Challenging the known: unusual case report of acromegaly and subclinical Cushing’s disease combination

Introduction

Pituitary adenomas (PAs), also named pituitary neuroendocrine tumors (PitNETs), are common benign intracranial tumors, accounting for 10% to 20% of intracranial tumors. The prevalence of PAs has risen to 115 cases per 100,000 people in recent decades (1). Pituitary-specific positive transcription factor 1 (Pit-1) regulates the expression of GH, PRL, and thyroid-stimulating hormone (TSH), while the steroidogenic factor 1 (SF-1) and endothelial transcription factor GATA2 regulate the expression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Tumor homeobox transcription factor 19 (TBX19), sometimes referred to as T-pit, regulates the expression of ACTH (2). By the manner of expression of transcription factors, plurihormonal PitNETs rarely demonstrate simultaneous GH and ACTH hypersecretion, as these hormones belong to distinct cell lineages (Pit-1 and T-pit, respectively) (3,4). In this case, we reported a rare plurihormonal PA caused by excessive production of GH, PRL, and ACTH that occurs simultaneously with Pit-1 lineage cells. Simultaneously, the transcription factor of T-pit was negative and manifested as acromegaly without any clinical features of Cushing’s syndrome. The possible biological mechanisms of this plurihormonal PAs were explored considering published literature on similar cases. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-312/rc).

Case presentation

A 41-year-old man had a history of thymic hyperplasia 10 years earlier and diabetes mellitus for 2 years. He presented to the endocrinology clinic with severe hyperglycemia, polydipsia, and polyuria of more than 3 months’ duration. Acromegaly and GH-secreting PAs were suspected due to typical acromegalic features. The patient was subsequently admitted for further evaluation. His phenotypic features of acromegaly (coarse skin, frontal bossing, broad nose, large tongue, large spade-like hands, and large feet), prompted a work-up for GH-secreting PA.

Following the diagnosis of diabetic ketosis with mild acidosis, intravenous insulin and intensive fluid resuscitation were initiated. After resolution of ketosis, treatment was transitioned to subcutaneous insulin and oral hypoglycemic agents.

The endocrine evaluation revealed a substantial elevation in serum GH levels, measuring 125.43 µg/L (0.00–10.00 µg/L reference ranges), and elevated IGF-1 levels of 679.8 ng/mL (58–219 ng/mL for age-matched males). Additionally, there was no suppression of GH production after a 75-g oral glucose tolerance test (OGTT), with a trough GH level of 4.69 µg/L (Table 1). The serum cortisol and ACTH levels showed no circadian variation, measuring 10.4 µg/dL (5–25 µg/dL, reference range) and 32.6 pg/dL (7.2–63.3 pg/mL, reference range) at 0 a.m., respectively. Additionally, the level of 24-hour urine-free cortisol (24 h UFC) was significantly high at 135.7 µg/24 h (3.5–45.0 µg/24 h, reference range) (Table 2, preoperative). These findings indicated ACTH-dependent hypercortisolemia. The plasma ACTH, cortisol, and 24 h UFC results following a low-dose dexamethasone suppression test (0.5 mg orally every 6 hours for 48 hours) indicated that suppression did not occur. However, after a high-dose dexamethasone suppression test (2 mg orally every 6 hours for 48 hours), suppressibility was observed. Collectively, these findings were consistent with Cushing’s disease.

Additional pituitary hormones were assessed (Table 3): TSH levels exhibited a modest reduction, while free triiodothyronine (FT3) and free thyroxine (FT4) levels were normal, indicating central hypothyroidism. The chest computed tomography (CT) scan revealed normal results, but the ultrasonography investigations indicated the presence of hepatomegaly, splenomegaly, and goiter. The pituitary magnetic resonance imaging (MRI) detected the existence of a pituitary macroadenoma that is invading, with measurements of 17 mm × 15 mm × 23 mm (Figure 1), and growing into the sphenoid sinus (Knosp2). Ultimately, the endocrine and imaging findings were consistent with a diagnosing of a pituitary macroadenoma secreting GH with autonomous ACTH production. All diagnostic evaluations were completed without barriers related to test availability, financial constraints, or cultural factors. The key clinical events, diagnostic evaluation, treatment, and follow-up of the patient are summarized in Table 4.

Figure 1 Pituitary MRI revealed the presence of a pituitary macroadenoma measuring 17 mm × 15 mm × 23 mm with a downward growing trend of the mass. (A) Coronal T1-weighted MRI; (B) Sagittal T1-weighted MRI. MRI, magnetic resonance imaging.

