Cushing syndrome secondary to a mediastinal carcinoid tumor: a case report

Abstract

Neuroendocrine tumors (NET) are a rare and diverse set of malignancies that can develop anywhere within the body. ACTH-producing mediastinal NETs often originate from the thymus in the anterior mediastinum and are very rare. Primary diagnostic modalities for NETs include CT scan, MRI, scintigraphy, and Ga-DOTA PET scan. Here we report a case of a young male without any past medical history presenting with hypercortisolism secondary to a middle mediastinal typical carcinoid tumor. The patient underwent a successful resection which reduced serum ACTH levels. To the best of our knowledge, this is the first case of Cushing syndrome caused by a middle mediastinal NET.

Introduction

Hypercortisolism, also known as Cushing syndrome, has a prevalence range of 39–79 cases per million. Cushingoid appearance (including buffalo hump and moon face), fatigue, depression, sexual dysfunction, hyperglycemia hyperlipidemia, and decreased bone density are common manifestations of the disease [1]. Hypercortisolism could be due to pituitary adenoma (Cushing disease), Ectopic adrenocorticotropin hormone (ACTH) releasing masses, adrenal masses, and exogenous corticosteroid usage [2].

Neuroendocrine tumors (NETs) are rare causes for ectopic ACTH-releasing hypercortisolism. NETs are derived from neural and endocrinal linage and could originate from different sites [3]. Even though they are divided into different grading based on their pathology and behavior, surgery is a curative option. Other treatment options include somatostatin analogs and targeted therapy [4].

Here, we present an otherwise healthy patient with Cushing’s syndrome caused by NET in the mediastinum. He received medications to control the symptoms, and thereafter, the surgical team resected the tumor as the ideal treatment option.

Case presentation

A 28 y/o Iranian male, without any prior medical conditions, presented to Imam Khomeini hospital with a complaint of gradual onset obesity, weakness, depressive symptoms, and loss of libido from a year ago. He did not have any history of addiction, cigarette smoking, or alcohol consumption and was not taking any kind of medication. In physical examination, central obesity, purplish striae around the abdomen, and buffalo hump were notable (Fig. 1a and b). Additionally, he had high blood sugar in his tests. Supplementary lab tests were obtained with a high suspicion for Cushing syndrome. Serum cortisol level at 8 AM after low dose dexamethasone suppression test was 28.6 (5.2–22.4), and ACTH was 179 pg/ml (up to 46). Cortisol level was also elevated in the high-dose dexamethasone suppression test. With our suspicion confirmed and given the high dose suppression test results and high level of ACTH, a brain MRI of the pituitary was performed to see if there is an ACTH-releasing tumor. The brain MRI showed no sign of a pituitary tumor, so the patient underwent abdominal ultrasound and abdominopelvic computed tomography (CT) scan in search for an ectopic intra-abdominal ACTH secreting tumor, which also showed no positive finding. A thoracic CT scan was subsequently performed, revealing a suspicious lesion in the mediastinum. An octreotide whole-body scintigraphy also reported a lesion in the mid-thoracic region (Fig. 2a). A PET-CT scan with Ga-DOTATATE was then obtained, finding a solitary 17 × 12.5 mm lesion in the paratracheal area in proximity to superior vena cava (SCV) and aorta (Fig. 2b). Prior to surgery, a diagnostic bronchoscopy was performed with unremarkable results.

Fig. 1.

a Fat deposition in posterior neck area (buffalo hump) at presentation. b Central obesity and purplish striae in abdominal area at presentation

Fig. 2.

a Octreotide scintigraphy showing uptake in mediastinal region. b Coronal and axial view of Ga-DOTATATE PET-CT scan revealing an avid lesion in para-tracheal region

