Paraneoplastic syndromes are defined by symptoms or signs resulting from damage to organs or tissues that are remote from the site of malignant neoplasms or its metastasis. They are due to tumor secretion of functional hormones or peptides or are related to immune cross-reactivity with the host tissue. In particular, paraneoplastic endocrine syndromes are mainly caused by ectopic hormone production by the tumor such as PTHrP in humoral hypercalcemia in malignancy and ACTH in ectopic ACTH syndrome. Recently, it has been reported that a specific form of hypophysitis is caused as an immune-mediated paraneoplastic syndrome; paraneoplastic autoimmune hypophysitis, in which an ectopic pituitary antigen expression in the tumor evoked autoimmunity against pituitary-specific antigens, resulting in hypophysitis and exhibiting the injury of specific anterior pituitary cells by cytotoxic T cells. This novel clinical entity, paraneoplastic autoimmune hypophysitis consists of several conditions such as anti-PIT-1 hypophysitis and a part of isolated ACTH deficiency and immune checkpoint inhibitor-related hypophysitis with common mechanisms. These conditions can explain at least in part, the underlying mechanisms of acquired specific pituitary hormone deficiencies. In addition, it is important to apply a comprehensive discipline of onco-immuno-endocrinology to understand the pathophysiology and this approach; the expansion and application of immune-mediated paraneoplastic syndrome to endocrine diseases may give a new clue to understand pathophysiology of the autoimmunity against endocrine organs.

1. An immune-mediated paraneoplastic syndrome; a novel clinical entity paraneoplastic autoimmune hypophysitis has been defined.

2. Paraneoplastic autoimmune hypophysitis consists of anti-PIT-1 hypophysitis and a part of isolated ACTH deficiency and immune checkpoint inhibitor-related hypophysitis with common underlying mechanisms.

3. The ectopic pituitary antigen expression in the tumor evoked autoimmunity against pituitary-specific antigens, resulting in hypophysitis and exhibiting the injury of specific anterior pituitary cells by cytotoxic T cells.

4. It is important to apply a comprehensive discipline of onco-immuno-endocrinology to understand the pathophysiology.

Paraneoplastic syndromes are defined by symptoms or signs resulting from damage to organs or tissues that are remote from the site of malignant neoplasms or its metastasis [1]. It is estimated that 10–15% of cancer patients suffer from paraneoplastic syndromes. In addition, paraneoplastic syndromes are the second direct cause of death (27% of cases) in cancer patients, after cancer itself. Therefore, it is important to recognize, diagnose, and treat paraneoplastic syndromes appropriately [2].

Most of paraneoplastic endocrine syndromes occur because the tumor secretes hormones or substances that mimic normal hormones. Endocrine abnormalities including humoral hypercalcemia in malignancy and Cushing’s syndrome caused by ectopic ACTH syndrome are the representative ones. On the other hand, most paraneoplastic neurologic syndromes/disorders are immune-mediated. In this condition, ectopic expression of neuronal antigen in the tumor evokes autoimmunity and produces autoantibodies with cross-reactivity of autoantigens and/or cytotoxic T cells injure neuronal tissues. Recently, it has been reported that similar immune-mediated mechanisms can cause specific forms of hypophysitis; paraneoplastic autoimmune hypophysitis, in which an ectopic pituitary antigen expression in the tumor evoked autoimmunity against pituitary-specific antigens, resulting in hypophysitis with the injury of specific anterior pituitary cells by cytotoxic T cells. Interestingly, this novel clinical entity, paraneoplastic autoimmune hypophysitis consists of several conditions such as anti-PIT-1 hypophysitis and a part of isolated ACTH deficiency and of immune checkpoint inhibitor (ICI)-related hypophysitis with common underlying mechanisms. In this review, endocrine paraneoplastic syndrome and the novel clinical entity paraneoplastic autoimmune hypophysitis will be discussed.

