CASE REPORT
Adrenocortical carcinoma mimicking lung cancer and responding to vinorelbine/carboplatin and pemetrexed/carboplatin
Oluf Dimitri Røe,1,2,3 Per Arne Oppegaard,4 Mona-Elisabeth Revheim,5 Aud Svindland6
1Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway 2Cancer Clinic, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway 3Department of Oncology, Aalborg University Hospital, Aalborg, Denmark 4Department of Internal Medicine, Levanger Hospital, Levanger, Norway 5Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway 6Department of Pathology, Oslo University Hospital, Oslo, Norway
Correspondence to Dr Oluf Dimitri Røe, olufdroe@yahoo.no
Accepted 23 October 2014
SUMMARY
Adrenocortical carcinoma is an aggressive cancer, with an incidence of 0.5-2 per million. We present a case of adrenocortical carcinoma with all the clinical and partly immunohistochemical features of disseminated undifferentiated lung cancer, and ‘accidentally’ treated as such. Four cycles of carboplatin-vinorelbine conferred partial response in the adrenal, lung and disappearance of a 2 cm subcutaneous iliac nodule that had appeared suddenly before the first course. Owing to progression, four cycles of carboplatin-pemetrexed were administered inducing partial response and then stable disease for an additional 12 months. As fluoro-D-glucose (FDG)-positron emission tomography (PET) only showed activity in the adrenal, laparoscopic adrenalectomy was performed. Three months later FDG-PET revealed a lung nodule unresponsive to carboplatin-pemetrexed, removed by wedge resection. Finally, re-evaluation by a tertiary centre confirmed adrenocortical carcinoma with Ki67-50% in the adrenal and the lung. The patient is alive and tumour free almost 3.5 years after retrospective diagnosis of metastatic adrenocortical cancer.
BACKGROUND
Adrenocortical carcinoma (ACC) is a rare but aggressive cancer, with an incidence of 0.5-2 per million; it has a bimodal age distribution with a peak in children <5 years old and adults between 4th and 5th decade of life.1-3 Some cases are asso- ciated with rare genetic syndromes, such as the Beckwith-Wiedemann syndrome in childhood ACC, and in adult cases the Li-Fraumeni, multiple endo- crine neoplasia type 1 (MEN1) and Lynch syn- drome.45 The prognosis of this disease is dismal as the diagnosis usually presents at an advanced stage and the median survival is 12 months.6 Surgery may be curative but relapse is common even in early stages. Adjuvant treatment with mitotane, a peroral drug, has shown a survival benefit in a retrospective study of 177 patients. Mitotane was approved for this disease more than 40 years ago;7 8 it is a compound derived from the insecti- cide DDT. Its mode of action is inhibition of adre- nocortical cells and their production of hormones. In the metastatic setting, several phase I-II trials with combinatorial regimens have failed, but a recent large randomised study showed that etopo- side, doxorubicin and cisplatin plus mitotane were superior to streptozocin plus mitotane, increasing progression-free survival from 2.1 to 5 months, but
regrettably showing no statistical difference in overall survival.9
In clinical practice, sometimes there are unpleas- ant surprises, such as in this case, where the patient had been treated for what we believed was advanced lung cancer for 2.5 years until we realised he had a metastatic ACC. Mistakes are failures that clinical doctors would usually not want to publi- cise. However, given the rarity of ACC and how it mimicked metastatic lung cancer, it is clearly a case that we learned from and would naturally want to share with our colleagues. Moreover, the lung cancer chemotherapy regimens seemed to benefit our patient with minor side effects. There are no previously published accounts of these combina- tions for treating ACC. This ‘accidental’ treatment response is also a valid reason to share this case history, as the 1-year survival of metastatic ACC still is only 15%. Without knowing that it was ACC, the multidisciplinary team decided to perform relatively aggressive surgery based on fluoro-D-glucose (FDG)-positron emission tomog- raphy (PET) findings, which retrospectively was correct, as surgery is the only curative treatment of ACC.1
CrossMark
To cite: Røe OD, Oppegaard PA, Revheim M- E, et al. BMJ Case Rep Published online: [please include Day Month Year] doi: 10.1136/bcr-2014- 206225
Ethical considerations
Informed consent was obtained from the patient prior to writing this manuscript.
