Primary small cell neuroendocrine cancer of adrenal gland: a rare extrapulmonary small cell cancer

Abstract

Small cell cancer is an aggressive neoplasm of neuroendocrine origin that is most commonly found in the lungs. However, up to 5% of cases can be extrapulmonary. These have been reported to be located in the gastrointestinal and genitourinary systems and rarely in other locations. Only five prior cases of small cell cancer have been reported where the primary lesion is at the adrenal gland. Here we present the case of a female patient in her mid-50s who presented with right upper quadrant pain and was diagnosed with metastatic small cell carcinoma of the adrenal gland. The patient received palliative chemotherapy for her metastatic cancer and was ultimately admitted to hospice after progression of her disease. This case and the accompanying literature review highlight a rare manifestation of extrapulmonary small cell cancer.

Background

Small cell carcinoma (SCC) is a highly malignant poorly differentiated neoplasm of neuroendocrine origin that primarily arises in the lungs. It is characterised by early metastasis including to the liver, bones and brain. It portends a bad prognosis, with 5-year survival for metastatic disease of less than 5%.¹

Though most commonly found in the lung, 5% of SCCs are reported from outside the lung, in what has been termed extrapulmonary small cell cancer (EPSCC). This is most commonly reported in the gastrointestinal tract (approximately 20%), genitourinary (approximately 18%) and gynaecological origin (11%) cases. Many cases have an unknown primary site.^{2 3} Very rarely it has been reported to originate from the endocrine system, including the adrenal gland. Metastatic EPSCC has a similar aggressive course as pulmonary SCC, though significant differences in outcomes have been noted between different sites of origin for this tumour.³

Case presentation

A female patient in her mid-50s with a medical history significant for hypertension and diabetes presented to our emergency room with a history of right upper quadrant pain intermittently for the last 1 month that had progressively gotten worse. On presentation, the patient was haemodynamically stable with normal vital signs. On physical examination, she had diffuse right upper quadrant tenderness with a negative Murphy sign. The rest of her physical examination was unremarkable.

Investigations

Laboratory tests on admission showed a normal complete blood count. A complete metabolic panel showed mildly elevated liver enzymes with aspartate transaminase at 134 U/L, alanine transaminase at 150 U/L and mildly elevated bilirubin at 2.1 g/dL. Alkaline phosphatase was 212 U/L.

Due to concerns for hepatobiliary pathology, the patient initially had an ultrasound of the right upper quadrant. This was negative for any hepatobiliary pathology. The patient was subsequently admitted for further workup. On admission, a CT of the abdomen and pelvis was ordered. This showed a heterogeneous right adrenal mass measuring up to 3.9×8.1×4.4 cm, which was concerning for neoplastic process with direct invasion of the adjacent right lobe of the liver with tumour thrombus in the hepatic portion of the inferior vena cava (IVC) (figure 1). CT of the chest showed multiple intrathoracic lymph nodes thought to be metastatic. MRI of the brain was negative for any metastasis. The patient had endocrine workup done including serum cortisol, adrenocorticotrophic hormone, testosterone, androstenedione and serum catecholamine levels checked that were all unremarkable. She underwent laparoscopic adrenalectomy of the right side. Pathology of this was consistent with primary small cell cancer of the adrenal gland (figures 2–4). The microscopic appearance of the normal adrenal gland is depicted for reference as well (figures 5 and 6).

Figure 1.

CT of the abdomen and pelvis with contrast showed a 3.9×8.1 cm mass in the right adrenal gland.

Figure 2.

H&E stained section at 40× magnification showing nuclear moulding and fine salt and pepper chromatin.

Figure 3.

Immunohistochemical stain. Synaptophysin showing strong cytoplasmic positivity in tumour cells.

Figure 4.

Another neuroendocrine immunohistochemical marker. Chromogranin showing strong cytoplasmic positivity in tumour cells.

Figure 5.

