DOI: https://doi.org/10.21203/rs.3.rs-1682659/v1
Background:
Accurate and early diagnosis of Cushing’s syndrome is challenging. Ectopic production of adrenocorticotropic hormone (ACTH) by carcinoid tumors is relatively rare and may not be detected.
The tumors that produce ectopic ACTH are usually bronchopulmonary or thymic in origin and are rarely of gastrointestinal origin. To our knowledge, there is only one published case of an ectopic ACTH secreting primary hepatic carcinoid tumor with consistent biochemical markers and symptoms that resolved with resection.
Patient findings:
This report describes a rare case of a patient who had Cushing syndrome from the ectopic secretion of adrenocorticotropic hormone by a hepatocellular carcinoma (HCC) with neuroendocrine features.
Conclusions:
Ectopic ACTH secretion is typically a clinical diagnosis that is confirmed after surgical resection of the ectopic source. Only few reports were found to describe ectopic ACTH secretion in HCC. Our case illuminates the significance of clinical and immunohistochemical studies to establish the appropriate diagnosis in patients with tumors believed to secrete ACTH. Additionally, absent immunostaining has been also described in some patients with ectopic ACTH secretion.
Ectopic ACTH Syndrome (EAS) is a rare disorder, accountable for about 5–20% of all Cushing syndrome cases and almost 10–20% of ACTH-dependent patients(1).
It was first described and named in the early 1960s by Liddle (2)and soon afterward by Meador(3).
Distinguishing the group of EAS patients from all Cushing syndrome patients is essential in the management of this condition due to different therapeutic approaches(4).
Searching for the tumor that produces ACTH is an essential step in EAS management and elimination of the ACTH-producing source usually leads to a significant reduction of symptoms and helps to restore normal serum cortisol levels(5).
In the majority of cases, the source of ectopic production of ACTH is mediastinal or pulmonary, but it can also be produced by tumors originating from other parts of the body, such as pheochromocytomas and neuroendocrine tumors in pancreas or gastrointestinal tract(4).
Prognosis of EAS is variable, and it usually depends on the ectopic source of ACTH production. Pulmonary carcinoid usually has a promising prognosis; whereas small-cell lung cancer, medullary carcinoma of the thyroid, and gastrinoma are less common and could be life threatening(6).
There is limited literature on HCC producing cortisol and dehydroepiandrosterone (DHEA) secretion. Hence the need to increase awareness for prompt management with improved prognosis.
Here, we report a rare case of ectopic ACTH syndrome in a patient with hepatocellular carcinoma (HCC) who presented with cushingoid features, profound lower extremity edema, hypotension, hypokalemia, and markedly elevated ACTH. Liver biopsy was consistent with poorly differentiated HCC with neuroendocrine features.
A 59-year-old male with a history of hypertension, hyperlipidemia, obesity class II, parotid cancer status post right parotidectomy, adjuvant radiation and, chemotherapy; and hypothyroidism presented to our facility with a complaint of polyuria, polydipsia, fatigue, headaches, and bilateral pedal edema two months.
On admission, the patient was found to have persistent hypertension (Systolic Blood Pressure > 150 mmHg) despite being on 3 antihypertensive medications.
He was hemodynamically stable, and his physical examination was significant for a right submandibular fullness.
Initial Laboratory workup on admission showed hypokalemia (potassium 2.3mmo/L), mild hypomagnesaemia (magnesium 1.8mg/dL), glucose 111mg/dL, serum bicarbonate 38mmol/L, calcium 8.5mg/dL morning cortisol 30.1 (normal level: 6-19mcg/dl), and ACTH 430 (normal range: 6–50 pg/ml). His morning supine aldosterone < 1 (normal range 3–16 ng/dl).
Abdominal ultrasound showed a hepatic mass, confirmed on computer tomographic scan (CT scan) and magnetic resonance imaging (MRI) as a right indeterminate 6.9 cm hepatic mass with central hypodensity and a 2.6 cm hypodensity at the liver dome (Fig. 1). Liver biopsy showed a poorly differentiated hepatocellular carcinoma (HCC) with neuroendocrine features (Fig. 2).
