Acquired isolated ACTH deficiency co-occurrence with breast cancer irrespective of paraneoplastic syndrome: coincidence or inevitability

Background

Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is characterized by secondary adrenal deficiency with low cortisol production and normal secretion of pituitary hormones other than ACTH. Acquired ACTH deficiency is associated with trauma, Sheehan’s syndrome, lymphocytic hypophysitis, empty sella, and post-radiation therapy, with some individuals potentially having an autoimmune etiology (1, 2).

Recent advances in the understanding of pituitary autoimmunity have led to the characterization of a novel clinical concept known as secondary hypophysitis or paraneoplastic pituitary-directed autoimmunity. This novel clinical condition, paraneoplastic autoimmune hypophysitis, has a common underlying mechanism, in which ectopic expression of pituitary antigens in coexisting neoplasms triggers autoimmunity against pituitary-specific cells such as corticotrophs (3).

However, the frequency of adult-onset IAD combined with malignancy remains relatively low. Therefore, it is unclear whether the complication of malignancy in IAD is inevitable or a rare coincidence. Herein, we present a case of acquired IAD that developed during breast cancer treatment.

Case presentation

At the age of 47, a female patient was diagnosed with clinical stage II breast cancer and underwent a partial mastectomy with subsequent radiotherapy. Since the extracted specimens expressed both estrogen and progesterone receptors and lacked human epidermal growth factor receptor 2, additional treatment with a luteinizing hormone-releasing hormone (LHRH) analog and an aromatase inhibitor was performed. The patient did not receive immunotherapy for breast cancer treatment.

At 51 years of age, she experienced fatigue and general malaise. One year later, she was diagnosed with secondary adrenal insufficiency and referred to our department. She had a height of 155.2 cm and weighed 46.1 kg (body mass index: 18.1 kg/m²), with no previous history of autoimmune diseases. She had been diagnosed with depressive disorder at the age of 16 and was undergoing treatment with duloxetine hydrochloride and lamotrigine. A comprehensive interview at diagnosis eliminated the possibility of the use of exogenous glucocorticoids or other drugs to suppress the hypothalamic–pituitary–adrenal axis, such as opiates through any mode of administration.

Investigation

Her vital findings were unremarkable, and there were no abnormalities in common blood laboratory findings such as hypoglycemia, hyponatremia, or eosinophilia; however, low levels of plasma ACTH (16.6 pg/mL) and cortisol (2.5 μg/dL) were noted, leading to the suspicion of secondary adrenal insufficiency.

Pituitary and peripheral hormone levels were measured to screen for hypopituitarism, and anterior pituitary function was assessed using stimulation tests (4, 5). Evaluation of LH)was excluded because of treatment with the LHRH analog; however, the menstrual cycle was regular before the initiation of the LHRH analog treatment. Similarly, thyroid function was normal. Based on the clinical practice guideline (4), these results indicate that central hypothyroidism or hypogonadism was not actively suspected. As shown in Table 1, the responses of ACTH and cortisol to stimulation tests using insulin and tetracosactides (ACTH_1–24) were partially impaired. Moreover, anterior pituitary hormone secretion remained unaffected, and urine-free cortisol levels were relatively low, supporting the theory of secondary adrenal insufficiency. Magnetic resonance imaging revealed no morphological abnormalities in the pituitary gland or hypothalamus (Fig. 1).

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Images of the pituitary gland. Enhanced T1-weighted magnetic resonance imaging of the pituitary gland revealed no morphological defects.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 3; 10.1530/EDM-23-0129

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Given her diagnosis of adult-onset IAD during breast cancer treatment, we hypothesized that the patient developed acquired IAD as a form of paraneoplastic autoimmune hypophysitis. However, ectopic expression of ACTH, proopiomelanocortin (POMC), or pituitary-specific transcription factor-1 (PIT-1), as previously reported in paraneoplastic autoimmune hypophysitis (3, 6, 7), was not detected in the tissue specimens of breast cancer (Fig. 2). There was no evidence of paraneoplastic syndrome or other causes, such as trauma, delivery, or inflammation; therefore, the patient was considered to have idiopathic IAD.

