Ectopic Adrenocorticotropic Hormone Syndrome Due To Olfactory Neuroblastoma: A Case Report And Literature Review

Posted on July 14, 2025 by MaryO

Abstract

Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a cause of Cushing’s syndrome usually associated with neuroendocrine tumors. Olfactory neuroblastoma (ONB) is a rare malignant neoplasm of the olfactory epithelium. This is the case of a 56-year-old woman with an ONB presenting with EAS. After initiating metyrapone, she developed a  Pneumocystis jirovecii  pneumonia. Following successful treatment of the infection, she underwent surgical tumor excision and radiotherapy, which has been in remission for the past 3 years. The authors provide a literature review of the 30 previously published cases of ONB presenting with EAS. Most were reported in middle-aged men, with a recurrence rate of 15.6% (3 patients eventually died). A total of 9.5% of all reported had an infection after starting corticosteroid-blocking therapy. ONB is a very rare cause of EAS with poor prognosis and a relapsing course. In the presence of severe hypercortisolism, chemoprophylaxis for common opportunistic agents must be considered.

Summary

Ectopic adrenocorticotropic hormone secretion syndrome (ACES) is a cause of Cushing’s syndrome commonly associated with neuroendocrine tumors. Olfactory neuroblastoma (ON) is a rare malignant tumor of the olfactory epithelium. We describe the case of a 56-year-old woman with ACES secondary to ON. After starting metyrapone, the patient developed  Pneumocystis jirovecii pneumonia . The infection was treated, the tumor was surgically removed, and she received radiotherapy. The patient has maintained remission for the past 3 years. We review the 30 previously reported cases of ACEs secondary to ON. Most occurred in middle-aged men, with a recurrence rate of 15.6% (3 patients died). Ninety-five percent of these cases had an infection after starting control of hypercortisolism. ON is a rare cause of ACEs with a poor prognosis and high recurrence rate. In the presence of hypercortisolism, chemoprophylaxis for common opportunistic agents should be considered.

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Section snippets

Case description

Production of adrenocorticotropic hormone (ACTH) from nonpituitary tumors – known as ectopic ACTH syndrome (EAS) – is the cause of ACTH-dependent hypercortisolism in up to 18% of all cases of Cushing’s syndrome. 1  EAS is more commonly associated with neuroendocrine tumors located in the chest, namely small-cell lung carcinoma, bronchial carcinoids and thymic neuroendocrine tumors. 2  These are followed less frequently by breast, colon, gastric, pancreatic and prostate cancers.2, 3, 4, 5, 6

Management and evidence

We consider our case particularly interesting for two reasons: the rarity of an ONB as a cause of the EAS (there are only 30 other cases reported worldwide) (Table 1) 30, 31, 32, 33, 34, 35, 36, 37, 38 and clinical progression with an opportunistic infection after starting corticosteroid-blocking therapy. To identify the 30 cases referenced we performed a literature review across PubMed, until August 2024, using the

Areas of uncertainty

Although there is some doubt about the elevated infectious risk of these patients, not only due to hypercortisolism but also after starting steroid-blocking therapy, diagnosis of these complications is frequently delayed. Additionally, infectious chemoprophylaxis is not routinely instituted in these patients. Our case highlights these areas of discussion.
Once ACTH secretion is detected, steroid-blocking therapy is often initiated to control symptoms related to Cushing’s syndrome. Metyrapone and

Guidelines

Due to the rarity of ONB presenting with ACTH secretion, there are no specific and well-established guidelines that delineate the management of these conditions presenting simultaneously, but there are recommendations for the treatment of each of them separately.2, 13, 45, 46
Regarding ONB management, surgery must be considered whenever it is feasible, and adjuvant radiotherapy is recommended in every case.13, 46 Adjuvant and neoadjuvant chemotherapy can be considered, depending on the initial

Conclusions and recommendations

EAS secretion is a cause of Cushing’s syndrome and should be suspected in the presence of signs and symptoms of severe hypercortisolism, even without the typical Cushing’s syndrome stigmata. Although ONB is a very rare cause of the ACTH syndrome, it should not be missed considering its poor outcome when left untreated. Hypercortisolism should be controlled until it is possible to treat the underlying tumor, bearing in mind that normalizing cortisol levels can precipitate opportunistic

Funding

None declared.

Conflicts of interest

None declared.