Immunohistochemical staining showed that tumor cells were positive for AE1/AE3 and HepPar-1 (faintly positive) and are negative for CK-7, CD-20, Chromogranin, synaptophysin, Melan-A, inhibin, NKX-3.1, S-100, PAX-8, TTF-1, CDX-2, arginase, AFP, ACTH and p40.
P53 shows wild type expression and Ki-67 proliferative index is 50–60%. Immunopurified (CK-7-ve, CK-20 ve and HepPar-1 faintly positive) favors a poorly differentiated
hepatocellular carcinoma.
Due to the involvement of the right and middle hepatic vein and the left portal vein, resection was not an option but eventually had embolization done.
Electrolyte derangement was managed via supplementation, and patient started antihypertensive, spironolactone, and a cortisol antagonist. Blood pressure, glycemic control, and symptoms ameliorated significantly, and the patient required just a brief course of steroid replacement therapy.
He was considered for locoregional and systemic approaches with Atezolizumab or bevacizumab but had paclitaxel and carboplatin with improvement in symptom.
HCC is the fifth most common cancer in men and the seventh in women with a paraneoplastic incidence of 43.6%; mostly erythrocytosis, hypoglycemia, hypercalcemia, high cholesterol, porphyria cutanea tarda, and myositis(7). There is limited literature on HCC producing cortisol and dehydroepiandrosterone (DHEA) secretion.
Sacerdote et al. first reported on a 52-year-old diagnosed with ACTH-independent ectopic Cushing's syndrome (CS) from an HCC producing cortisol and DHEA similar to our case(8). However, ectopic ACTH production was confirmed with immunostaining in a resected tumor unlike in our case report.
Ectopic ACTH secretion is usually diagnosed clinically, with endocrine testing and imaging; and confirmed after surgical resection of the ectopic source by remission of symptoms and demonstration of ACTH in the tumoral specimen. Typically, this latter is used to be an essential element for confirming diagnosis. However, absent immunostaining has been described in some patients with ectopic ACTH secretion(9, 10).
Some researchers suggested that negative immunostaining for ACTH was a result of tumoral cells secretion of either high molecular weight ACTH precursors or low molecular weight ACTH-derived peptides which would not be recognized by antibodies used for immunohistochemistry (10). In other cases, the tumor was found to be negative for ACTH at immunohistochemistry but the full-sized ACTH peptide was detected in other tests such as High-performance liquid chromatography proposing that ACTH was secreted by the tumor cells but not stored within the cell, probably because of the accelerated peptide production rate (9).
Weeda et al. reported on a 16-year-old boy of Dutch and Moroccan descent diagnosed with calcifying nested stromal epithelial tumor of the liver with Cushing's syndrome who responded to surgical resection(11). Extraction of appropriate the mRNA by real-time PCR (RT-PCR) is highly specific. Improvement in hypercortisolism with ketoconazole and metyrapone is the mainstay of treatment, and tumor resection when resectable(12).
There is scarcity in the literature on ACTH producing HCC. Further research should be conducted into the genetics and epigenetics of this condition as there is good response to treatment. The present case elucidates the significance of combined clinical and immunohistochemical studies to confirm the proper diagnosis in patients with tumors believed to secrete ACTH.
Adrenocorticotropic hormone (ACTH)
Computer tomographic scan (CT scan)
Dehydroepiandrosterone (DHEA)
Ectopic ACTH Syndrome (EAS)
Hepatocellular carcinoma (HCC)
Magnetic resonance imaging (MRI)
Ethics Approval and consent to participate:
All personally identifiable information has been withheld and complete patient anonymity was guaranteed. Ethical approval is not required for this case report in accordance with local guidelines.
Consent for publication
A verbal consent was obtained from the patient to use his clinical data and images for publication of this case report.
No identification of the patients’ identity is present neither in the manuscript nor in the images.
Data Availability Statement.
All data discussed in this study are included in this article. Further enquiries can be directed to the corresponding author.
Competing Interests Statement:
The authors have no conflicts of interest to declare.
Funding Sources:
There are no funding sources to report.
Author Contributions:
MA: Conception and design. MA, EI, AV: Collection and assembly of data. MA, EI, AV, IH: Article writing and final approval of article.
Acknowledgement:
We would like to thank Dr. Eugene H. Lewis III, DO, FCAP and Judith Aquino for their help and arrangements.