CASE PRESENTATION
The patient, a woman in her early 50s, had rheumatoid arthritis for several years, which was treated with methotrexate; there was no family history of cancer. She had smoked for the past 30 years but quit the previous year. She had no weight loss or other symptoms of an advanced cancer and was WHO performance status 0. In May 2011, she was admitted to our hospital with acute pain of the right flank. An ultrasound scan showed intra-parenchymatous bleeding of the right adrenal gland. No definite aetiology was estab- lished. The lesion was increasingly painful and the patient had several hospital admissions because of this.
INVESTIGATIONS
Subsequent CT scan at our hospital showed a lung tumour in the right upper lobe, multiple suspect metastatic nodules in both lungs and a cystic tumour in the left adrenal gland. The CA19-9 was marginally elevated (27kIE/L, range 0-27) and the
BMJ
Learning from errors
chromogranin A (CGA) fivefold (15.3 nmol/L, range 0-3), carci- noembryonic antigen (CEA) sevenfold (36 ng/ml, range 0-5) while CA125 and neuron-specific enolase (NSE) were normal (figure 1). The patient also had mild anaemia and leucocytosis.
A CT-guided Tru-cut lung biopsy from one of the metastases showed only atypical epithelial cells, positive CKAE1/AE3 and negative CK5/6, CK7, TTF1. An ultrasound-guided biopsy of the affected adrenal gland showed undifferentiated malignant
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cells and immunohistochemistry showed positive CKAE1/AE3 and vimentin and negative CK5/6, CK7, TTF1, BerEp4, chro- mogranin, synaptophysin, S100 and smooth muscle actin (SMA). No mutation in EGFR (epidermal growth factor recep- tor) gene exon 18-21 was found. For the evaluation of the extent of malignancy, an 2-deoxy-2-[18F]FDG PET/CT was per- formed in July 2011. The 18F-FDG PET/CT revealed increased 18F-FDG uptake in a spiculated tumour in the right upper lobe, which had grown from 6 to 18 mm in 3 years, and several small new lesions in the right and left lower lobe (figure 2; 18F-FDG PET/CT).
DIFFERENTIAL DIAGNOSIS
The primary pathologist’s report stated that the diagnosis could be ACC, but that cytokeratin CKAE1/AE3 positivity was not consistent with that, and thus primary lung cancer could not be ruled out. Moreover, negative TTF1 do not exclude the lung cancer diagnosis. Chromogranin and synaptophysin in the tumour were negative, excluding a neuroendocrine tumour, which made the elevated serum CGA unexplainable. As the hist- ology did not give a clear answer on the origin of the tumour, the clinical and radiological picture aided diagnosis. The patient had smoked cigarettes for many years, 18F-FDG PET/CT picture was consistent with primary lung tumour with metastasis to the lung and right adrenal, and the oncologist (ODR) and the pul- monary specialist (PAO) both agreed that the diagnosis of undif- ferentiated metastatic non-small cell lung cancer (NSCLC) was the most plausible.
TREATMENT
The patient received our standard treatment for metastatic NSCLC, four courses of carboplatin (AUC5, days 1 and 22) and
vinorelbine (55 mg days 1, 8 and 22), which were well tolerated with only minor fatigue and without delays. A subcutaneous nodule 2 cm in diameter in the left iliac, which had rapidly developed before start of treatment, disappeared after two courses, indicating chemosensitive disease. Evaluation by CT in October 2011 showed partial remission of all manifestations. A CT in December 2011 showed an increase in size of the ‘primary’ lung tumour but regression of the other lung lesions. Another CT scan performed in January 2012 showed new small lesions in both lungs. Now the CEA was normalised, CA19-9 had almost doubled and CGA was elevated 33-fold. CA19-9 can be elevated in lung carcinomas, and we speculated whether the massively elevated CGA was due to a tumour clone that was not apparent in the biopsies (figure 1).
