Expectorated metastatic adrenocortical carcinoma: a rare presentation of a rare tumour

Abstract

A 61-year-old woman who was originally diagnosed with locally advanced adrenocortical carcinoma (ACC) 10 years ago, developed massive haemoptysis while away from the UK. Initial investigations revealed a left upper lobe lesion requiring embolisation. Bronchoscopic evaluation was unsuccessful in identifying an underlying cause, and cytology was suggestive of an inflammatory cause. A rigid bronchoscopy was planned but prior to this the patient coughed up a lump of tissue which was sent for histopathological examination. Morphology and immunohistochemistry were consistent with metastatic ACC. ACC is a rare and aggressive tumour of the adrenal cortex. The histological appearances of ACC are similar to that of a carcinoid tumour, creating diagnostic difficulty given the presumed endobronchial origin of the expectorated material in this case. Accurate clinical information and judicious use of immunohistochemistry were key to making the diagnosis. To the authors knowledge, this is the first described case of expectorated metastatic ACC.

Background

This report describes the presentation and diagnosis of a rare metastatic tumour, and the importance of submitting relevant material for histopathological examination and correlation with clinical history.

Adrenocortical carcinoma (ACC) is a rare and aggressive tumour of the adrenal cortex with an incidence of around 1 per million population.¹ Prognosis of ACC is poor, with a 5-year survival of 15%–44%.² The diagnosis of ACC is based upon a number of criteria including clinical presentation, not just histology alone given the difficulty in differentiating between an adrenocortical adenoma and carcinoma.

We report a case of ACC with pulmonary metastases, presenting 10 years after original diagnosis of a locally invasive tumour. Part of the metastasis was expectorated by the patient, providing enough material for definitive diagnosis. This case demonstrates how diagnostic material can be obtained in unusual ways and the importance of excluding mimics at the same site.

Case presentation

A 61-year-old woman with a history of papillary thyroid carcinoma and locally aggressive ACC developed massive haemoptysis.

She originally presented 10 years previously with left sided abdominal pain, headaches, occasional vomiting and hypertension. On examination her abdomen was soft, with a large left-sided mass. An initial CT scan in France was reported as an 11 cm diameter lesion, most likely originating from the left adrenal gland, and extending into the inferior vena cava and right atrial appendage.

Following this she underwent elective laparotomy to remove the left kidney and adrenal gland, inferior vena cava and right atrial tumour thrombectomy with cardio-pulmonary bypass and circulatory arrest. She had a good postoperative recovery, and was treated with 5 years of adjuvant mitotane and discharged.

Five years after completing treatment, and ten years after the initial presentation, the patient developed significant haemoptysis whilst in France. Radiological investigations revealed a left upper lobe lesion of uncertain aetiology. The lesion was embolised under general anaesthetic, and she underwent further investigation on return to the UK.

Investigations

CT pulmonary angiogram (CTPA) was performed following embolisation, which showed multiple pulmonary metastases, mediastinal lymphadenopathy, bilateral pulmonary emboli and a new lesion in the left renal bed which could represent a recurrence of the original tumour or a metastatic deposit.

Bronchoscopy was performed but was unable to yield further information, and biopsy was not possible due to bleeding at this stage. A further rigid bronchoscopy was planned, but prior to this the patient spontaneously expectorated a large lump of tissue which she brought to clinic.

The tissue was formalin-fixed and sent to cellular pathology for examination.

The expectorated material consisted of a small dark brown nodule (figure 1) measuring 15×15×6 mm and resembling part of a lymph node with attached cream material. The nodule was bisected and all embedded.

Figure 1.

Expectorated nodule, bisected and paraffin embedded.

The microscopic features were sheets of epithelioid cells with a mixture of eosinophilic and clear cytoplasm arranged in a trabecular and nested pattern with scattered mitoses (figure 2). Slides from the patient’s original adrenal tumour in 2009 (figure 3) were pulled from filing and examined for comparison. The morphology was consistent with the original tumour.

Figure 2.

Haematoxylin & eosin (H&E) stained sections from expectorated tumour (100× and 400× magnification) show epithelioid/clear cells with nested architecture.

Figure 3.

Histology from original primary adrenocortical carcinoma (H&E, 100× and 400× magnification) showing epithelioid cells with eosinophilic cytoplasm arranged in a trabecular pattern.

Confirmatory immunohistochemistry was undertaken, and the tumour cells showed strong and diffuse positivity for CD56, synaptophysin, melan-A and weaker staining for inhibin and calretinin (figure 4). The tumour cells were negative for chromogranin (CGA), cytokeratin 7 (CK7), cytokeratin 20 (CK20), thyroid transcription factor 1 (TTF-1) and thyroglobulin. The morphology and immunophenotype were consistent with metastatic adrenocortical carcinoma (ACC).

Figure 4.

Immunohistochemical staining pattern for metastasis (200× magnification). Top left: positive membranous CD56; top middle: focal cytoplasmic inhibin staining; top right: positive cytoplasmic synaptophysin; bottom left: weak diffuse cytoplasmic calretinin; bottom middle: focal cytoplasmic melan-A; bottom right: negative chromogranin A.

Differential diagnosis

Many different tumours can present with expectoration of tumour material, although this is a very rare occurrence.³ The most common causes are metastatic renal cell carcinoma, followed by primary lung cancer. In this case the history of primary ACC was the most important consideration.

The histological appearances resembled a neuroendocrine tumour. Given the nested architecture, presence of necrosis and relatively high mitotic rate, an atypical carcinoid tumour was the top differential diagnosis. Endobronchial carcinoid tumours have been described. The tumour cells showed staining for CD56 and synaptophysin but were negative for chromogranin, which is a more specific marker for carcinoid tumours.

