A 18 year old male presented with features of Cushing's syndrome including weight gain, facial puffiness, and striae. Laboratory tests confirmed ectopic cortisol secretion from an adrenal tumor. Imaging revealed a large right adrenal mass invading nearby structures with lung metastases. Biopsy supported a diagnosis of metastatic adrenocortical carcinoma. Surgery was not possible and the patient was started on palliative chemotherapy with ketoconazole.

1. ADRENOCORTICAL
CARCINOMA

2.  Mr. KS, 18 y.o. male referred from NSH with
features of cushing’s syndrome
 He presented with 6/12 hx of cutaneous striae,
hirsutism (excessive hair growth) truncal obesity,
puffy face, weight gain +/-30kg, fatigue

3.  24 hr urinary Cortisol: 3889 / 3931 mcg/24hr (N 150- 772)
 Serum Cortisol midnight 1617 nmol/l
morning 1569 nmol/l
 Serum ACTH midnight < 0.2 (N 1.6-13.9)
morning < 0.2
• Dexamethasone supression test -
Negative (cortisol1551)
 Serum Testosterone 4.1 nmol/l

4. CT scan revealed a large lobulated and enhancing lesion originating from the
right adrenal gland with involvement of retrohepatic IVC & liver and atleast 2 lung
metasteses noted

5.  Its appearance, coupled with the patient history, physical
exam, and laboratory data strongly suggested an
unresectable metastatic adrenocortical carcinoma
 Patient discharged with palliative chemotherapy-
ketoconazole

6.  Mrs. DW, fit 87 y. o. female presented to private with symptomatic
anaemia with unexplained bleeding in about March/ April last year.
 She had 4 Gastroscopies, 2 Colonoscopies, a barium follow-through
and a nuclear scan study was suggestive of bleeding from terminal
ileum.
 She then had a resection of the terminal ileum but has continued
bleeding.

7.  She then had a capsule endoscopy study which was unsatisfactory but did show
some blood in the stomach. some telangiectatic spots were noted and it was
thought that these may be the cause of the bleeding.
 Since then she has required regular blood transfusions every month.
 She usually presents with melaena without any acute haemodynamic event.
 She had a previous left adrenocortical carcinoma which was operated in 1991 in
private.

8.  CT Abdomen:
revealed a 6.5 cm relatively vascular mass arising anterior to the upper pole
of the left kidney infiltrating the posterior wall of the stomach just distal to the
OG junction highly suggestive of recurrence of adrenal carcinoma.
 CT Guided Biopsy: inadequate

10.  Estimated incidence of 0.5-2 per 106 patients per
year
 Peaks of age distribution at age <10 and in the 4 th
and 5th decades
 Scattered reports of gene associations, but rarity of
lesion precludes clear associations

11.  60-65% are functional and produce hormone excess related symptoms
> rapidly progressive cushing syndrome
> mixed cushing syndrome and an androgenital disorder
> 75%are locally aggressive at the time of diagnosis, median survival of 18
months following diagnosis. Tumor grade important for survival
 35-40% are non functional tumors ( or asymptomatic functioning tumors)
> abdominal pain / mass, weight loss, fatigue, nausea

12.  Hormonal studies can be a first diagnostic test which
confirms ectopic steroid hormone secretion, leading to an
imaging and tissue diagnosis.

13.  24 hour urinary cortisol exrection
> More than 90% of Cushinoid patients have free cortisol levels greater than
200mcg/ 24 hours. 97% of normals have levels less than 100mcg/ 24 hours
 ACTH measured with serum cortisol will demonstrate
ACTH independent nature of hypercortisolism.

14.  Other steroids are elevated:
 androstenediol and adrosetenedione
 DHEA and DHEA-S
 11- deoxycortisol
 urinary 17- ketosteroids
 aldosterone
 Many intermediate enzymes are defective or
dysregulated, leading to inefficient steroid production
and precursor buildup

15.  Serum Testosterone
 Serum DHEA and DHEA-S
 24 hour urinary ketosteroids
 Plasma estradiol and/ or estrone
 Plasma aldosterone/ renin
 Urinary catecholamines/ metanephrines in all
patients

16.  CT detects 98% of adrenal carcinomas
 MRI scanning can also provide vascular invasion/
tumor thrombosis information.
 Also provides many incidentalomas
 Malignant lesions tend to be > 5cm, have irregular
shapes/ blurred margins, and be heterogeneously
enhancing.