Paraneoplastic endocrine syndromes mostly result from the production of bioactive substances from neoplastic cells, of endocrine or neuroendocrine origin [3]. The clinical manifestations of these ectopic hormonal secretion are sometimes clinically indistinguishable from eutopic hormonal secretion, resulting in the difficulties at the diagnosis. A number of neuroendocrine tumors (NETs) such as gastrointestinal-NETs, lung NETs, adrenomedullary and adrenocortical tumors, skin and thyroid tumors, originating from endocrine organs can cause paraneoplastic endocrine syndromes; however, the great majority of paraneoplastic endocrine syndromes are associated with highly malignant tumors originated from non-endocrine tissues mainly involving the lungs, breasts, prostate, ovaries, skin, colon, and certain forms of hematological malignancies. Therefore, tumors arising from virtually any tissue have been implicated, albeit rarely (Table 1). Ectopically produced bioactive substances from endocrine and non-endocrine neoplasms are mostly peptides and hormones, and less commonly biogenic amines, steroids or thyroid hormones [3, 4]. The precise mechanism that initiates ectopic hormonal synthesis and release during the neoplastic transformation still remains to be defined. The secretion of these hormones is usually aberrantly regulated; therefore, it generally is autonomic pattern, which are different from eutopic secretion [4].

Recently, the underlying mechanisms, especially in ectopic ACTH syndrome of aberrant expression have been reported [5]. Compelling evidences suggest that ectopic ACTH syndromes may arise from the use of alternative POMC promoter regions. A transcription factor E2F binds to the POMC promoter and upregulates its transcription. The POMC promotor especially in distal region is generally heavily methylated; however, in studies of ACTH-producing bronchial, thymic, and pancreatic NETs [6], that region was hypomethylated compared to corresponding normal (non-ACTH expressing) tissues, resulting in the increased promoter activation [7, 8].

The other possible mechanism may be explained by inflammatory microenvironment surrounding the tumor [9]. Gp130 cytokines such as leukemia inhibitory factor and interleukin(IL)-6 act as paracrine factors for inducing corticotroph POMC expression [10]. Therefore, it is possible that these inflammatory responses, including IL-6 in the tumor microenvironment, may play a role in the ectopic expression of POMC. While the classic promoter responded as expected to LIF and CRH stimulation, this distal promoter showed enhanced basal activity that was downregulated with LIF and CRH exposure. Interestingly, studies in ACTH-producing PitNET, the upstream promoter showed demethylation in patients with ubiquitin carboxyl-terminal hydrolase 8 (USP8) mutations, while tumors with a more aggressive phenotype tended to show demethylation in the second promoter region. Taken together, these findings suggest that demethylation may regulate activities of the two promoters, leading to different biologic phenotypes from typical ACTH-producing pituitary tumors. In addition, the robust basal activity of the second promoter may underlie the excess production of ACTH in ectopic ACTH-secreting tumors [8].

Apart from the mechanisms of ectopic hormone production, one unique form of paraneoplastic endocrine syndromes is consumptive hypothyroidism [11]; a severe form of hypothyroidism occurs due to the ectopic high expression levels of thyroid hormone inactivation enzyme type 3 deiodinase (D3) in the tumors. Thus far, more than 40 cases have been reported and most of cases are children [12]. Endocrinological findings are characterized by high TSH, low T3 and T4, and high rT3 levels because of the increased activity of D3 in the tumor. Usually hepatic vascular or fibrous tumors and gastrointestinal stroma tumors are associated with this syndrome. For the differential diagnosis from primary hypothyroidism, a requirement of supraphysiological dose of exogenous hormone and elevation of rT3 levels are key characteristics for the diagnosis [11].

In terms of immune-mediated paraneoplastic endocrine syndrome, it is rare but it has been reported that adipsic (or essential) hypernatremia is involved in this mechanism. Adipsic hypernatremia is a rare condition of hypernatremia caused by a deficiency in thirst regulation and vasopressin release. Na(x) is the sodium-level sensor, a membrane-bound protein, which is a non-selective tetrodotoxin-sensitive cation channel expressed in the hypothalamus involved in sodium homeostasis [13]. Interestingly, the patient with adipsic hypernatremia exhibited circulating autoantibodies against Na(x), along with a ganglioneuroma robustly expressing Na(x). Intravenous injection of the immunoglobulin fraction of the patient’s serum into mice recapitulated hypernatremia with a compliment-dependent hypothalamic neuronal injury [14]. Further analysis of a cohort study of adipsic hypernatoremia consisting of 22 patients revealed that 72% of patients exhibited circulating autoantibodies that reacted with mouse subfornical organ (SFO) where Na sensor resides [15]. Hypothalamic functional abnormalities were found in 37.5% of the patients with positive SFO immunoreactivity. Moreover, six patients were diagnosed with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation/neural tumor syndrome after the diagnosis of adipsic hypernatremia, in which the symptoms resemble to Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation & Autonomic Dysregulation (ROHHAD) syndrome. ROHHAD syndrome is characterized by hypothalamic symptoms with rapid-onset obesity in early childhood, pituitary hormonal disorders, and autonomic symptom disorders, which sometimes shows hypernatoremia. It has been suggested that a part of ROHHAD syndrome may be associated with an autoimmunity against hypothalamic neurons [16]. As the underlying mechanisms, it has been shown that the binding of autoantibodies against Na(x) induced a complement-dependent neuron toxicities [14].

