Long-term survival in recurrent adrenocortical cancer
Md Shuayb,1 Arunangshu Das,1 Mirza Nazim Uddin2
1Square Oncology & Radiotherapy Centre, Square Hospital, Dhaka, Bangladesh 2Square Hospital, Dhaka, Bangladesh
Correspondence to
Dr Md Shuayb, Square Oncology & Radiotherapy Centre, Square Hospitals Ltd. Dhaka, 1205, Bangladesh; m.shuayb@yahoo.co.uk
Received 13 May 2018 Accepted 23 May 2018
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To cite: Shuayb M, Das A, Uddin MN. BMJ Supportive & Palliative Care Epub ahead of print: [please include Day Month Year]. doi:10.1136/ bmjspcare-2018-001568
ABSTRACT
Adrenocortical carcinoma (ACC) comprises approximately 0.02% of all malignant tumours, which are a very small fraction of a group of cancers that affect in 0.7 to 2 in 1 000 000 people per year. Recurrence is very common even after complete resection and prognosis is poor. We report a case of a sporadic form of ACC found in a 41-year-old Asian Bangladeshi man. His tumour was surgically excised completely with negative margins and he did not receive any adjuvant therapy. Four years later, adrenal adenoma was developed at his opposite side which was also excised. Then after a total duration of 7 years, he developed recurrence in both adrenal glands and extensive metastases to bilateral lungs, liver and abdominal wall. As per FIRM-ACT study, we started treatment with etoposide, doxorubicin, cisplatin plus mitotane (EDP-M), and the patient responded dramatically. He became symptom free and achieved radiological partial response just on completion of three cycles. To our knowledge, this is the first case of ACC in Bangladesh published in the literature. Managing rare cancers is always challenging due to the fact that clinicianslack practical experience in it. We believe that patient with a rare cancer with poor prognosis like ACC may also survive long, and extensive metastases can also be controlled.
BACKGROUND
Adrenocortical carcinoma (ACC) is a rare, aggressive, poor prognosis cancer. It accounts for 0.02% of all cancers with an estimated yearly incidence of 0.7 to 2 cases per million populations.12 Five-year overall survival (OS) is 32%-48% with a median duration of 2 years for complete surgical resection and 1 year for residual disease.2 Prognosis is worse in metastatic disease; 5-year OS is<15%.1 3 Most are functioning tumours.2 We report the case of a non-functioning ACC surgi- cally excised but with recurrence in the opposite adrenal gland with hepatic, bilateral pulmonary and abdominal wall
metastases 7 years later. A good response was obtained with etoposide, doxoru- bicin, cisplatin plus mitotane (EDP-M) chemotherapy.
CASE PRESENTATION
A 41-year-old Asian Bangladeshi man with comorbid bronchial asthma presented with a right lumbar region progres- sive hard lump for 1 month. Abdom- inal CT scan showed a 15.3×13×17 cm heterogeneous mass with solid, cystic and calcified components between the liver and right kidney, compressing and displacing the above structures including the pancreas and adjacent vessels (figure 1). Subsequently, CT-guided fine-needle aspiration cytology (FNAC) found atyp- ical cells suggestive of adrenal cortical neoplasm and pheochromocytoma. His serum cortisol was 13.6 µg/dL. He under- went right-sided adrenalectomy. Opera- tive findings were an encapsulated right adrenal mass loosely adherent with the surrounding structures. The specimen measured 18x16x6cm and weighed 1.5 kg. On microscopic examination, it was a malignant tumour composed of large polypoid epithelial cells in sheets, clusters and around blood vessels. They showed acidophilic cytoplasm, nuclear hyperchromatia and marked pleomor- phism. Frequent mitosis, giant cells and areas of necrosis were seen. The number of mitosis was >20 per high power field (HPF). Surgical margins were tumour free with no capsular and venous invasion. Features were compatible with ACC. Immunohistochemistry was positive for melan-A and inhibin but negative for cyto- keratin and epithelial membrane antigen (EMA). A final immunohistochemical diagnosis of ACC was made.
