, 31,37 have stated that cerebral metastases were extremely rare.
Steroid assays: “Non-hormonal” adrenocor- tical carcinomas are not without steroidogenic activity. Rather, they are incapable of forming excess active hormones, such as cortisol, aldos- terone, androgens, or estrogens.
Cholesterol
20:22 D
17
Pregnenolone
17a-Hydroxy- pregnenolone
DHA
3
17
3
3
Progesterone
17a-Hydroxy-
Androstenedione
progesterone
Corticosterone
Cortisol
Testosterone
Estrogen
Aldosterone
The work of Fukushima and Gallagher20 has shown that so-called “non-functioning” tu- mors can form pregnenolone, and that its metabolites occur in the urine in the form of pregn-5-ene-30,20a-diol and pregnane-3a,20a- diol. More recent work by Fantl17 and her col- leagues has confirmed and extended this to show that 16a-hydroxylated metabolites of pregnenolone may also occur in the urine. The tumors of Cases 3 and 20 were found to have this secretory pattern. Thus, some of these tumors appear to have enzymic defects involving the 45-3ß-hydroxysteroid dehydroge- nase-isomerase system(s) and possibly the 17a- hydroxylase, which account for failure of pregnenolone utilization (Fig. 7). Enzymic defects could also account for the presence of clear cells in some tumors (vide supra). If there is a deficiency of the C20:22 desmolase system, cholesterol utilization will be pre- vented and with its esters, it will accumulate in the cytoplasm and give the tumor cells a lipid-laden clear appearance. This is the cause of the appearance of the adrenal in congenital lipoid hyperplasia, a rare form of the adreno- genital syndrome.49
Therefore in the followup of patients treated for adrenocortical carcinomas, with- out overt function, it is essential that the uri- nary metabolites of pregnenolone are studied and used as tumor index substances to gauge the clinical status of the patient rather than the typical adrenal steroid products.
Treatment: The primary mode of treat- ment remains surgery, which was carried out in 57 out of 65 patients recorded in the litera- ture. While others37 claim that this tumor is radioresistant, we found that high doses of external irradiation may be beneficial (Cases 10-12). In our hands, a response to radio- therapy indicates that the tumor may also respond to chemotherapy.
Hutter and Kayhoe29,30 and Bergenstal and Hertz5 have described the oral administration
of o,p’-DDD for the treatment of adrenocorti- cal carcinomas with prednisone being given concomitantly if signs of adrenal insufficiency are suspected. Gastro-intestinal toxic manifes- tations (diarrhea, nausea, and vomiting) de- velop in 83% of patients, neurologic symp- toms (somnolence and lethargy) in 41%, and skin rashes in 14%. Other effects such as dizzi- ness, muscle tremor, headache, confusion, and weakness have also been noted. The control of these symptoms is achieved by reducing the total dose or by giving the drug intermit- tently.
Because responses to o,p’-DDD occur slowly, treatment should be continued for at least 8 weeks, provided the side effects are not too severe. The dramatic but rather short-lasting response to combination chemotherapy in ad- dition to radiotherapy in one patient (Case 11) suggests that this form of therapy may be more effective than o,p’-DDD alone.
In view of these findings, it seems worth- while to propose that treatment might be at- tempted in a manner similar to that employed for other highly malignant tumors, namely surgery, radiotherapy, and combination chemo- therapy.
Prognosis: This tumor carries a poor prog- nosis. Of 61 patients on whom survival data are available, 42 were dead within 1 year, and of those 24 died within the first 2 months. No correlation was found between age at diagno-
sis or sex and the survival. The only long-term (18 year) survivor in the literature is pre- sented in this series.
CONCLUSION
For “non-hormonal” adrenocortical tumors, surgery remains the treatment of choice, with radical excision whenever feasible, even if this necessitates the removal of adjacent ad- herent organs, e.g. kidney, or spleen. Intra- venous pyelography and arteriography are the best aids to diagnosis. The functional capacity of these tumors must be assessed before sur- gery, and we recommend that the following should be measured: (A) 24 hour urinary 17- hydroxy- and 17-oxosteroids and steroid me- tabolites of pregnenolone; (B) morning and evening plasma cortisol levels; (C) response to ACTH stimulation; and (D) dexametha- sone suppression.
Postoperatively, the presence of lymph node involvement may be assessed by lymphangiog- raphy. We have found radiotherapy to be use- ful in the treatment of residual tumor and metastases. While chemotherapy with o,p’- DDD is of limited value, a combination of other chemotherapeutic agents may give more beneficial results. The course of the disease should be monitored by serial urinary steroid metabolite studies.
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