References (46)

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Reconstructive Liposuction for Residual Lipodystrophy After Remission of Cushing’s Disease

Posted on July 3, 2025 by MaryO

​Abstract

Cushing’s syndrome (CS) is often presented due to an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, characterized by high chronic cortisol levels. Surgical resection of the pituitary adenoma is the primary treatment, but long-term metabolic and physical sequelae can persist, affecting psychological well-being and social functioning. Glucocorticoids are directly involved in alterations of fat metabolism, favoring centripetal adiposity. Even after hormonal normalization, patients may experience residual lipodystrophy. Impairment of body image may cause psychological distress and social isolation. The objective is to illustrate the potential therapeutic value of reconstructive liposuction in restoring body image and psychological well-being in a patient with persistent lipodystrophy after Cushing’s disease remission.

We report a case of a 16-year-old female with recurrent Cushing’s disease secondary to a pituitary microadenoma, confirmed by elevated urinary free cortisol and magnetic resonance imaging (MRI). It was initially treated with transsphenoidal resection in 2019; disease recurrence was confirmed and again treated in 2024. Despite intervention, the prolonged hypercortisolism developed into secondary lipodystrophy, leading to severe body image dissatisfaction and social withdrawal. Thyroid function remained euthyroid, ruling out metabolic contributors. Because of the psychological distress caused by persistent fat redistribution, the patient underwent elective liposuction in 2025. Postoperative follow-up revealed reduced psychological distress and improved well-being and self-esteem. Reconstructive liposuction can play a key role in the treatment and management of persistent post-CS lipodystrophy, contributing significantly to psychological recovery. Prospective studies evaluating surgical criteria and long-term psychosocial outcomes are needed to define eligibility criteria and assess outcomes, leading to the development of clinical guidelines for aesthetic interventions in post-CS recovery.

Introduction

Corticotroph pituitary adenomas (corticotropinomas) are pituitary tumors that secrete excess adrenocorticotropic hormone (ACTH), causing endogenous Cushing’s syndrome (CS). Most of these adenomas are sporadic and monoclonal, although in some rare cases, they are associated with germline mutations (e.g., in USP8) or genetic syndromes [1,2]. Clinically, excess ACTH causes a classic presentation with centripetal obesity, purple striae, muscle asthenia, hypertension, and emotional disturbances such as depression or anxiety [3-5]. Chronically elevated cortisol levels promote fat deposition in central body regions – face, neck, torso, and abdomen – at the expense of relative thinning of the limbs [3], leading to lipodystrophy that can seriously affect the patient’s quality of life.

At the molecular level, glucocorticoids stimulate the differentiation of preadipocytes into mature adipocytes and enhance lipoprotein lipase activity in peripheral fat tissues [6], thereby increasing the uptake of circulating fatty acids and the storage of triglycerides. At the same time, they increase hepatic lipogenesis and modulate cortisol receptor homeostasis (e.g., 11β-HSD1 in adipose tissue), favoring visceral fat distribution [6]. Although glucocorticoids can induce acute lipolysis, they exert chronic lipogenic effects – especially in subcutaneous adipose tissue – which promotes fat accumulation in the face, neck, and trunk [6]. This central adiposity, characteristic of CS, is further enhanced by increased hepatic lipogenesis and the overexpression of 11β-HSD1 in adipose tissue, which amplifies the local action of cortisol [6].

Case Presentation

In 2019, a 16-year-old female patient was initially diagnosed with a 4 × 3 mm pituitary microadenoma (Figure 1), following clinical suspicion of Cushing’s disease. The diagnosis was confirmed through imaging studies and endocrinological testing, which revealed consistently elevated urinary free cortisol levels ranging from 459 to 740.07 µg/24 hours (normal range: <50 µg/24 hours), indicative of endogenous hypercortisolism. No dynamic load tests (such as dexamethasone suppression or ACTH stimulation) were performed, as the diagnosis was supported by the clinical context and laboratory findings. Moreover, no clinical or biochemical evidence of adrenal insufficiency was observed during follow-up.

T1-weighted-sagittal-MRI-scan-showing-a-corticotroph-pituitary-microadenoma-(4-×-3-mm)-circled-in-red
Figure 1: T1-weighted sagittal MRI scan showing a corticotroph pituitary microadenoma (4 × 3 mm) circled in red

The lesion is localized within the anterior pituitary gland, consistent with an ACTH-secreting adenoma causing Cushing’s disease in the patient.

MRI, magnetic resonance imaging; ACTH, adrenocorticotropic hormone

The patient underwent transsphenoidal endonasal resection of the pituitary tumor in 2019. Although initially successful, disease recurrence was confirmed, and a second endonasal transsphenoidal surgery was performed in 2024. Despite these interventions, the prolonged hypercortisolism led to the development of secondary lipodystrophy, manifesting as centripetal fat accumulation, a dorsal fat pad, and disproportionate truncal adiposity (Figure 2). These physical alterations had a significant psychosocial impact, as reported by the patient during follow-up visits, resulting in body image dissatisfaction, low self-esteem, and social withdrawal. No formal psychometric scales were administered.

