Adrenal insufficiency after curative-intent gastric cancer treatment: a case report

Despite declining incidence over the past 50 years, gastric adenocarcinoma still constitutes a major global health burden and is currently the fifth most common malignancy worldwide [1, 2]. Early-stage gastric adenocarcinoma is often curable [2]. Unfortunately, more than 40% of patients present with advanced gastric cancer, which entails very poor prognosis and a median overall survival of less than a year among those fit for chemotherapy [1‐3]. The most frequent sites of metastases are the liver and peritoneum, while the adrenal glands are less commonly invaded [4]. Immediate impact on health is, however, potentially larger due to the risk of adrenal insufficiency, which can present acutely as a life-threatening adrenal crisis. Adrenal insufficiency is the clinical manifestation of deficient production or action of glucocorticoids. The underlying causes to adrenal failure can be primary or central (secondary or tertiary) [5]. Addison’s disease (that is, autoimmune adrenalitis) is the most common cause of primary adrenal insufficiency in developed countries, while long-term administration of exogenous glucocorticoids and prolonged suppression of hypothalamic secretion of corticotropin-releasing hormone is the most frequent risk factor for central adrenal insufficiency [5, 6]. Adrenal metastases are not rare and glucocorticoid therapy is very common in patients with advanced cancer, stressing the importance of an awareness of the mechanisms of adrenal insufficiency among all health professionals involved in clinical cancer care.

A 68-year-old White male presented with fatigue and unintentional weight loss at the 2-year follow-up visit after distal gastrectomy and lymphadenectomy due to locally advanced gastric adenocarcinoma. The medical history included hypertension and hypothyroidism, and the primary gastric cancer treatment consisted of perioperative chemotherapy according to the fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) protocol [2, 7]. According to a local oligometastatic treatment protocol, a left adrenalectomy was performed at the time of the gastrectomy due to a suspect adrenal metastasis detected on diagnostic imaging that had remained unchanged at preoperative evaluation imaging. The adrenal mass proved to be histologically benign with nodular hyperplasia, but no signs of malignant cells, while the pathology report of the gastrectomy specimen indicated high risk of recurrence, including a distressing ypTNM (pathological tumor–node–metastasis) stage after preoperative treatment, according to the American Joint Committee on Cancer (AJCC) staging manual 8th edition, and poor tumor regression according to Becker (Table 1) [8, 9].

Physical examination revealed a tired, cachectic man reporting 8 kg of unintentional weight loss over the last months, skin hyperpigmentation, and low blood pressure (100/70 mmHg). Routine blood tests showed minor deviations of serum electrolytes; elevated plasma potassium (5.0 mmol/L, reference range 3.5–4.6 mmol/L) and decreased plasma sodium (135 mmol/L, reference range 137–145 mmol/L). A routine control computed tomography (CT) scan, performed 2 weeks prior to the visit, revealed a 3 cm × 6 cm right adrenal mass (Fig. 1).

The patient history of contralateral adrenalectomy, together with clinical symptoms and signs, biochemical findings, and imaging, was indicative of adrenal insufficiency. Primary adrenal insufficiency was confirmed by decreased serum cortisol levels (73 nmol/L at 9 am, reference range 135–540 nmol/L), increased plasma adrenocorticotropic hormone (ACTH) levels (89 pmol/L, reference range 1.6–14 pmol/L), and a positive (that is, no steroid response) ACTH stimulation test. Glucocorticoid replacement therapy (10 mg of hydrocortisone twice daily) was initiated in consultation with an endocrinologist, with rapid improvement in fatigue, normalized body weight, and normalized serum electrolytes. Pathological examination of an ultrasound-directed biopsy of the right adrenal gland was consistent with metastasis from the previously treated gastric adenocarcinoma. The cancer cell proliferation rate was high and the predictive biomarkers human epidermal growth factor receptor 2 (HER2) and programmed death ligand 1 (PD-L1), were negative. The final diagnosis was thereby primary adrenal insufficiency caused by surgical removal of the left and gastric cancer metastatic invasion of the right adrenal gland. Mineralocorticoid replacement therapy was not initiated after balancing the potential side effects of mineralocorticoid  therapy (edema, muscle weakness, electrolyte deviations) against the expected complications of advanced cancer and chemotherapy, together with the poor prognosis that metastasized gastric cancer entails.