The patient underwent an uncomplicated transsphenoidal resection. No intraoperative or postoperative complications or unanticipated adverse events were observed. Immunohistochemistry showed strong GH and Pit-1 positivity with focal ACTH staining, while T-pit was negative, supporting a Pit-1-lineage tumor with aberrant ACTH expression rather than true dual-lineage differentiation. Hematoxylin and eosin staining of the resected tissues, which showed significant acidophilic cell infiltration, suggesting the possibility of a PA (Figure 2). Immunohistochemical analysis demonstrated diffuse strong immunoreactivity for GH (~90%, Figure 3A) and PRL (~70%, Figure 3B), with focal sparse ACTH staining (Figure 3C). Pit-1 was strongly expressed in most tumor cells (Figure 3D), CK8/18 was positive (Figure 3E), whereas T-pit (Figure 3F), estrogen receptor (ER) and GATA3 were negative (ER and GATA3 data not shown). These findings support a mammosomatotroph (Pit-1 lineage) tumor with aberrant/ectopic ACTH expression.

Figure 2 H&E staining of the resected tumor sample revealed acidophilic cells. H&E, hematoxylin and eosin.

Figure 3 Immunohistochemical results of multiple hormone levels. GH (A) and PRL (B) were strongly expressed in the tumor; however, ACTH had only sporadic expression (C); Pit-1 (D) and CK8/18 (E) were strongly expressed in most of the adenoma cells, but T-pit was negative (F). ACTH, adrenocorticotropic hormone; CK8/18, cytokeratin 8/18; GH, growth hormone; Pit-1, pituitary-specific transcription factor 1; PRL, prolactin.

Hydrocortisone was administered for 3 consecutive postoperative days and then discontinued. Postoperative pituitary hormonal assays indicated no requirement for long-term pituitary hormone replacement. The patient was discharged on postoperative day 7. To re-evaluate pituitary function and the effect of the surgical excision, the patient was readmitted 3 months after the operation. The clinical symptoms and metabolic co-morbidities, such as diabetes mellitus and hypertriglyceridemia, showed significant improvement. Ultrasonography revealed reductions in thyroid and splenic volumes, although hepatomegaly remained unchanged.

Adrenal function in the immediate postoperative period was evaluated using a standard hydrocortisone-withdrawal approach. Perioperative hydrocortisone was administered for 3 days to prevent acute adrenal insufficiency and then discontinued. Endogenous adrenal function was assessed by measuring morning serum cortisol 24 hours after hydrocortisone cessation, thereby avoiding interference from exogenous glucocorticoids. The postoperative cortisol level measured off replacement therapy was within the physiological range (18.9 µg/dL; Table 3), indicating preserved hypothalamic-pituitary-adrenal axis function and no requirement for continued glucocorticoid replacement.

Endocrine assessment showed a marked postoperative decline in ACTH and cortisol levels. Although the diurnal rhythm had not yet fully re-established in the early postoperative period, the low-dose dexamethasone suppression test demonstrated adequate cortisol suppression, confirming biochemical remission of Cushing’s syndrome. In contrast, biochemical remission of acromegaly was not achieved. Both thyroid and gonadal functions recovered to normal ranges.

Comparison of preoperative and postoperative hormone levels demonstrated that the pituitary macroadenoma was responsible for the concomitant overproduction of GH and ACTH. Furthermore, this patient exhibited thymic hyperplasia and PA consecutively, raising the suspicion of multiple endocrine neoplasia. To confirm this diagnosis, we conducted whole exon sequencing detection, which ultimately ruled out the presence of this condition. The patient remains under regular follow-up.

All procedures performed in this study were in accordance with the ethical standards of the ethical committee of Shenzhen Second People’s Hospital and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

PAs are characterized by hormone hypersecretion, with clinical phenotypes determined by the cell of origin and the predominant hormone produced (5). Most functioning PAs exhibit symptoms associated with the production of a single hormone. However, immunohistochemical studies have demonstrated that some PAs express and secrete multiple hormones simultaneously (6). The most reported plurihormonal adenomas coexpress GH, PRL, and/or TSH or LH and FSH (2), and such tumors usually belong to one cell lineage. A PA rarely produces multiple anterior pituitary hormones of more than one lineage (7) .

Plurihormonal PAs, accounting for 10–15% of all functioning PAs histologically (8), should be suspected in the presence of clinical or biochemical hypersecretion of two or more adenohypophysial hormones (9). Clinically, the diagnosis of multihormonal PAs is typically established using immunohistochemistry or in situ hybridization to identify the classification of hormones contained within the tumor cells (10). The differentiation relies on systematic immunohistochemical evaluation of the tumor (11,12). Plurihormonal tumors that deviate from the expected lineage specificity are observed (13), as in our case.