Non-small cell lung cancer was also considered given the endobronchial site as locally invasive tumours can involve the bronchus, but the histological appearance and immunoprofile were not compatible. Metastatic thyroid carcinoma was considered given the previous clinical history, but this tumour lacked papillary nuclear features characteristic of papillary thyroid carcinoma and was negative for TTF-1 and thyroglobulin making thyroid an unlikely origin.

Overall, the history and histopathological findings confirmed a metastasis from the original locally advanced ACC.

Treatment

The patient was managed with steroids after the initial episodes of haemoptysis, and continued treatment despite significant weight gain.

Following the diagnosis of pulmonary emboli on CTPA, she was commenced on low molecular weight heparin then switched to rivaroxaban.

Surgical debulking was considered but taking into account the patient’s wishes and prognosis, mitotane alone was restarted, as it was tolerated well when previously given as adjuvant treatment at the time of first diagnosis. Systemic chemotherapy consisting of etoposide, doxorubicin and cisplatin with mitotane (EDP-M) is standard of care and was discussed with the patient, but she felt her quality of life would be better with mitotane alone.

The patient had good support from family, friends and her church, and was referred to the community palliative care team.

Outcome and follow-up

Following diagnosis of metastatic disease, an updated CT scan showed disease progression with the largest lung metastasis measuring 38 mm. Recurrent disease was also confirmed in the left adrenalectomy/nephrectomy bed.

Nine months on from a tissue diagnosis of metastatic ACC, and over a year after presenting with haemoptysis, the patient was still alive and receiving mitotane.

The patient coughed up several more pieces of presumed tumour following the initial episode. The largest fragment was the size of a chickpea.

Discussion

ACC is a tumour derived from cells in the adrenal cortex. They are rare tumours (1/1 000 000 incidence), with a predilection for females and a peak in the fifth and sixth decades of life.¹ They represent up to 14% of adrenal incidentalomas. ACCs are mainly sporadic, but can feature as part of hereditary syndromes such as Beckwith-Wiedemann syndrome and Li-Fraumeni syndrome.

Half of ACCs are functional presenting with virilisation, or a mixed syndrome with Cushing’s and virilisation. Non-functional tumours typically present with gastrointestinal symptoms, or back pain resulting from mass effect. In this case the patient presented with abdominal pain, vomiting, headaches and hypertension.

The cases are mostly unilateral, affecting the left adrenal more often than the right, as was the case with this patient. Most tumours are high grade at time of diagnosis with two-thirds poorly differentiated or undifferentiated.¹ Disease stage at diagnosis predicts prognosis, with stage I patients having an expected 5-year survival of 80%, dropping to 5-year survival of 13% in stage IV.⁴

Surgical resection is the primary management option, with some patients receiving adjuvant radiotherapy or adjuvant chemotherapy. Mitotane is frequently used in the management of ACC to inhibit steroidogenesis, resulting in adrenal insufficiency.⁵ Mitotane is recommended in the adjuvant setting following surgery in patients with incomplete resection or high risk of recurrence, and has been shown to improve recurrence free survival.⁶ However it is not without risks. There are side effects and toxicity if mitotane levels are not adequately controlled, and concomitant corticosteroid therapy is required. Treatment options in advanced stage ACC are limited, and treatment failure is common despite aggressive management with mitotane and combination chemotherapy (EDP-M).⁷

Tumours of the adrenal gland may be primary or secondary, and a combination of morphology and immunohistochemistry helps guide diagnosis, particularly when differentiating adrenal cortical tumours from medullary tumours (phaeochromocytoma). The majority of adrenal cortex tumours stain positive for inhibin, calretinin and melan-A, as seen in our case.⁸ Chromogranin is negative in cortical tumours and mostly positive in phaeochromocytoma, and synaptophysin is largely unhelpful as it may be positive in either tumour. Tyrosine hydroxylase staining is specific for adrenal medullary tumours but not routinely available in most histopathology departments. None of the markers are 100% sensitive and specific, and should be used together in a panel.

The only absolute criteria for diagnosis of malignancy in an adrenal cortical tumour is local invasion and metastasis, as ACC can be histologically identical to an adrenal adenoma. Several systems have been used to better differentiate benign and malignant adrenal cortex tumours and predict prognosis, most commonly the Weiss and modified Weiss criteria. Tumours are scored for cytological and architectural features, and evidence of locally aggressive disease including vascular and capsular invasion. A score of 3 or more (maximum score is 9 in Weiss and 7 in modified Weiss) indicates aggressive behaviour. On review of the primary tumour histology in this case, the tumour scored 6 with the Weiss criteria and 4 on the modified Weiss. Locally advanced disease was present in this case, with tumour extending into the right atrium.

Tumour expectoration is an extremely rare presentation of pulmonary metastatic disease. There have been around 30 cases of patients expectorating tumour fragments, arising from primary and secondary tumours.^{3 9–11} There is no name for this clinical phenomenon, though some authors proposed histoptysis or oncoptysis.¹⁰ To the authors knowledge, this is the first described case of an expectorated metastasis from an ACC. A rare tumour with an even rarer presentation.

Learning points.

• Spontaneously expectorated material should not be discarded immediately. If substantial or suspicious, it should be fixed and sent for histopathological examination.

• Providing accurate clinical information for pathologists is crucial, as the tumour could have been incorrectly diagnosed as carcinoid based on morphology alone and basic immunohistochemistry.

• Treat pathology specimen requests like referring to another medical specialty and you will not go far wrong.