Preoperative-and-intraoperative-images-of-the-patient
Figure 2: Preoperative and intraoperative images of the patient

A and B panels show the anterior and posterior views prior to liposuction, demonstrating centripetal adipose accumulation characteristic of Cushing’s syndrome. The C panel shows the intraoperative stage following abdominal and flank liposuction, with placement of drainage tubes, and visible reduction in subcutaneous fat volume.

A thyroid function panel revealed a slightly elevated thyroid-stimulating hormone (TSH) level (4.280 μUI/mL; reference range: 0.270-4.200), with total and free T3 and T4 values within normal limits, ruling out clinically significant hypothyroidism as a confounding factor for her phenotype. The biochemical profile suggested a euthyroid state, despite borderline TSH elevation, which was interpreted as a subclinical or adaptive response to chronic cortisol excess (Table 1).

Parameter Normal Range Patient’s Value
Cortisol (µg/24 hour) 58.0 – 403.0 459.5 – 740.07
TSH (µUI/mL) 0.270 – 4.200 4.280
Total T3 (ng/mL) 0.80 – 2.00 1.02
Free T3 (pg/mL) 2.00 – 4.40 3.33
Total T4 (µg/dL) 4.50 – 12.00 8.63
Free T4 (ng/dL) 0.92 – 1.68 1.36
Table 1: Comparison between the patient’s hormone levels and standard reference ranges

A persistently elevated 24-hour urinary cortisol range is observed, consistent with endogenous hypercortisolism. The thyroid profile remains within normal limits, with a mildly elevated TSH in the absence of overt thyroid dysfunction. These findings support the functional and metabolic profile characteristic of Cushing’s syndrome.

TSH, thyroid-stimulating hormone

The procedure targeted lipodystrophic regions identified through clinical examination and patient concerns, rather than formal imaging or anthropometric measurements. It aimed to restore body contour, alleviate somatic distress, and improve her overall self-perception and quality of life. Postoperative follow-up revealed patient-reported improvements in body image and psychological well-being. While these outcomes were not evaluated with formal instruments, the clinical improvement was evident and significant from the patient’s perspective, highlighting the role of plastic surgery not only as a reconstructive tool, but also as a therapeutic strategy for restoring dignity and social functioning in patients recovering from CS.

Discussion

After successful treatment of the pituitary adenoma, many metabolic parameters improve; however, fat distribution usually only partially reverses. Longitudinal studies show that, in the medium term, weight and abdominal circumference decrease, and there is some redistribution of fat toward the limbs following cortisol remission [3].

For example, Bavaresco et al. (2024) observed that, after hormone levels normalized, total fat was reduced and part of it shifted from the visceral area to the legs [3]. Nevertheless, their review highlights that a significant proportion of patients continue to present with residual visceral adiposity and moderate obesity (body mass index, or BMI >25), despite hormonal control [7]. In our case, truncal adiposity persisted based on clinical assessment, though no formal anthropometric measurements were performed.

Although liposuction is not traditionally considered first-line therapy for cortisol-induced lipodystrophy secondary to Cushing’s disease, increasing evidence from related lipodystrophic syndromes supports its clinical utility. For instance, in human immunodeficiency virus (HIV)-associated cervicodorsal lipodystrophy, Barton et al. (2021) conducted a 15-year retrospective analysis comparing liposuction and excisional lipectomy, finding that 80% of patients undergoing liposuction alone experienced recurrence, while none of the patients treated with excisional lipectomy showed recurrence – albeit with a higher risk of postoperative seroma formation [7]. These findings underscore that, while liposuction may be less durable than excision, it remains a viable option for selected cases, especially when used for contouring or as an adjunct [7]. Similarly, the Endocrine Society guidelines on lipodystrophy management emphasize the importance of personalized approaches, particularly when localized adipose accumulation contributes to persistent metabolic dysfunction or psychological distress [8]. Akinci et al. (2024) also highlight that, even in partial or atypical lipodystrophy syndromes, patients often report substantial impairment in quality of life due to disfiguring fat redistribution [9]. In this context, liposuction should not be dismissed as merely cosmetic but considered part of a functional and psychosocial rehabilitation strategy. The present case exemplifies this rationale, as the patient – despite biochemical remission of Cushing’s disease – continued to experience debilitating body image disturbances and emotional distress, which were ameliorated following targeted liposuction. This supports the integration of body-contouring procedures into multidisciplinary care protocols for endocrine-related lipodystrophies, especially when residual physical stigma persists after hormonal normalization [7-9].