The concept of paraneoplastic autoimmune hypophysitis has recently been reported [17]. It consists of several conditions such as anti-PIT-1 hypophysitis and a part of isolated ACTH deficiency and of immune checkpoint inhibitor-related hypophysitis with common underlying mechanisms. In these conditions, the tumor ectopically expresses pituitary-specific antigens, resulting in an autoimmunity against specific pituitary antigens. Circulating autoantibodies against pituitary antigen are the disease marker but specific cytotoxic T cells play an essential role in the pituitary cell injury (Fig. 1) [17]. There are a couple of unique characteristics of paraneoplastic autoimmune hypophysitis. Most of immune-mediated paraneoplastic syndromes, the antigen protein is generally membrane proteins such as ion channel and receptors as in observed in paraneoplastic neurological syndrome; however, in paraneoplastic autoimmune hypophysitis, the antigen is hormone itself or transcription factor. Transcription factor is particularly unique because it generally localizes in the nucleus and it is difficult to be exposed on cell surface as antigen. The other point is that in paraneoplastic autoimmune hypophysitis, not autoantibodies but cytotoxic T cells play an essential role in the specific cell injury. Each condition of paraneoplastic autoimmune hypophysitis is discussed in detail below.

Fig. 1

The common underlying mechanisms in paraneoplastic autoimmune hypophysitis.

Tumor cells ectopically express pituitary specific antigens and autoimmunity is induced. Specific cytotoxic T cells recognize pituitary cells via specific epitopes presented with HLA class I.

Anti-PIT-1 hypophysitis is characterized by acquired specific deficiency in GH, PRL, and TSH. Indeed, GH-, PRL-, and TSH-producing anterior pituitary cells were disappeared in the pituitary of the patients [18]. Circulating anti-PIT-1 antibodies were detected as a specific disease marker but cytotoxic T cells that react with PIT-1 epitope play an essential role in the development of disease. Interestingly, the pituitary tissue derived from patient-induced pluripotent stem cells (iPSCs) presented the PIT-1 epitope with HLA class I antigen, suggesting that PIT-1 protein can be a target of cytotoxic T cells [19]. Recently, in vitro model using the pituitary tissue derived from patient-iPSCs and specific cytotoxic T cells isolated from the patient’s peripheral blood showed a specific cell injury (unpublished data, manuscript in revision), demonstrating that cytotoxic T cells are responsible for the development of disease. As the underlying mechanisms, complicated tumors ectopically expressed PIT-1, resulting in a breakdown of immune tolerance for PIT-1 protein [20]. Thus far, thymoma, diffuse large cell lymphoma, and unknown origin of malignancy have reportedly been a cause of this paraneoplastic autoimmune hypophysitis. This disease is extremely unique in the aspect of autoimmunity against transcription factor because in most autoimmune diseases demonstrating autoantibodies against transcription factor or nuclear protein, these autoantibodies are generally produced as a result of the cell disruption and do not play a causal role.

Adult-onset isolated ACTH deficiency has been considered as an autoimmune disease but the underlying mechanisms have been largely unclarified [21, 22]. Interestingly, it has been reported that in ICI-related hypophysitis, particularly in PD-1/PDL-1 inhibitor-related hypophysitis, ACTH is specifically impaired, resulting in an isolated ACTH deficiency as endocrine immune related adverse events (irAE) [23]. Recently, isolated ACTH deficiency as a form of paraneoplastic syndrome has been reported [24]. A 42-year-old woman with isolated ACTH deficiency was diagnosed with large cell neuroendocrine carcinoma (LCNEC). The LCNEC tissue exhibited an ectopic ACTH expression and lymphocyte infiltration. Circulating autoantibody against the POMC protein was detected in the patient, suggesting a presence of autoimmunity against POMC. In addition, patient’s lymphocytes in the peripheral blood specifically reacted toward POMC protein, indicating a presence of specific cytotoxic T lymphocytes that can attack corticotrophs. These data indicated that the ectopic ACTH expression in the tumor evoked the autoimmunity to corticotrophs and caused isolated ACTH deficiency as a form of paraneoplastic syndrome.