Six weeks after surgery, whole abdomen CT scan was normal. Regular follow-up with yearly abdominal ultrasound was done. Four years later, a left supra renal mass was suspected on sonography; CT
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scan identified a well-defined, almost rounded homo- geneously isodense lesion approximately 7.1×6.2cm at the same region suggestive of adenoma. His chest radiograph and blood chemistries were normal. Serum cortisol was 9.4ug/dL and 24 hours urinary
vanillylmandelic acid (VMA) was 18.92 mg. Left adre- nalectomy was performed. The excised specimen was 10 cm in maximum diameter and 283.5g. The cut surface was mostly necrotic and partly solid. Micro- scopic appearance showed an encapsulated benign tumour composed mostly of granular cytoplasm mixed with cells and clear cytoplasm arranged in trabeculae and sheets. A diagnosis of adrenocortical adenoma was made and he was placed on oral prednisolone 30 mg/ day.
Following surgery, he was well for nearly 3 years but then developed pain in both hypochondriac and lumbar regions and anterior abdominal wall swelling. Symptomatic treatment with pain killers did not help. On palpation, there was a 5 cm firm swelling with ill-defined margins close to the surgical scar on his left anterior abdominal wall. A CT scan of abdomen and thorax noted bilateral adrenal heterogeneously enhancing soft tissue density masses 4.6×3.5 cm (right) and 4.6×4.1 cm (left). Another heterogeneously enhancing soft tissue density of 4×3.6 cm was in the left upper anterior abdominal wall. There were also heter- ogeneously enhancing ill-defined hypodense areas at segment VI, VII and VIII of the right lobe of liver and multiple nodules of variable sizes in all lobes of both lungs (largest about 1.2cm in diameter). FNAC from the abdominal wall mass suggested metastatic ACC. A smear showed adequate cellular material with malig- nant tumour cells in the background of necrotic debris. The tumour cells were monomorphic and likely neuro- endocrine. The morning serum cortisol was 13.9 µg/dL and urinary VMA was 9.53 mg/24 hours.
He was deemed inoperable. Palliative chemotherapy was started with doxorubicin (40 mg/m2) on day 1; etoposide (100mg/m2) on days 1, 2 and 3; cisplatin (40 mg/m2) on days 1 and 2 and continuous oral mito- tane (2g in four divided doses) daily. A total of six cycles were planned at four weekly intervals. Abdom- inal symptoms resolved completely 15 days after starting chemotherapy. On interim assessment after three cycles, his CT chest and abdomen showed stable adrenal masses and the number and size of the liver and lung lesions decreased >30%compared with pre-chemo CT scan. The size of the abdominal wall nodule was just under 1 cm in diameter compared with the previous size of 4 cm (figure 2).
DISCUSSION
The adrenal gland is a rare site for malignancy. ACC has a bimodal age incidence, under 5 years in children and fourth to fifth decades in adult.2 3 Male to female ratio is 1:1.5.3 Most ACCs are sporadic but may be part of a hereditary syndrome, that is, Li-Fraumani syndrome, Beckwith-Wiedmann syndrome, familial polyposis coli, congenital adrenal hyperplasia, type-1 multiple endocrine neoplasia and B-catenin mutations.3 Bilateral ACCs are infrequent, 2%-6%.2 Functioning tumours make up 60%, more so in women.2 While
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the most common features of functioning tumours are Cushing’s syndrome and virilisation, non-functioning tumours cause flank pain and fullness from abdominal masses. 23
Radiological diagnosis by magnetic resonance or CT images is important because suprarenal masses >6 cm have highly malignant potential.2 Surgical removal of adrenal mass >6 cm is recommended; FNAC is only suggested where surgery is impossible and radiolog- ical diagnosis cannot be made.2 In our case, malig- nancy was suspected by large CT mass, diagnosed in FNAC sampling and confirmed by postoperative histopathology.