Body image disorders, such as those secondary to CS or lipodystrophy, significantly impact self-perception, self-esteem, and social functioning. For example, a study by Alcalar et al. (2013) reported that patients with active Cushing’s disease had significantly lower SF-36 scores – particularly in emotional role functioning and mental health domains – compared to controls [10]. Similarly, Akinci et al. (2024) described that patients with partial lipodystrophy demonstrated marked reductions in EQ-5D index values and visual analog scale (VAS) scores, indicating impaired health-related quality of life [9]. These findings underscore that fat redistribution disorders can substantially compromise psychosocial well-being, even after endocrine remission.

This is especially relevant in women, where sociocultural stereotypes surrounding female physical appearance reinforce thinness, symmetry, and youthfulness as standards of personal value and social acceptance [1]. This societal context amplifies body dissatisfaction when visible physical changes occur, even after the clinical remission of endocrine diseases, often leading to social withdrawal, anxiety, or depression [3,10]. Within this framework, plastic surgery – such as reconstructive liposuction – has proven to be a valuable therapeutic tool, offering physical restoration that can enhance self-confidence and promote social reintegration [4]. Postoperative follow-up in our case revealed patient-reported improvements in body image and psychological well-being. While these outcomes were not assessed using formal psychometric tools, the clinical benefit was evident from the patient’s perspective. This aligns with prior findings demonstrating the psychosocial value of reconstructive surgery, which can enhance self-esteem and social reintegration after physical disfigurement [11,12]. These observations underscore the role of plastic surgery not only as a reconstructive intervention, but also as a therapeutic strategy for restoring dignity and quality of life in patients recovering from CS.

Although validated psychometric instruments such as the Body Image Quality of Life Inventory (BIQLI) and the Dysmorphic Concern Questionnaire (DCQ) are available to assess body image disturbances, these were not applied in our case. Nonetheless, they represent useful tools for evaluating subjective impact in both clinical practice and research settings. The BIQLI evaluates the effect of body image on various aspects of life – social interactions, self-worth, sexuality, and emotional well-being – using a Likert scale ranging from -3 (very negative impact) to +3 (very positive impact), providing a quantifiable assessment of its influence on quality of life [5]. The DCQ, on the other hand, identifies dysfunctional concerns about perceived physical flaws by assessing behaviors such as avoidance, mirror checking, and concealment; higher scores are associated with suspected body dysmorphic disorder (BDD) [6]. These tools are useful for initial diagnosis, surgical candidate selection, and postoperative follow-up, as they objectively measure subjective changes related to body image. Their advantages include ease of use, clinical validity, and applicability in research settings. However, they also have limitations: they do not replace comprehensive psychological evaluation, may be influenced by cultural context, and do not detect deeper psychiatric comorbidities. Therefore, a multidisciplinary and ethically grounded approach – integrating plastic surgery, endocrinology, and psychology – is essential to ensure safe and patient-centered treatment planning.

Aesthetic liposuction is associated with significant improvements in perceived body image and patient quality of life [11]. For example, Papadopulos et al. (2019) observed statistically significant increases in perception of one’s own body appearance and high satisfaction with postoperative results [12]. These aesthetic gains were accompanied by psychological improvements: the same study documented an increase in emotional stability and a reduction in postoperative anxiety [12]. Similarly, Kamundi (2023) found that nearly all assessed dimensions of quality of life improved after liposuction (p < 0.05 in most of them). Altogether, these findings suggest that liposuction not only corrects physical alterations typical of CS, but also strengthens self-esteem and psychological well-being by substantially improving satisfaction with one’s body image [11].

Moreover, self-esteem influences adherence to medical treatments and lifestyle changes. By improving self-image through reconstructive surgery, it is plausible that the patient feels more motivated to maintain healthy habits, such as diet and regular exercise, that prevent metabolic relapse [12,13].

Nonetheless, it is important to emphasize that liposuction, in this context, should be viewed as a reconstructive complement, not a primary treatment. There are no established protocols or formal guidelines that explicitly include plastic surgery in the care of cured CS; the decision is personalized, based on the residual functional and psychological impact.

Conclusions

Reconstructive plastic surgery, though not a primary therapeutic approach for CS, plays a key role in enhancing patients’ quality of life following remission. Liposuction, in particular, offers a safe and effective solution for persistent lipodystrophy, providing aesthetic benefits with minimal scarring, rapid recovery, and low complication rates in properly selected patients.