17.  Stage I — Disease confined to the adrenal gland and
<5 cm in diameter (approx 20%)
 Stage II — Disease confined to the adrenal gland and
>5 cm in diameter (approx 20%)
 Stage III — Local invasion that does not involve
adjacent organs or regional lymph nodes(approx20%)
 Stage IV — Distant metastases or invasion into adjacent
organs plus regional lymph nodes (approx 40%)

18. Complete surgical resection is the primary treatment
modality

19. Complete resection is the strongest predictor
of disease free survival

21.  Unresectable tumors include those that invade the
celiac plexus/ vascular structures/ SMA/ aorta

22.  In a case review of 46 patients at MSKCC, 3 histologic
factors correlated with survival:
 tumor> 12cm
 6 or more mitotic figures/ 10hpf
 presence of histologic evidence of intratumoral
hemorrhage
 5 year survivals:
▪ 0 factors: 83%
▪ 1 factor: 42%
▪ 2 factors: 33%

23.  There are scattered case reports demonstrating
improved pain when palliative XRT used for
localized lesions

24.  Review of the literature reveals case reports,
retrospective treatment data, and reviews.
 A few phase II trials do exist from some
cooperative or national groups
 No true modern- design controlled phase III trials
exist

25.  1,1- dichloro-2-(o-chlorophenyl) ethane (o,p-DDD).
 Chemical relative to DDT
 It produces selective adrenocortical necrosis in both the adrenal tumor and
metastases
 Reported in 1960 by Bergenstal
 Subsequent NCI study in 1966 in 138 patients
 Noted “reduced symptoms” in about half the patients
 Another study (Haak, Netherlands) retrospectively looked at a series of 96
patients treated from 1959- 92
 62 patients were treated with mitotane during their course
 Of the 30 who achieved serum levels >14mg/L, they had a greater survival

26.  Metyrapone (11B hydroxylase inhibitor)
 Ketoconazole
 Aminoglutehamide

27.  Italian series showed no
survival difference
between two groups of
completely resected
patients
Effect of adjuvant mitotane (n = 11) compared with no treatment (n = 15) on the
disease-free interval in patients with localized or regional adrenocortical carcinoma.

28.  Of 19 patients treated at MD Anderson cancer center, 8
patients received it adjuvantly, 5 patients received it
transiently, 6 patients did not receive any.
 Disease free interval was actually shortest in the adjuvant
group

29.  Various systemic cytotoxics have been used for
advanced disease, usually for those failing
mitotane.
 Most studied have been Etoposide, cisplatin,
and adriamycin.
 Paclitaxel and Temozolamide have recently
demonstrated antitumor activity in vitro

30.  Original studies utilized Cisplatin and Doxorubicin with
Cyclophosphamide or 5-FU. Response Rate was 20%
 Cisplatin/ Etoposide reported to have an 11% response
rate
 Phase II studies with varying reported efficacy exist

32.  Italian study
 28 patients enrolled
 Etoposide (100mg/ m2) d5-7; Doxorubicin (20mg/ m2) d1,8; Cisplatin
(40mg/ m2) d1,9 every 4 weeks
 Concomitant mitotane up to 4g/ day
 Complete Response in 2 patients
 Partial Response in 13 patients
 Overall response of 54%
 Stable disease in 8, progessive in 5

33.  Recurrences that are amenable to re- operation
may be resected for long term survival
 5 year survivals compare from 57% in those
amenable to resection to 0% for those who are not

34.  Italian registry: 140 resections
 Recurrences in 52 (37%)
▪ Locally in 13
▪ Distant in 25
▪ Local + Distant in 14
 20 patients underwent re- resection
▪ 5 yr survival of 50% in those resected
▪ 5 yr survival of 8% in those not resected

35.  MSKCC: 47 patients with recurrent/ metastatic disease
Patients who had a complete second resection had a
median survival of 74 months (5-year survival, 57%),
whereas those with incomplete second resection had a
median survival of 16 months (5-year survival, 0%).
MSKCC: Memorial Sloan Kettering Cancer Centre

36.  Adrenocortical carcinoma is a rare disease that often
presents late
 Primary curative therapy is surgical
 No role for adjuvant chemotherapy has been demonstrated
to date
 Palliative therapy with mitotane may be useful; its palliative
effect may be entirely due to adrenolytic effect

37.  Reoperation appears to be the only long term curative
option in recurrent cases
 Cytotoxic chemotherapy in the advanced/ metastatic
setting has not been definitively demonstrated to be useful
in controlled trials
 EDP-M may be useful in metastatic settings; more
evaluation is needed