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Immunofluorescence staining in breast cancer tissues (A) and mouse pituitary tissue (positive control) (B). Immunostaining was performed using an anti-ACTH antibody (Abcam Cat# ab74976, RRID: AB_1280736), anti-POMC antibody (Abcam Cat# ab254257, RRID: AB_3102024), and anti-PIT-1 antibody (Sigma-Aldrich Cat# HPA050624, RRID: AB_2681192) as the primary antibody. The nuclei were counterstained with Hoechst 33342 (Nacalai Tesque, Kyoto, Japan). Representative images at low (10×) and high (40×) magnifications are shown. Scale bar: 100 μm.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 3; 10.1530/EDM-23-0129

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Treatment

She received hydrocortisone replacement therapy, and the symptoms of secondary adrenal insufficiency improved markedly.

Outcome and follow-up

The patient has been taking hydrocortisone replacement therapy at 20 mg per day for over 1 year without experiencing any signs of adrenal insufficiency or glucocorticoid excess.

She was persuaded that IAD was not a result of the breast cancer or its therapy and continued with her breast cancer treatment utilizing LHRH analog without any recurrence.

Discussion

The symptoms of IAD are wide ranging, often atypical and nonspecific, and include fatigue, malaise, weakness, nausea, and abdominal pain (1). Several adrenal insufficiency symptoms are similar to the nonspecific symptoms associated with malignancies. Therefore, the diagnosis of IAD remains challenging, especially in individuals with cancer, and some cases of IAD evade detection or have delayed diagnosis. Its diagnosis is critical because glucocorticoid replacement therapy can improve symptoms and quality of life.

Although cases of various malignancies such as gastric cancer, leukemia, and colon cancer coexisting with IAD have been reported (8, 9, 10), the relationship between these neoplasms and IAD remains undefined. We previously reported several cases of paraneoplastic autoimmune ACTH deficiency in which ectopic expression of ACTH in coexisting neoplasms triggered autoimmunity against pituitary-specific cells (3, 6). Paraneoplastic syndromes are signs of harm to organs far from the neoplasm or its metastatic site. Interestingly, the most frequently ectopically expressed pituitary hormone in tumors is ACTH, which is observed even in individuals with tumors without hormone production. Thus, when we encounter a case of IAD accompanied by a malignant tumor, it is reasonable to suspect that paraneoplastic autoimmune ACTH deficiency may be the etiologic agent; however, in the present case, the expression of ectopic ACTH or POMC could not be determined in the breast cancer tumor tissues. It is important to note that investigating the cause of IAD, even if it is unrelated to paraneoplastic syndrome, can be crucial in helping the patients understand and accept their condition.

There are three potential explanations for this finding. First, IAD in this case was probably a coincidental complication of breast cancer. The incidence of malignancy has increased and become a primary cause of mortality in Japan, with breast cancer being the predominant subtype among females (11). Second, if this case represents a form of paraneoplastic autoimmune ACTH deficiency, the histological analyses of ACTH-expressing cells in malignant neoplasms may be insufficient in terms of technical and diagnostic aspects. Therefore, technical methodologies are required to accurately determine ectopic manifestations. In addition, the impact of other molecules (e.g. T-PIT or corticotropin-releasing hormone) affecting the hypothalamus or corticotrophs expressed in the tumor tissues remains to be elucidated. Finally, individuals with IAD are a heterogeneous subset in terms of clinical profiles, encompassing variations in hormonal impairment and autoimmune predisposition (12). Further studies are required to elucidate the characteristics of IAD caused by paraneoplastic syndromes. This case emphasizes the need for further investigation into the complex interplay between endocrine disorders and cancer.

In conclusion, we report a case of acquired IAD that developed during breast cancer treatment. This was not characterized as a form of paraneoplastic syndrome, as no ectopic expression of ACTH or POMC was detected in the tumor tissue.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding statement

This work was partially supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKENHI, grant numbers 18K08514 (GI), 21KK0149 (HB), and 21K08555 (GI)), Harmonic Ito Foundation (GI), and Foundation for the Promotion of Cancer Research in Japan (GI).

Patient consent

Written informed consent was obtained from the patient. The patient consented to the submission to the journal.

Author contribution statement

HB, MN, and MY provided clinical care. SU analyzed the data, wrote most of the manuscript, and prepared all the figures and tables. HB and GI edited the manuscript. MY, HF, and WO contributed to the critical revision of the article for important intellectual content.