Plurihormonal tumors may be classified as monomorphous, in which multiple hormones are expressed by a single cell population, or plurimorphous, characterized by distinct hormone expression in different tumor cell populations (6,14,15). These unusual plurihormonal adenomas are classified as a distinct entity (16). Since either an immunohistochemical study using double staining or an electron microscopic study, was not performed in this case, it remains unknown whether GH-PRL and ACTH are synthesized in the same or different cells.

According to the 2022 World Health Organization (WHO) Classification of Pituitary Tumors, mammosomatotroph tumor of Pit-1 lineage was diagnosed for this patient. However, mammosomatotroph tumors exhibiting focal ACTH immunoreactivity in the absence of T-pit expression have not been previously reported (17). It is well-established that mammosomatotroph tumors belonged to Pit-1 do not produce ACTH derived from the T-pit lineage. Although the overproduction of ACTH was established in this case, it is unclear whether it belongs to a specific subtype of mammosomatotroph tumors or if it is an unknown form.

Because transcription factors usually define pituitary cell lineages and PAs are typically monoclonal, it is exceptionally uncommon for a single tumor to cause both acromegaly and Cushing’s disease concurrently. Nevertheless, our patient exhibited the characteristics, and the expression pattern of transcription factors in PA did not align with the established expression manner of transcription factors. Based on the established manner of transcription factors expression pattern, Pit-1 and T-pit are expected to be positive. However, the immunohistochemistry analysis revealed significant positivity to Pit-1, whereas no immunoreactivity to T-pit was seen. The fact suggested that the clinical phenotypes were not compatible with immunohistochemical investigations completely, and the known transcription factors could not explain the occurrence and development of this PA, and there are other unknown transcription factors and differentiation mechanisms. Matsuno et al. reported a case of intracavernous invading somatotroph macroadenoma with high serum GH, PRL, and ACTH levels in 1996 (18). Tahara et al. described a rare case of Cushing’s disease caused by a PA producing ACTH and GH concomitantly that expressed ACTH and GH in the same adenoma cells, and transcription factors NeuroD1 and Pit-1 were aberrant expressions which probably participates in this unusual differentiation state (19). Consequently, they postulated that unidentified transcription factors, in addition to Pit-1, which are regularly produced with GH, PRL, and ACTH, were present in this adenoma. Furthermore, they proposed that these adenomas could originate from pluripotent primordial stem cells with several hormone-producing capabilities.

Acromegaly is often identified following a prolonged period of excessive release of GH. Based on our analysis of the facial changes depicted in the images spanning the last decade, it is reasonable to assume that the onset of the patient’s pituitary tumor began to develop 10 years ago. The endocrine evaluation of the pituitary gland for the patient, both pre- and post-surgery, revealed that the PA was characterized by excessive production of GH and ACTH, demonstrating the presence of a multi-hormonal tumor with a translineage pattern. An unresolved question is why this patient exhibited biochemical hypercortisolism in the absence of overt cushingoid features. Recognizing this rare phenomenon has important clinical implications. We have reviewed the existing body of literature regarding acromegaly and Cushing’s disease or subclinical Cushing’s disease, specifically focusing on cases where a solitary PA is the underlying etiology. Several potential mechanisms have been proposed (Figure 4).

Figure 4 Potential mechanisms of this case, unproven mechanism with red dotted arrow. −, inhibit; +, promote. ↑, upregulate; ↓, downregulate. ACTH, adrenocorticotropic hormone; CD, Cushing’s disease; GH, growth hormone; HMW, high-molecular-weight; PC 1/3, prohormone convertase 1/3; PRL, prolactin.

First, excessive GH secretion may partially counteract systemic effects of hypercortisolemia by modulating local cortisol regeneration (20). GH/IGF-1 signaling has been reported to down-regulate expression and activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in key metabolic tissues, thereby reducing local conversion of inactive cortisone to active cortisol; this mechanism may, at least in part, explain the relative paucity of overt Cushingoid stigmata in some patients with concurrent GH excess (21-23). Consistent with this, acromegalic patients exhibit increased metabolic clearance of cortisol due to GH-mediated inhibition of 11β-HSD1 (24) and reduced glucocorticoid bioavailability has been described in both experimental and clinical settings (25). Moreover, a rare case of Cushing’s disease without cushingoid features has been reported due to a partial defect in the 11β-HSD1 activity protective against cortisol excess (26). Therefore, we propose the following hypothesis to explain the co-secretion of ACTH and the absence of Cushingoid features: the persistently elevated GH concentrations, by inhibiting 11β-HSD1 activity, may have reduced tissue exposure to cortisol. This, in turn, could have triggered a compensatory increase in ACTH secretion, leading to corticotroph hyperplasia. Over a decade, this hyperplastic process might have progressed to neoplasia, resulting in a functional ACTH-secreting component within the original mammosomatotroph tumor.