Radiological evaluation after 3 months (six cycles) of first line palliative chemotherapy, according to fluorouracil plus lecovorin, and irinotecan (FOLFIRI), showed no signs of extra-adrenal metastases and stable disease regarding the adrenal mass [10]. The latter was hence treated locally with stereotactic body radiotherapy (SBRT); 50 Gray in five fractions. The patient has thereafter been evaluated clinically together with radiology (CT, chest and abdomen) and laboratory tests (including a complete blood count, basic metabolic panel, liver panel, and the gastrointestinal cancer markers CEA, CA 19-9, and CA125) every 2–3 months. More than 17 months after the pathology-confirmed relapse of gastric adenocarcinoma, the patient is fully recovered and clinically well on glucocorticoid replacement therapy and with no radiological or biochemical signs of active malignant disease, except the residual right adrenal gland metastasis (Fig. 2).

In this report, we present a case of adrenal insufficiency caused by surgical removal of the left adrenal gland in conjunction with distal gastrectomy due locally advanced gastric adenocarcinoma, followed by recurrent metastatic invasion of the right adrenal gland 2 years after primary treatment. The patient recovered fully on glucocorticoid replacement therapy and the metastatic disease was controlled during an unexpectedly long time period using a less conventional multimodal treatment approach: irinotecan-based doublet chemotherapy followed by stereotactic body radiotherapy (Additional file 1: Fig. S1).

Inherent weaknesses of case reports are the lack of reproducibility and generalizability. There is also a risk of overinterpreting the benefits of the described multimodal treatment approach in this frail patient population. We still believe that this case report merits publication since adrenal insufficiency induced by malignant disease and its treatment is probably not rare, and there is a risk of delayed clinical management since symptoms mimic those of advanced cancer. The reported long-term survival is indeed encouraging, and even if only a small subset of patients gain from this approach, it is worth reporting since large randomized controlled trials are highly unlikely to take place.

Primary adrenal insufficiency is, by definition, caused by innate dysfunction of the adrenal glands [5, 6]. One well-functioning adrenal gland is generally enough to support adequate hormonal secretion [11]. Common symptoms of adrenal insufficiency include fatigue, weight loss, abdominal pain, nausea, and vomiting [5, 6]. Skin hyperpigmentation and hypotension are typical clinical signs, while biochemical findings include hyponatremia and hyperkalemia [5, 6]. Symptoms of adrenal insufficiency are typically unspecific, causing a delay in diagnosis and treatment initiation, but an adrenal crisis with hypovolemic shock can also be the first clinical presentation [5, 6]. In case of adrenal crisis, acute presentation is typically preceded by physiological stress, such as surgery, trauma, or infection [5, 6]. There are three main goals in the diagnosis of adrenal insufficiency; to confirm low cortisol secretion, to determine if the insufficiency is primary or central, and to establish the underlying cause. The treatment of adrenal insufficiency is glucocorticoid and, in selected cases, mineralocorticoid replacement therapy [5, 6]. An adrenal crisis requires intravenous glucocorticoids and immediate fluid resuscitation, including correction of electrolyte disturbances [5].

Consequent to an abundant blood supply, the adrenal glands are a common location for distant metastases, most frequently from malignant melanoma, lung, breast, renal, and gastrointestinal cancers [12]. The prevalence of adrenal insufficiency due to bilateral metastases has been reported to be low (3–8%) [13]. To our knowledge, there exist no systematic reports of primary adrenal insufficiency, following unilateral adrenal metastasis, in patients with a history of contralateral adrenalectomy, as described herein. Historically, locoregional therapy, including of adrenal metastases, is rarely considered in the metastasized setting [14]. Surgical management, that is adrenalectomy, has, however, recently been shown to improve outcomes in selected patient populations [15]. SBRT, including CT‐based planning and image guidance to deliver high doses of radiation with high precision to target lesions, constitutes a less aggressive locoregional treatment alternative [16]. SBRT of adrenal metastases has been reported to be clinically meaningful when systemic disease is under control [17].

In summary, this case highlights the importance of recognizing the clinical and biochemical symptoms and signs of adrenal insufficiency in all health care facilities managing patients with cancer, but also the role of locoregional treatment in the oligometastatic setting. The first can prove complicated since the classic symptom picture (fatigue, weight loss, abdominal pain, nausea, and vomiting) of adrenal insufficiency overlaps with that of advanced, especially gastric, cancer [5, 6, 18]. Still, adrenal glands are common sites of metastatic invasion and, although rare, adrenal insufficiency is a potentially life-threatening condition that is crucial to recognize, diagnose, and treat, accurately and timely. Metastasized gastric adenocarcinoma carries a dismal prognosis, but multimodal treatment, including locoregional therapy of oligometastatic disease, can prove beneficial in selected cases with systemic therapy disease control.