Important differential diagnoses (D/D) include adrenal adenoma, pheochromocytoma and renal cell carcinoma (RCC). ACC>95 g are usually malignant.2 2 The Weiss criteria are probably the most efficient way of differentiating malignant from benign tumours based on microscopic characteristics.3 They include high mitosis rate (>5 per 50 HPF), atypical mitoses, venous invasion, high nuclear grade, absence of cells with clear cytoplasm (<25% of cells), diffuse growth pattern (more than one-third of the tumour), necrosis, sinusoidal invasion and capsular invasion; ACC is diag- nosed by any three of these nine criteria.3 High mitotic activity, variable cellularities, marked pleomorphism and necrosis in our case indicated ACC. The second
D/D, pheochromocytoma, was unlikely due to the absence of raised VMA and Cushing’s features. The third D/D, metastatic RCC, was excluded as tumour cells were negative for cytokeratin and EMA and posi- tive for inhibin and melan-A.4
Radical excision is the mainstay of treatment for resectable ACC.2 3 Mitotane, an adrenolytic and immunosuppressive agent, is the only ACC drug approved.1-3 5 Residual disease and/or high Ki67 (>10%) should be treated with adjuvant mito- tane for a minimum of 2years, as recommended by European Society for Medical Oncology.3 Adju- vant mitotane may delay and, sometimes, prevent disease recurrence.3 The FIRM-ACT study, the only randomised phase III trial, established that EDP-M is the standard of care for advanced or metastatic ACC.1 Despite some serious adverse events like bone marrow toxicity (11.5%), infections (6.8%) and thromboem- bolic events (6.8%), it showed promising activity in overall response and progression-free survival as first-line and second-line therapies.1 Our case was initially resectable and well managed with surgery with complete resection. However, Ki-67 was not tested and adjuvant treatment not offered as there was no established guideline in early 2011. After 4 years, adrenal adenoma was diagnosed in the opposite side and adrenalectomy performed. Finally, after a total
Case report
duration of 7 years, he had recurrence in both adrenal glands with multiple liver, bilateral lung and abdom- inal wall metastases and inoperable. EDP-M pallia- tive chemotherapy was started after multidisciplinary team discussion.
In general, ACC is aggressive and local recurrence and distant metastases are common.2 3 Most are diag- nosed in advanced stages and local or distant recurrence rate is as high as 80% even after complete resection.2 Adverse prognostic factors include distant metastases, incomplete resection, older ages (>45 years) and high grade.23 Our patient was stage II (tumours>5 cm with no extra-adrenal invasion or lymph node metastases)2 3 at initial diagnosis and apparently disease free for 7 years. Then he progressed to extensive metastatic disease but well controlled with partial response to three cycles of EDP-M. His symptoms disappeared, liver lesions and lung nodules markedly decreased and abdominal wall lesion significantly reduced.
CONCLUSIONS
To our knowledge, this is the first case of ACC in Bangla- desh. Managing rare cancers is always a challenge. Our patient achieved partial response with EDP-M chemo- therapy even with extensive metastases. This illustrates that a person with a rare poor prognosis cancer can have prolonged survival, and extensive metastases be controlled.
Acknowledgements We thank our patient for giving the consent to publish his own case.
Contributors MS was responsible for acquisition of clinical information from the patient and wrote the whole manuscript. AD was the primary oncologist and involved in the clinical management of the patient. MNU coordinated clinical management. All authors read and approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Next of kin consent obtained.
Provenance and peer review Not commissioned; internally peer reviewed.
@ Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
REFERENCES
1 Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med 2012;366:2189-97.
2 Vilchis-Cárdenas MA, López-Verdugo JF, Aragón-Tovar AR, et al. Adrenocortical carcinoma: a case report and literature review. Rev Mex Urol 2011;71:47-56.
3 Berruti A, Baudin E, Gelderblom H, et al. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23:vii131-8.
4 British Columbia Cancer Agency (BCCA). Cancer drug manual: mitotane. 2013 (Retrieved 25 Apr 2018).
5 Sangoi AR, Fujiwara M, West RB, et al. Immunohistochemical distinction of primary adrenal cortical lesions from metastatic clear cell renal cell carcinoma: a study of 248 cases. Am J Surg Pathol 2011;35:678-86.