Owing to the rapid recurrence of new lesions and an apparent non-squamous NSCLC diagnosis, four courses of pemetrexed (800 mg days 1 and 22) and carboplatin (AUC5 days 1 and 22) were administered from February to April 2012. There was a complete response of the lung tumour and some of the meta- static nodules in the lungs as well as a marked shrinkage of the adrenal tumour. These courses were also well tolerated with minor side effects.
In November 2012, methotrexate and steroids were reinstated due to increasing rheumatoid arthritis symptoms.
CA19-9, an epithelial tumour marker of the upper gastro- intestinal tract and CGA, a neuroendocrine marker, were repeat- edly measured due to elevated values. The CGA, even if very high, did not appear to follow the clinical pattern, while CA19-9 appeared to follow the response after the pemetrexed- carboplatin treatment (Time-line from the first diagnosis, PET-CT findings, treatments, responses and biomarkers are sum- marised in figure 1).
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OUTCOME AND FOLLOW-UP
Surprisingly, the situation stabilised without any treatment with a progression free interval of 1 year, and an 18F-FDG PET-CT in March 2013 showed stable but active disease only in the right adrenal gland (figures 2 and 3). The tertiary centre MDT meeting decided to operate and the adrenal gland was laparo- scopically extirpated in May 2013.
A control CT 2 months later revealed a 3 mm nodule in the right upper lobe and 1 month later the size was increased to 8 mm. After re-induction with three courses of pemetrexed-car- boplatin, this solitary nodule progressed to 19 mm in October 2013. A full-body 18F-FDG PET/CT in October 2013 showed uptake only in this nodule (figure 4). Wedge excision of the tumour was performed in November 2012 by video-assisted thoracoscopy and the histology was identical with that of the adrenal, undifferentiated carcinoma.
Owing to uncertainty of the diagnosis, our pathologist required re-evaluation of the PET-positive lung tumour and adrenal gland at the tertiary centre at Oslo University Hospital (OUS). Gross inspection of the lung and adrenal specimens dis- played delineated heterogeneous, white-yellow viable to red nec- rotic tumours with apparent clear margins. Microscopically, a diffuse growth pattern interrupted by necrotic areas was found.
Irregular epithelioid cells with eosinophilic cytoplasm were pre- dominant, but giant cells with nuclear pleomorphism and hyper- chromasia were also seen throughout the tumour with groups of atypical spindle cells. No specific mesenchymal or oncocytic dif- ferentiation was identified. The average mitotic activity was 15/ 10 high-power fields (HPFs), the proliferation index Ki67 was 50% and multiple atypical mitotic figures were seen. An immu- nohistochemical panel showed that the tumours were diffusely positive for vimentin, patchy positive for AE1/AE3 keratin and Melan A, and multifocal clusters of tumour cells stained for cal- retinin. Negative staining was seen for EMA, CK7, CK20, CK5/ 6, BerEP4, TTF1, chromogranin, synaptophysin, S-100, SMA, inhibin and CD117c-kit (figure 5). Based on tumour morph- ology and immunoprofile the final diagnosis was pleomorphic ACC. The patient was then started on adjuvant mitotane, is still alive and tumour free 3 years and 4 months after the retrospect- ive diagnosis of metastatic adrenocortical cancer.