This case underscores the importance of addressing both physical and psychosocial sequelae after endocrine stabilization. A multidisciplinary approach – encompassing endocrinology, neurosurgery, and plastic surgery – not only restores physical appearance but also contributes to emotional recovery, self-esteem, and overall patient satisfaction.

References

  1. Tatsi 😄 Cushing syndrome/disease in children and adolescents. Endotext [Internet]. Feingold KR, Ahmed SF, Anawalt B, et al. (ed): MDText.com, Inc., South Dartmouth (MA); 2000.
  2. Mir N, Chin SA, Riddell MC, Beaudry JL: Genomic and non-genomic actions of glucocorticoids on adipose tissue lipid metabolism. Int J Mol Sci. 2021, 22:8503. 10.3390/ijms22168503
  3. Bavaresco A, Mazzeo P, Lazzara M, Barbot M: Adipose tissue in cortisol excess: what Cushing’s syndrome can teach us?. Biochem Pharmacol. 2024, 223:116137. 10.1016/j.bcp.2024.116137
  4. Nieman LK: Molecular derangements and the diagnosis of ACTH-dependent Cushing’s syndrome. Endocr Rev. 2022, 43:852-77. 10.1210/endrev/bnab046
  5. Patni N, Chard C, Araujo-Vilar D, Phillips H, Magee DA, Akinci B: Diagnosis, treatment and management of lipodystrophy: the physician perspective on the patient journey. Orphanet J Rare Dis. 2024, 19:263. 10.1186/s13023-024-03245-3
  6. Peckett AJ, Wright DC, Riddell MC: The effects of glucocorticoids on adipose tissue lipid metabolism. Metabolism. 2011, 60:1500-10. 10.1016/j.metabol.2011.06.012
  7. Barton N, Moore R, Prasad K, Evans G: Excisional lipectomy versus liposuction in HIV-associated lipodystrophy. Arch Plast Surg. 2021, 48:685-90. 10.5999/aps.2020.02285
  8. Brown RJ, Araujo-Vilar D, Cheung PT, et al.: The diagnosis and management of lipodystrophy syndromes: a multi-society practice guideline. J Clin Endocrinol Metab. 2016, 101:4500-11. 10.1210/jc.2016-2466
  9. Akinci B, Celik Gular M, Oral EA: Lipodystrophy syndromes: presentation and treatment. Endotext [Internet]. Feingold KR, Anawalt B, Boyce A, et al. (ed): MDText.com, Inc., South Dartmouth (MA); 2024.
  10. Alcalar N, Ozkan S, Kadioglu P, Celik O, Cagatay P, Kucukyuruk B, Gazioglu N: Evaluation of depression, quality of life and body image in patients with Cushing’s disease. Pituitary. 2013, 16:333-40. 10.1007/s11102-012-0425-5
  11. Kamundi RK: Determining the Impact of Liposuction on Patient Satisfaction of Quality of Life and Body Image: A Prospective Study in Nairobi, Kenya. University of Nairobi, Nairobi; 2023.
  12. Papadopulos NA, Kolassa MJ, Henrich G, Herschbach P, Kovacs L, Machens HG, Klöppel M: Quality of life following aesthetic liposuction: a prospective outcome study. J Plast Reconstr Aesthet Surg. 2019, 72:1363-72. 10.1016/j.bjps.2019.04.008
  13. Saariniemi KM, Salmi AM, Peltoniemi HH, Charpentier P, Kuokkanen HOM: Does liposuction improve body image and symptoms of eating disorders?. Plast Reconstr Surg Glob Open. 2015, 3:461. 10.1097/GOX.0000000000000440

From https://www.cureus.com/articles/376886-reconstructive-liposuction-for-residual-lipodystrophy-after-remission-of-cushings-disease-a-case-report#!/

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Double Synchronous Functional Pituitary Adenomas Causing Acromegaly and Subclinical Cushing Disease