The patient was listed for a resection by video-assisted thoracoscopic surgery (VATS) technique. During the procedure, the solitary tumor was detected, but the tumor’s proximity and adhesion to SVC and aorta limited the surgeon’s ability to perform optimal resection, and therefore, open thoracotomy was applied instead. Tumor and lymph node resection was performed successfully. Figure 3 illustrates the gross appearance of the resected tumor. No significant bleeding was found during surgery, and no perioperative complication occurred, including surgical site infection. Pathology assessment of tumor revealed a neoplasm with a uniform round to ovoid nuclei with salt and pepper chromatin, clear to granular acidophilic cytoplasm arranged in small nests. Mitotic figures and necrosis are not found. In the immunohistochemical study (IHC), perinuclear CK staining, strong chromogranin, synaptophysin, and ACTH staining with about 1% proliferative activity (Ki-67) are noted. The cells were negative for GATA3 and S100 (Fig. 4). Additionally, one out of five resected lymph nodes had equivocal evidence of tumor invasion. ACTH level was measured on the second postoperative day, which was decreased to less than 5 pg/ml. The patient was started on oral corticosteroids and mineralocorticoids as replacement therapy which eventually was tapered off. After discharge from the hospital, he has been under close surveillance for signs of recurrence. His symptoms started to decrease during the follow-ups, and his clinical signs (like purplish striae, buffalo-hump, and moon-shaped face) diminished.

Fig. 3.

Gross appearance of the resected tumor

Fig. 4.

Pathological findings of the study. A H&E staining show low-grade neuroendocrine tumor (40X magnification). B CK staining shows perinuclear staining. C Chromogranin staining D Strong positivity for ACTH. E IHC study for Ki-67reveal less than 1% nuclear staining; compatible with well-differentiated neuroendocrine tumor

Discussion

The patient was a young man with signs and symptoms of hypercortisolism who was diagnosed with a tumor in the middle mediastinum, which is a unique place for NET. He was treated with surgical tumor resection that caused a decline in serum cortisol levels.

Cushing syndrome is most commonly associated with exogenous corticosteroid administration. Endogenous hypercortisolism is either ACTH-dependent or ACTH-independent. Cushing disease, which is an ACTH-releasing tumor, is responsible for 70% of endogenous cases. After that, adrenal neoplasms with 20% and ectopic ACTH-releasing tumors with about 10% follow [5, 6]. When a patient presents with hypercortisolism symptoms, evaluating cortisol indicators is needed after taking history and performing a physical exam. When hypercortisolism was confirmed, serum ACTH levels should be checked. If the biochemical study shows elevated ACTH levels, pituitary MRI with gadolinium enhancement must be performed to rule out Cushing’s disease. If there is no sign of a pituitary tumor, imaging workups for finding an ectopic ACTH-releasing tumor should be implemented. Previous studies have suggested the usage of CT scan, MRI, or scintigraphy to study these ectopic tumors, which can detect them in 70–90% of cases. There is still a challenge to identify those tumors that were not recognized by the mentioned modalities. The gadolinium-DOTA somatostatin analog PET/CT increases the sensitivity to 88–93% and specificity to 88–95%. In our case, a PET scan was used to enhance the detection accuracy and detect the tumor in the mediastinum. On the other hand, whenever ACTH levels are normal or low, adrenal-protocol imaging has to be done to study the ACTH-independent tumor [2]. It must be noted that, when hypercortisolism is suspected, examining common complications of the disease such as hypertension, diabetes, and loss of bone density, must be performed [7, 8].

NETs have different subtypes, including atypical carcinoids, which are very scarce (0.2% of thoracic malignancies) and could induce Cushing’s syndrome [9]. The gastrointestinal tract and lungs are the most common sites for NETs, respectively. To the best of our knowledge, primary mediastinal NETs are exceptionally uncommon, and there are very few published reports about them which are mainly in the anterior mediastinum [10]. Accordingly, this manuscript might be the first to report a case of hypercortisolism caused by a middle mediastinal NET.

The surgical resection is considered the curative treatment in the early stages of the disease and might be performed as palliative therapy to alleviate symptoms [9]. The preferred surgical method is through video-assisted thoracoscopy (VAT) as a minimally invasive technique. Still, open thoracotomy must be considered in those whose the tumor is not reachable or resectable with VAT (like the presented case). Medical treatment with somatostatin analogs, chemotherapy, or targeted therapy (for example, mTOR inhibitors) could be used as adjunctive therapy or in cases that surgical resection is not feasible or desirable. The 5-year survival of atypical carcinoids is related to the tumor’s grade and stage and ranges from 50 to 80%. Following the resection of the functional tumor, it is expected of the hormone levels to fall. Like any other neoplasm, close follow-up must be performed to control the symptoms and tumor recurrence.

Although this report presents just one case afflicted with hypercortisolism due to functional middle mediastinal NET, we suggest consideration of this diagnosis in workups of patients with Cushing’s syndrome.

Declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

Investigations were in accordance with the Helsinki Declaration of 1964 and all subsequent revisions.