DISCUSSION
Metastatic NSCLC has a median survival of 12 months and metastatic ACC has a 1-year survival of only 15% with even fewer treatment options.9 This disease is generally considered to be chemoresistant, however, there are case reports of long-term
Learning from errors
survivors of advanced ACC treated in a multimodal fashion.10 In a large recent trial on ACC, combinations of mitotane with etoposide, doxorubicin and cisplatin were tried, without improving overall survival.9 In a small retrospective series radio- therapy was seemingly effective in a palliative setting with clin- ical or radiological responses in 10 of 12 cases.11 The current case is presented because it has important teaching points regarding diagnosis and treatment of this rare cancer.
The first lesson is the difficulty of obtaining a correct clinical and pathological diagnosis of ACC, especially when the clinical presentation apparently does not fit with the suggested diagno- sis. In this case our patient was primarily treated under the diag- nosis of a disseminated NSCLC, with metastasis to the right adrenal; it was only later that it was revealed to be quite the opposite, an ACC with metastasis to the lungs. An important clinical detail was the presentation of the cancer with bleeding in the adrenal tumour. In a large series of adrenal bleeding, 6.4% had adrenal neoplasm and 10/14 cases were metastatic. However, as an ACC is rare, there is a much higher possibility that adrenal bleeding could represent a primary ACC.12 The re-evaluation in a tertiary centre concluded that the morpho- logic features were strongly suggestive of a pleomorphic ACC. Diagnosis of an ACC is not easy, as it shares several similarities with other types of cancers.13 The ACC has no pathognomonic immunohistochemical profile,14 but positive immunostaining for vimentin, Melan A and calretinin, and negative CK7, BerEPA4 and TTF1 staining strongly support the diagnosis. The tumours in this case additionally stained positive for cytokeratin AE1/ AE3. Although AACs are typically cytokeratin negative, some studies have reported ACCs with cytokeratin positive cells, 15-17 and a recent publication refers to approximately 20% positive staining for CAM5.2.3
The second lesson was the surprising effect of vinorelbine, an antitubuline and pemetrexed multifolate inhibitor in combin- ation with carboplatin, when we realised that the patient had ACC. Both these regimens were clearly active in all manifesta- tions, in the lungs as well as in the adrenal tumour, and it seems that there were two populations of the tumour, the first vinorel- bine sensitive and the second pemetrexed sensitive. The largest reduction of tumour was seen with the first-line treatment with vinorelbine-carboplatin, but shortly after four cycles some small lung lesions emerged that were not seen previously. These were reduced after four cycles of pemetrexed-carboplatin. This indi- cates a separate effect of the two drugs combined with the car- boplatin. Monotherapy of carboplatin has not been published, but there are reports of the effect of cisplatin monotherapy. The progression free interval without treatment for over 1 year after second-line treatment was also not expected, nor was the dis- appearance of 18F-FDG-positive lesions in the lung, while the tumour in the adrenal gland still maintained metabolic activity (figures 2 and 3). To the best of our knowledge there are no published reports on ACC treated with pemetrexed or vinorel- bine. In this case we verified partial response with compounds and relapse-free survival of over 2 years. Is there any molecular rationale that these compounds should be effective in ACC? Several molecular features of ACC could explain the effect of these compounds as overexpression of the TOP2A.18
Finally, the wrong diagnosis could have lead to treatment inferior to that which is recommended, and to toxicities due to non-recommended treatment and even worse outcome. The adrenal and the lung lesions were not eradicated by the chemo- therapy. However, successful radical surgery of remaining PET-positive lesions and no local relapse in either site after exci- sion seem to have prolonged this patient’s life.
Learning points
Adrenocortical carcinoma diagnosis can be missed due to clinical and morphological similarities with other cancers. Owing to the rarity of this cancer, a well-founded suspicion should elicit an early second opinion at a referral centre.
In this case, new chemotherapy doublets, vinorelbine- carboplatin and pemetrexed-carboplatin showed clinically meaningful effect in this case of metastatic adrenocortical carcinoma.
Radical surgery of remaining positron emission tomography- positive lesions seems to have prolonged this patient’s life.