Posted on July 1, 2025 by MaryO

Abstract

Double pituitary adenomas with growth hormone (GH) and adrenocorticotropic hormone (ACTH) secretion are very rare. They are responsible for acromegaly with hypercortisolism. Subclinical corticotropic adenomas are exceptional.
Herein, we report the case of a patient with double functional pituitary adenomas causing acromegaly and subclinical Cushing’s disease. A 45-year-old woman was referred to our Department for suspected acromegaly. Her past medical history included diabetes mellitus treated with oral antidiabetic drugs and hypertension.
On physical examination, she had a large prominent forehead, thickened lips, increased interdental spacing, prognathism, and enlarged hands and feet. No signs of hypercortisolism were found. Biological investigations showed an elevated insulin growth factor-1 (IGF-1) level at 555 ng/mL, a GH nadir after 75 g oral glucose tolerance test at 2 ng/mL, a morning cortisol level at 158 ng/mL, an ACTH level at 64 pg/mL, a thyroid stimulating hormone (TSH) level at 2.26 mIU/L, and a free thyroxine (FT4) level at 12.8 pmol/L. Cortisol level after low-dose dexamethasone suppression test was 86 ng/mL.
The diagnosis of acromegaly associated with Cushing’s disease was established. Pituitary magnetic resonance imaging showed a pituitary macroadenoma with no clear limits. The patient underwent transsphenoidal tumor resection. The pathological examination revealed two separate pituitary adenomas. The positivity to ACTH and GH was 100% and 80%, respectively.
This case emphasizes the necessity of an evaluation of all the pituitary axes in case of adenoma in order not to miss a double hormonal secretion or more even in the absence of suggestive clinical signs.

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Johns Hopkins Pituitary Patient Education Day

Posted on June 16, 2025 by MaryO

October 25 @ 9:00 am – 1:00 pm

The annual Pituitary Patient Education Day is a free event that features presentations from Johns Hopkins pituitary experts.

To RSVP, please email pituitaryday@jhmi.edu. Space is limited. Each person can bring up to one guest. If you RSVP yes but you cannot make it, please inform us as soon as possible by email, so that the slot can be offered to someone else.

List of presentations will be posted when finalized. Topics covered in previous years include:

Free
1800 Orleans Street, Zayed 2117
Baltimore, Maryland 21287 United States

410-955-5000

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Ectopic ACTH-secreting Pheochromocytoma Without Typical Signs of Cushing Syndrome

Posted on May 3, 2025 by MaryO

Abstract

This case report describes a 42-year-old female with a rare pheochromocytoma presenting without classic Cushingoid features but with uncontrolled hypertension, type 2 diabetes, and recurrent headaches. Despite the absence of typical signs, biochemical analysis revealed elevated cortisol and ACTH levels, and imaging showed a 6 cm adrenal mass. The patient was stabilized preoperatively with alpha-blockers and metyrapone before undergoing a successful laparoscopic adrenalectomy. Histopathology confirmed pheochromocytoma with aggressive features. Postoperatively, her blood pressure and symptoms improved, and her cortisol levels normalized. This case underscores the diagnostic challenges of ACTH-secreting pheochromocytomas without classic hypercortisolism signs and emphasizes the need for thorough endocrine and imaging assessments. Surgical resection remains the definitive treatment, with long-term follow-up essential to monitor for recurrence. This case contributes to the limited literature on the coexistence of pheochromocytoma and ectopic ACTH secretion.

Introduction

Ectopic ACTH-dependent tumors are rare, comprising approximately 5%–10% of Cushing syndrome cases, and are infrequently associated with pheochromocytomas, making this a unique presentation [1, 2]. Pheochromocytomas, though rare, can present as adrenal incidentalomas, often discovered during imaging for unrelated conditions. They represent 7% of adrenal incidentalomas and pose clinical challenges due to the risk of hormonal hypersecretion, including excess catecholamines and cortisol [1]. This case highlights the coexistence of an ectopic ACTH-producing tumor and pheochromocytoma, a combination rarely reported in the literature [3, 4]. While Cushing syndrome typically arises from adrenal or pituitary sources, ectopic ACTH secretion from pheochromocytomas presents a diagnostic and therapeutic challenge due to its rarity and aggressive potential [4–6]. Early diagnosis is crucial, particularly in cases with comorbidities like hypertension and diabetes, which are common in pheochromocytomas [1, 2]. This case underscores the need for a multidisciplinary approach to managing rare endocrine tumors.

Case report

A 42-year-old female from Mexico City presented with a history of treatment-resistant hypertension and a newly identified adrenal mass. She had no history of alcohol or tobacco use and led a generally healthy lifestyle. She was diagnosed with type 2 diabetes five years before symptoms appeared and developed hypertension five years before hospitalization, managed with valsartan and amlodipine verapamil.

The patient’s hypertension worsened, with blood pressure readings reaching 200/160 mmHg. She presented with asthenia and adynamia, and a CT scan revealed a 4 cm right adrenal mass, confirmed as 4.7 cm on a subsequent scan (Fig. 1). No signs of metastasis were observed. Upon hospital admission, her physical examination revealed a blood pressure of 95/84 mmHg, a heart rate of 95 beats per minute, a respiratory rate of 28 breaths per minute, and a systolic murmur. She exhibited no Cushingoid features.