H&E section of the normal adrenal gland at 4× magnification showing zona fasciculata (right upper) and glomerulosa (left lower).

Figure 6.

H&E section at 40× magnification of the same area. The vacuolated lightly eosinophilic cells having small rounded nuclei are of zona fasciculata, and tubular structures lined by eosinophilic columnar cells represent zona glomerulosa.

Differential diagnosis

The initial presentation of right upper quadrant pain and elevated liver enzymes were suspicious for hepatobiliary pathology. However, CT of the abdomen revealed an adrenal neoplasm. The size of the tumour was large and it was irregular in shape and invading the surrounding tissue, raising strong suspicion of an aggressive cancer. Table 1 presents the differences between benign and malignant adrenal masses. Surgical resection confirmed the diagnosis of adrenal SCC in our patient.

Table 1.

The differences between benign and malignant adrenal masses

	Benign adrenal lesions	Malignant adrenal lesions
Size	<4 cm	>4 cm
Shape	Regular with sharp margins	Irregular with blurry margins
Texture	Usually homogeneous	Usually heterogeneous
Haemorrhage/necrosis	Rare	Common
Density	<10 Hounsfield units	>10 Hounsfield units

Treatment

On admission, the patient was treated with intravenous fluids and pain medications. Her hospital course was complicated by multiple pulmonary embolisms likely from her IVC thrombus for which she was treated with anticoagulation. She was discharged in a stable condition on oral apixaban.

Outcome and follow-up

The patient followed up with oncology as an outpatient and was treated with cisplatin and paclitaxel as an outpatient. She completed four cycles of chemotherapy; however, she developed significant side effects from the chemotherapy and her functional status declined. This was complicated by severe back pain due to metastasis to the vertebral column.

On follow-up imaging, she had progression of her disease with an increase in her primary tumour size and a significant increase in the size of the liver metastasis (figures 7 and 8). After a discussion with a multidisciplinary team, the patient decided to pursue a comfort care pathway and was admitted to a hospice facility.

Figure 7.

Repeat CT of the abdomen and pelvis with contrast on follow-up showed the adrenal mass had increased in size to 5.0×9.4 cm.

Figure 8.

Repeat CT of the abdomen showed significant increase in the size of the liver metastasis.

Discussion

Neuroendocrine tumours (NETs) can be found throughout the body and originate from neuroendocrine cells. They are diagnosed based on histology and immunohistochemistry. According to WHO classification, they can be classified based on their grade and tumour activity. The neuroendocrine tumour grade 1 (NET G1) is the most benign form with the least tumour activity. These are followed by NET G2, NET G3 and neuroendocrine carcinoma (NEC). NEC is the most malignant form and itself can be classified into small cell NEC (or just small cell cancer) and large cell NEC. NECs are by definition poorly differentiated, much more aggressive and have significantly worse outcomes as compared with other NETs.¹

Small cell cancer is most frequently found in the lungs, in around 95% of cases. However, like other NETs, it can be found all over the body including the gastrointestinal, genitourinary and endocrine systems.^{2 3} A review of the literature shows only five prior cases of SCC of adrenal origin previously reported.^4–8 These have been summarised in table 2.

Table 2.

Summary of all the prior reported cases of small cell lung cancer located at the adrenal gland