Acknowledgements The authors thank Dr Thomas Keil and the Department of Nuclear Medicine, St Olavs Hospital for kindly providing the PET-CT pictures.
Contributors ODR treated the patient and wrote the manuscript. PAO also followed and treated the patient and contributed to the manuscript. M-ER performed the PET-CT analysis and co-wrote the manuscript. AS performed the immunohistochemistry and co-wrote the manuscript.
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES
1 Lebastchi AH, Kunstman JW, Carling T. Adrenocortical carcinoma: current therapeutic state-of-the-art. J Oncol 2012;2012:234726.
2 Bourdeau I, Mackenzie-Feder J, Lacroix A. Recent advances in adrenocortical carcinoma in adults. Curr Opin Endocrinol Diabetes Obes 2013;20:192-7.
3 Weissferdt A, Phan A, Suster S, et al. Adrenocortical carcinoma: a comprehensive immunohistochemical study of 40 cases. Appl Immunohistochem Mol Morphol 2014;22:24-30.
4 Mazzuco TL, Durand J, Chapman A, et al. Genetic aspects of adrenocortical tumours and hyperplasias. Clin Endocrinol 2012;77:1-10.
5 Raymond VM, Everett JN, Furtado LV, et al. Adrenocortical carcinoma is a Lynch syndrome-associated cancer. J Clin Oncol 2013;31:3012-18.
6 Urup T, Pawlak WZ, Petersen PM, et al. Treatment with docetaxel and cisplatin in advanced adrenocortical carcinoma, a phase II study. Br J Cancer 2013; 108:1994-7.
7 Lubitz JA, Freeman L, Okun R. Mitotane use in inoperable adrenal cortical carcinoma. JAMA 1973;223:1109-12.
8 Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 2007;356:2372-80.
9 Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med 2012;366:2189-97.
10 Fujii Y, Kageyama Y, Kawakami S, et al. Successful long-term disease-free survival following multimodal treatments in a patient with a repeatedly recurrent refractory adrenal cortical carcinoma. Int J Uro/ 2003; 10:445-8.
11 Ho J, Turkbey B, Edgerly M, et al. Role of radiotherapy in adrenocortical carcinoma. Cancer J 2013; 19:288-94.
12 Benavente-Chenhalls LA, Vella A, Farley DR, et al. Malignant adrenal neoplasm masquerading as worrisome adrenal hemorrhage. Ann Surg Oncol 2010;17:2710-13.
13 Berruti A, Baudin E, Gelderblom H, et al. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23(Suppl 7): vii131-8.
14 Lack EE. Tumors of the Adrenal Glands and Extraadrenal Paraganglia, AFIP Atlas of Tumor Pathology Vol. 8, 2008, American Registry of Pathology, ISBN: 978-1- 881041-01-6.
15 Coli A, Di Giorgio A, Castri F, et al. Sarcomatoid carcinoma of the adrenal gland: a case report and review of literature. Pathol Res Pract 2010;206:59-65.
16 Gaffey MJ, Traweek ST, Mills SE, et al. Cytokeratin expression in adrenocortical neoplasia: an immunohistochemical and biochemical study with implications for the differential diagnosis of adrenocortical, hepatocellular, and renal cell carcinoma. Hum Pathol 1992;23:144-53.
17 Kao CS, Grignon DJ, Ulbright TM, et al. A case report of adrenocortical carcinosarcoma with oncocytic and primitive neuroectodermal-like features. Hum Pathol 2013;44:1947-55.
18 Jain M, Zhang L, He M, et al. TOP2A is overexpressed and is a therapeutic target for adrenocortical carcinoma. Endocr Relat Cancer 2013;20:361-70.
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BMJ Case Reports: first published as 10.1136/bcr-2014-206225 on 12 November 2014. Downloaded from http://casereports.bmj.com/ on 5 April 2026 at National Library of Medicine.