Recent progress in cancer immunotherapy has enabled to save a part of patients with advanced cancer. However, irAE are unavoidable per se, because of the enhanced immune reactions. When using ICIs, especially, endocrine irAEs such as thyroiditis and hypophysitis are often observed. Although there are several proposed mechanisms underlying these endocrine irAE, it has recently reported that a part of ICI-related hypophysitis is caused as a form of paraneoplastic syndrome, named paraneoplastic autoimmune hypophysitis [25]. In patients with PD-1/PDL-1-related hypophysitis who exhibited isolated ACTH deficiency, 10% showed circulating anti-POMC antibodies and in the tumor tissues of these patients exhibited an ectopic expression of POMC, suggesting that at least in part of PD-1/PDL-1-related hypophysitis is caused as a form of paraneoplastic syndrome, which is a common underlying mechanism with anti-PIT-1 hypophysitis and the isolated ACTH deficiency. Therefore, it has been suggested that ectopic ACTH expression in tumors evoked autoreactive T-cell activation and ICI administration enhanced the autoimmunity, ultimately resulting in the specific injury of corticotrophs and isolated ACTH deficiency [25]. Interestingly, the most prevalent ectopic expression among the pituitary hormones is observed in ACTH as mainly experienced as ectopic ACTH syndrome. In addition, it has been reported that silent POMC expression is not rare and was observed in 48% of non-small cell lung cancer [26] and in carcinoid tumors without ectopic ACTH syndrome [27]. These data suggest that although ectopic ACTH syndrome is rare but tumors that ectopically express POMC in silent are relatively common and ICI treatment may enhance the autoimmunity against POMC, resulting in isolated ACTH deficiency as a form of paraneoplastic autoimmune hypophysitis.

In the paraneoplastic autoimmune hypophysitis, the phenotype is endocrine abnormality but the cause is tumor and the mechanisms is autoimmunity (Fig. 2). Therefore, out of bounds approach, a new concept of onco-immuno-endocrinology is necessary to understand comprehensively the pathophysiology of paraneoplastic autoimmune hypophysitis [28, 29]. Also, the expansion and application of immune-mediated paraneoplastic syndrome to endocrine diseases may give a new clue to understand pathophysiology of the autoimmunity against endocrine organs.

Fig. 2

A new principle onco-immuno-endocrinology is important to understand the pathophysiology of paraneoplastic autoimmune hypophysitis.

In paraneoplastic autoimmune hypophysitis, the phenotype is endocrine abnormality, the cause is malignancy, and the mechanisms are autoimmunity.

There are several issues to be addressed regarding paraneoplastic autoimmune hypophysitis. Firstly, clarification of the underlying mechanisms of ectopic pituitary antigen expression is important. Generally, pituitary specifically expresses various molecules including pituitary hormones and transcription factors such as ACTH and PIT-1. The expression of these molecules in the pituitary is tightly and specifically regulated in the normal condition; therefore, it has been suggested that the characteristics of tumorigenesis per se such as genomic instability, dysregulation of gene silencing including epigenetic changes, and the interaction with microenvironment are involved. Secondly, it is important to clarify how the immunogenicity of these ectopic proteins and resultant immune reaction are regulated. Thirdly, there have been several reports demonstrating that the specific genetic back ground mainly HLA haplotypes are associated with the risk of these diseases; therefore, the precise underlying mechanisms involved in the antigen presentation and interaction between T cells and target cells with HLA are needed to be elucidated.

In conclusion, a novel clinical entity paraneoplastic autoimmune hypophysitis has emerged. This condition includes anti-PIT-1 hypophysitis and a part of isolated ACTH deficiency and ICI-related hypophysitis with common underlying mechanisms, in which ectopic expression of pituitary antigens and tumor immunity play an important role.

Author thanks to Drs. Hironori Bando, Masaaki Yamamoto, Keitaro Kanie, Shin Urai, Ryoko Takeno, Genzo Iguchi, Ryusaku Matsumoto, Hidenori Fukuoka, Michiko Takahashi, and Kazuo Chihara for the contributions.

This study was supported by the Ministry of Health, Labor and Welfare (Hypothalamo-hypophyseal Disorders and Endocrine Syndrome with Sexual Differentiation and Maturation grant) and Growth Science Association.

Nothing to declare.

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