Notably, human studies have yielded variable results, and short-term changes in GH do not consistently alter 11β-HSD1 activity; thus, this proposed mechanism should be interpreted cautiously. The hypothesis of translineage or phenotypic plasticity is further supported by the tumor’s T-pit negativity, suggesting a noncanonical pathway for ACTH production rather than true corticotroph differentiation.

Turnover of adult pituitary cells is slow, the pituitary gland exhibits a plastic response to extrinsic stimuli throughout the lifespan (27). The occurrence of Cushing’s disease in our patient may be considered as the result regarding the role of pituitary regulatory mechanisms in the pathogenesis of pituitary homeostasis, physiological plasticity, and tumorigenesis. Even monoclonal mammosomatotroph tumor cells may undergo phenotypic transformation independent of the T-pit transcription factor, into corticotrophs to compensate for the increase in the metabolic rate of cortisol and the relative deficiency of cortisol in the body due to the overproduction of GH. Based on the T-pit negativity and the clinical timeline, we further hypothesize that a process of translineage transformation or dedifferentiation might have occurred. We speculate that over the prolonged course of acromegaly, a subset of the monoclonal mammosomatotroph tumor cells may have undergone a transformation into functional corticotrophs, independent of the T-pit transcription factor, thereby acquiring the capability to co-secrete ACTH. This mechanism may help explain the emergence of biochemical Cushing’s disease from a tumor initially diagnosed as a Pit-1 lineage adenoma.

An alternative hypothesis involves the secretion of a high-molecular-weight (HMW) form of ACTH with low biological activity, as suggested by Ohta et al. in a similar case (28). It is plausible that in our patient, the secretion of such an HMW ACTH contributed to the biochemical evidence of hypercortisolism without manifesting the full clinical phenotype of Cushing’s syndrome.

Third, clinically silent corticotroph adenoma lacks the presence of prohormone convertase 1/3 (PC 1/3), an enzyme responsible for precisely cleaving ACTH [1–39] from precursor molecules such proopiomelanocortin and pro-ACTH. In contrast, PA that cause overt Cushing’s disease exhibit a high abundance of PC 1/3 (29). It can be inferred that the reduced expression of PC 1/3 may selectively produce and release ACTH precursors that are physiologically inactive, which could explain the lack of Cushingoid characteristics to some extent. The expression of PC 1/3 in GH-ACTH producing PA is yet uncertain.

Mammosomatotroph adenoma typically does not exhibit excessive secretion or expression of ACTH. The distinctive presentation of our patient indicated the existence of a hitherto unidentified subtype of mammosomatotroph adenoma, characterized by distinct functional differentiation across multiple cell lineages. It is possible to postulate that the PA originates from a tumor of adenoepithelial stem cells with lineage differentiation. Additionally, it appears that the differentiation of anterior pituitary stem cells into corticotroph cells is not regulated by T-pit.

In summary, unusual plurihormonal tumors may not strictly conform to conventional lineage specificity. The distinction is dependent on systematic immunohistochemical analysis of the tumor, which tends to be inconsistent (13). The presence of GH-ACTH producing PAs is still not fully understood, and additional research is needed to clarify the involvement of transcription factors and the molecular processes that contribute to the cell development and characteristics of these plurihormonal PAs.

Conclusions

We report a rare Pit-1 lineage (mammosomatotroph) pituitary macroadenoma that secreted GH and PRL and exhibited focal ACTH expression despite negative T-pit staining. This discordance suggests noncanonical mechanisms of ACTH production (e.g., precursor/HMW ACTH secretion, aberrant expression or phenotypic plasticity) and warrants further molecular investigation. These findings enhance our understanding of the tendency for GH-secreting PA to originate from cell types with multiple hormone-producing capabilities. More research is required to clarify the specific cell from which adenohypophysial tumors originate and the methods by which they differentiate.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-312/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-312/prf

Funding: This work was supported by Shenzhen Science and Technology Innovation Program (No. JCYJ20230807115123046 to J. D.) and China International Medical Foundation (No. Z-2014-08-2424 to X.H). However, it is important to note that these funding organizations had no influence on the design, data analysis, or composition of this article.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-312/coif). X.H. reports the funding from China International Medical Foundation (No. Z-2014-08-2424). J.D. reports the funding from Shenzhen Science and Technology Innovation Program (No. JCYJ20230807115123046). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the ethical committee of Shenzhen Second People’s Hospital and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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