Case	Age/sex	Presentation	Laterality	Size (cm)	Comorbidities	Immunohistochemistry	Stage	Treatment	Outcome
Dong et al4	50s/M	Left back pain	Left	7.8×6.6	Unknown	NA	Locally advanced	Adrenalectomy and nephrectomy	NA
Chang et al5	60s/M	Asymptomatic	NA	NA	NA	Chromogranin A, synaptophysin	Metastatic	Etoposide, cisplatin	Died
Ogawa et al6	70s/M	Left flank pain	Left	5.1×3.6	DM	CD56, synaptophysin	Localised	Adrenalectomy and nephrectomy	Progression/died
Lee et al7	60s/F	Right flank pain	Right	11.4×6.5	Chronic hepatitis C, smoking history	Keratin AE1/AE3, synaptophysin, thyroid transcription factor-1	Localised	Adrenalectomy/ neoadjuvant etoposide and cisplatin	Remission
Limonnik et al8	60s/M	Left flank pain	Left	18.3×12.2	NA	NA	Localised	Resection, adjuvant chemoradiation	Remission
Our case	50s/F	Right flank pain	Right	3.9×8.1 cm	HTN, DM	Chromogranin A, synaptophysin	Extensive metastases	Palliative chemotherapy	Progression

NA; Non-applicable

DM, diabetes mellitus; HTN, hypertension.

In a review of the prior reported cases, the mean age was 63.1 years. Most of the patients were in their 50s and 60s with only one patient reported to be in his 70s. Four of the prior reported cases were male and only one was a female. Three of the prior reported cases were located on the left side and one was reported on the right side. Our case was the second reported case on the right side. Laterality was not reported in one case. The presentation in most case was flank pain on the side of the tumour, with one patient being asymptomatic at the time of presentation. Only one patient reported by Lee et al⁷ was reported to have a smoking history. This is consistent with prior studies that show no significant association of smoking with EPSCC.⁹ All the patients were diagnosed based on biopsy and immunohistochemistry.

Outcomes were reported in four of the prior cases. Three patients reported by Ogawa et al,⁶ Lee et al⁷ and Limonnik et al⁸ had localised disease to the adrenal gland with no local or distant invasion at the time of presentation. One patient reported by Ogawa et al had only localised disease to the adrenal gland and underwent laparoscopic adrenalectomy. Since he was in his 70s with multiple comorbidities, he was not given any adjuvant chemotherapy. This patient was found to have metastasis to the spleen on 6-month follow-up scans and subsequently passed away from his cancer.

On the other hand, the two patients reported by Lee et al and Limonnik et al both had localised disease as well at presentation. The patient reported by Lee et al initially underwent a biopsy that was consistent with small cell cancer. The patient subsequently received three cycles of etoposide and cisplatin that resulted in significant reduction in the size of the tumour and this was followed by adrenalectomy. The patient remained disease free on follow-up. The patient reported by Limonnik et al also had localised disease, and underwent adrenalectomy along with chemotherapy and radiation and was disease free at the time of reporting. It is interesting to note that two of the patients who received adjuvant chemotherapy for their localised disease are still living while one patient who did not receive adjuvant chemotherapy for his localised disease had progression of his disease and passed away.

Two of the prior reported cases were metastatic or locally advanced at the time of presentation. One case reported by Chang et al⁵ does not have any description and only reports the case in a table. The patient had metastatic disease at presentation and received an unknown number of doses of etoposide and cisplatin but ultimately passed away from his cancer. The other patient reported by Dong et al⁴ was found to have metastasis to lymph nodes in the thyroid gland and colon. The patient also had left renal vein thrombosis and underwent left adrenalectomy and nephrectomy. The authors do not mention any follow-up or disease course for this patient.

Our patient also had metastatic disease at the time of presentation and did not respond to chemotherapy in the form of etoposide and cisplatin. She eventually decided to enrol in hospice after the progression of her disease.

Learning points.

• Small cell cancer is an aggressive neoplasm of neuroendocrine origin that is most commonly found in the lungs; however, up to 5% of cases can be extrapulmonary.

• Extrapulmonary small cell cancer (EPSCC) is most commonly located in the gastrointestinal and genitourinary systems. Very rarely this has been reported to originate from the adrenal gland as well.

• Diagnosis is based on biopsy. Treatment involves tumour resection accompanied by adjuvant chemotherapy and/or radiotherapy.

• Outcomes for metastatic and locally advanced EPSCC like pulmonary small cell cancer are very poor.

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