 

The imaging identified a hyperdense area at the lower pole of the left kidney. A heterogeneous image was visualized in the right adrenal gland, characterized by a hypodense lesion measuring 40 × 47 × 43 mm, with a density of 36 Hounsfield units (HU) in the simple phase, 107 HU in the venous phase and 61 HU in the delayed phase (15 min), with an absolute washout of 64%.

Figure 1

The imaging identified a hyperdense area at the lower pole of the left kidney. A heterogeneous image was visualized in the right adrenal gland, characterized by a hypodense lesion measuring 40 × 47 × 43 mm, with a density of 36 Hounsfield units (HU) in the simple phase, 107 HU in the venous phase and 61 HU in the delayed phase (15 min), with an absolute washout of 64%.

Initial laboratory tests showed elevated white blood cells (11 000/mm3), hemoglobin of 12.5 g/dl, and platelet count of 305 000/mm3. Blood chemistry indicated hyperglycemia (132 mg/dl), hyponatremia (129 mEq/l), and hypokalemia (3.4 mEq/l). Cortisol levels were elevated at 31.53 μg/dl, and a 1 mg low-dose dexamethasone suppression test showed cortisol levels of 16.65 μg/dl and 14.63 μg/dl, suggesting ACTH-dependent Cushing syndrome.

ACTH levels were 24 pg/ml, which, while elevated, were not suppressed. However, elevated 24-h urinary metanephrines (9881 μg/24 h) confirmed the presence of pheochromocytoma. The patient’s aldosterone-to-renin ratio was measured, revealing a ratio of 4. The serum aldosterone level was 5 ng/dl (138 pmol/l), while plasma renin activity was recorded at 1.1 ng/ml/h.

Imaging revealed a 4.7 cm right adrenal mass with a density of 36 Hounsfield Units and an absolute washout of 64%, with no signs of malignancy (Fig. 1).

The patient’s hypertension was initially managed with prazosin and metoprolol, but her blood pressure spiked to 200/160 mmHg during a hypertensive crisis, requiring nitroprusside. Surgical intervention was planned after diagnosis was confirmed.

The patient underwent a successful laparoscopic right adrenalectomy. The tumor measured 6 cm, and histopathology confirmed a pheochromocytoma with a PASS score of 4, indicating potential for aggressive behavior (Table 1). Histological and immunohistochemical analysis revealed the tumor’s characteristic organoid pattern (Zellballen) with chromogranin and synaptophysin positivity in principal cells and S100 protein staining in sustentacular cells, consistent with pheochromocytoma (Fig. 2). Postoperatively, her blood pressure stabilized, and symptoms of palpitations and sweating resolved. She has weaned off antihypertensives, and a follow-up dexamethasone suppression test showed a significant reduction in cortisol levels (1.2 μg/dl), indicating successful tumor removal.

 

Table 1

Histopathological report.

HISTOPATHOLOGICAL DIAGNOSIS
Specimen from right adrenalectomy:
Pheochromocytoma measuring 6×6 cm (positive for chromogranin 7, synaptophysin +S100, with sustentacular cells staining positive)

  • Marked nuclear pleomorphism: 1 point
  • Diffuse growth pattern: 2 points
  • Capsular invasion: 1 point
Total: 4 points.
Tumors with a score greater than 4 may exhibit aggressive biological behavior.

 

Histological and microscopic findings of adrenal Pheochromocytoma. (A) Macroscopic appearance. The ovoid tissue specimen has a light, smooth, soft external surface. The cut surface reveals a dark inner surface with light and hemorrhagic areas. Two cystic lesions with smooth walls are observed in the center (gross view). (B) A well-demarcated hypercellular lesion with an organoid pattern (Zellballen), separated by thin fibrovascular septa (Hematoxylin and eosin stain, 40×). (C) Nest of polygonal principal cells with ample eosinophilic granular cytoplasm, well-defined plasma membranes, hyperchromatic nuclei, and mild nuclear pleomorphism. Adjacent to the principal cells are spindle-shaped sustentacular cells with eosinophilic cytoplasm (Hematoxylin and eosin stain, 400×). (D) Positive immunoreactivity for chromogranin in principal cells. (E) Intense cytoplasmic reaction for synaptophysin in principal cells (immunohistochemistry, 400×). (F) Positive immunoreactivity for S100 protein, showing nuclear and cytoplasmic staining in sustentacular cells (immunohistochemistry, 400×).

Figure 2

Histological and microscopic findings of adrenal Pheochromocytoma. (A) Macroscopic appearance. The ovoid tissue specimen has a light, smooth, soft external surface. The cut surface reveals a dark inner surface with light and hemorrhagic areas. Two cystic lesions with smooth walls are observed in the center (gross view). (B) A well-demarcated hypercellular lesion with an organoid pattern (Zellballen), separated by thin fibrovascular septa (Hematoxylin and eosin stain, 40×). (C) Nest of polygonal principal cells with ample eosinophilic granular cytoplasm, well-defined plasma membranes, hyperchromatic nuclei, and mild nuclear pleomorphism. Adjacent to the principal cells are spindle-shaped sustentacular cells with eosinophilic cytoplasm (Hematoxylin and eosin stain, 400×). (D) Positive immunoreactivity for chromogranin in principal cells. (E) Intense cytoplasmic reaction for synaptophysin in principal cells (immunohistochemistry, 400×). (F) Positive immunoreactivity for S100 protein, showing nuclear and cytoplasmic staining in sustentacular cells (immunohistochemistry, 400×).

Postoperatively, her course was uneventful, with stable blood pressure without antihypertensives. A follow-up evaluation revealed normal cortisol levels, and 24-h urinary metanephrines returned to normal (312 μg/24 h for metanephrines; 225 μg/24 h for normetanephrines). Repeat imaging showed no residual adrenal mass. At her most recent follow-up, the patient remained asymptomatic with normal laboratory values, and no recurrence has been detected.

Discussion

Ectopic ACTH-secreting pheochromocytomas are rare, accounting for a small percentage of ACTH-dependent Cushing syndrome cases [1, 4–6]. These tumors present diagnostic challenges, mainly when typical signs of Cushing syndrome, such as moon face, abdominal striae, or muscle weakness, are absent [3]. In this case, the patient exhibited only diabetes, uncontrolled hypertension, and recurrent headaches, symptoms that can also be attributed to pheochromocytoma itself [1]. The absence of Cushingoid features delayed the identification of ectopic ACTH secretion, making this case particularly difficult and unusual.

According to Gabi JN et al., most patients with ACTH-secreting pheochromocytomas present with severe hypercortisolism, including rapid weight gain and characteristic facial changes [3]. The absence of such features in this patient highlights the need to consider ectopic ACTH secretion in cases of adrenal masses, even without typical Cushing syndrome symptoms. This case illustrates how subtle presentations can lead to delayed diagnoses, emphasizing the importance of thorough evaluation in patients with adrenal tumors and metabolic abnormalities [1, 3].

The diagnostic approach for pheochromocytomas includes hormonal assays and imaging [7, 8]. Preoperative management for pheochromocytomas typically includes alpha-blockers to manage catecholamine excess [4, 7, 8]. This patient was managed with prazosin for blood pressure control and metyrapone to suppress cortisol production, consistent with clinical guidelines for managing ACTH-secreting tumors [5, 7, 8]. Despite the absence of Cushingoid features, careful preoperative preparation was essential to prevent complications during surgery.

Surgical resection is the definitive treatment for pheochromocytomas, particularly those secreting ACTH [8]. In this case, the patient underwent a successful laparoscopic adrenalectomy with no intraoperative complications. Histopathology confirmed a pheochromocytoma with marked nuclear pleomorphism and capsular invasion, suggesting potential aggressive behavior. Postoperatively, the patient’s blood pressure normalized, and her diabetes improved, aligning with outcomes reported in similar cases [4, 6]. Cortisol levels also returned to normal, demonstrating the effectiveness of adrenalectomy in resolving hypercortisolism.

A limitation in this case was the delayed recognition of ectopic ACTH secretion due to the absence of typical Cushingoid signs. The literature underscores the importance of considering this diagnosis, even in nonspecific cases [5].

Long-term management of pheochromocytomas, particularly those with aggressive features like capsular invasion, requires close follow-up [5, 7, 8]. Genetic testing should be considered, especially in patients with unusual presentations or family histories of endocrine disorders [1, 5]. Although not performed in this case, genetic testing could have provided further insight into the tumor’s etiology.

Acknowledgements

We thank the radiology department for interpreting the CT.

Conflict of interest

The authors declare no conflicts of interest related to this case report.

Funding

No external funding was received for this study.

Ethical approval

No approval was required.

Consent

Written informed consent was obtained from the patient and her parents to publish this case report and any accompanying images.

Guarantor

Froylan D. Martinez-Sanchez is the guarantor for this publication and accepts full responsibility for the work.

© The Author(s) 2025. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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