CASE REPORT OPEN ACCESS
Rare Association Between Neurofibromatosis Type 1 and Adrenocortical Carcinoma
Zachary Pluim1,2 (D | Joseph Do Woong Choi1 (D | Benedict Kakala1 | Jessica Wong3 | Roderick Clifton-Bligh4 | Mark Sywak3 | Julie Howle1
1Department of Surgery, Westmead Hospital, Sydney, New South Wales, Australia | 2Western Sydney University, Sydney, New South Wales,
Australia | 3Department of Endocrine Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia | 4Department of Endocrinology, Royal North Shore Hospital, Sydney, New South Wales, Australia
Correspondence: Zachary Pluim (30069231@westernsydney.edu.au)
Received: 21 October 2025 | Revised: 15 February 2026 | Accepted: 24 February 2026
Keywords: adrenocortical carcinoma | endocrine neoplasms | endocrine surgery | neurofibromatosis type 1 | pheochromocytoma
ABSTRACT
Although rare, adrenocortical carcinoma (ACC) should be considered in individuals with neurofibromatosis type 1 (NF1) pre- senting with adrenal incidentalomas. Despite pheochromocytoma being more prevalent in NF1, appropriate functional evalua- tion is important in this context to rule out adrenocortical carcinoma given its aggressive nature and poor prognosis.
1 Introduction
Neurofibromatosis type 1 (NF1) is a multisystem, autosomal dominant disorder typified by intertriginous freckling, café au lait macules, and neurofibromas [1]. It is an uncommon ge- netic disorder, with incidence of between 1 in 2500 and 3000 live births [2]. Although NF1 is primarily characterized by cu- taneous manifestations, there is an established association with several benign and malignant tumors, including malignant pe- ripheral nerve sheath tumors, gliomas, and pheochromocyto- mas [3]
Adrenocortical carcinoma (ACC) is a rare endocrine malig- nancy, with annual incidence of between 1 to 2 per million and known predilection toward females [4]. Presentation with symp- toms of hormone excess, particularly hypercortisolism and vi- rilisation, occurs in 40%-60% of cases [4]. Approximately 30% of cases present with non-specific symptoms secondary to local tumor growth, and a further 20%-30% of diagnoses are found incidentally on imaging [4].
There is a known association between ACC and several famil- ial cancer susceptibility syndromes, most notably Li-Fraumeni Syndrome and Beckwith-Wiedemann Syndrome in childhood,
and multiple endocrine neoplasia type 1 and familial adeno- matous polyposis in adulthood [5]. The potential relationship between NF1 and ACC is less recognized, with a possible causal relationship established by genetic analysis in only two cases [6, 7].
2 Case History/Examination
A 27-year-old female with a background of NF1 was being fol- lowed up in our service for tumor surveillance. Her surgical history included a C3-T8 spinal fusion secondary to kyphosco- liosis at 3years of age, and surgical resection of two thoracic plexiform neurofibromas and a left para-vertebral atypical neu- rofibromatous neoplasm. Her past medical history was other- wise significant for polycystic ovarian syndrome. There was no family history of NF1 or other endocrinopathies. On home cardiovascular monitoring, the patient experienced intermittent tachycardia up to 160 beats per minute, with associated parox- ysmal palpitations and anxiety concerning for a functional en- docrine tumor.
On surveillance PET FDG assessment of a known thoracic plexiform neurofibroma, an incidental FDG-avid left adrenal
@ 2026 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.
nodule was noted. Serial PET FDG eight months following re- vealed interval enlargement and increasing FDG-avidity, rais- ing suspicion for malignancy and prompting further adrenal nodule evaluation.
A computed tomography (CT) adrenal protocol revealed a rounded mass arising from the medial limb of the left adrenal gland measuring 22 ×20 ×22mm, with pre-contrast density of 35 HU, arterial density of 100 HU, portal venous density of 68 HU and delayed phase density of 49 HU (Figure 1). There were no features of local adrenal nodule invasion or regional lymph- adenopathy to suggest locally advanced or metastatic disease.
Further functional assessment with PET-Dotatate was under- taken which revealed a mild-to-moderate avidity 21 x 19 mm left adrenal nodule (Figure 2).
Preoperative serum and urine biochemistry revealed normal plasma metanephrines and urine catecholamines, with ele- vated morning serum cortisol of 819 nmol/L (reference range
A
20.76 mm
A
138-650 nmol/L). 24-hourly urinary metanephrines were normal, with mildly elevated metanephrine to creatinine ratio (0.12 mmol/mol, reference range <0.10mmol/mol) and 3-methoxytyramine to creatinine ratio (0.19 mmol/mol, refer- ence range <0.15 mmol/mol) (Table 1).
3 Differential Diagnosis I
Despite normal plasma metanephrines and urine catechol- amines, pheochromocytoma remained the leading differential given the patient’s history of NF1, episodic tachycardia and pal- pitations, imaging findings consistent with a neuroendocrine tumor, and mildly elevated metanephrine-to-creatinine and 3-methoxytyramine-to-creatinine ratios. Low-level catechol- amine secretion was deemed consistent with an early pheo- chromocytoma. In the context of elevated morning cortisol (819 nmol/L), functional tumors such as adrenal adenoma, or less likely ACC, remained differential diagnoses (Table 1).
4 |Conclusion and Results (Outcome and
I Follow-Up)
Given ongoing clinical suspicion for pheochromocytoma, pre- operative alpha-adrenergic blockade with phenoxybenzamine 10 mg daily was commenced 10 days prior to surgery. The patient was subsequently referred to an Endocrine surgeon for consid- eration of a left adrenalectomy. The patient was reviewed and consented for a left transabdominal adrenalectomy. Given the absence of suspicious nodal disease on preoperative imaging, with a small localized primary tumor, lymph node dissection was not undertaken. In the context of known severe kyphosco- liosis, previous spinal fusion and large meningocoele (Figure 3), neurosurgical consultation was obtained. Upon discussion, it was deemed that lateral decubitus positioning required for a laparoscopic approach was contraindicated in this patient, given the necessity for marked spinal flexion. An open adrenalectomy was therefore performed with the patient in a supine position. There was no intraoperative evidence of local tumor invasion or lymphadenopathy, and a left adrenalectomy was performed. The operation was unremarkable; however, the patient’s post- operative course was complicated by tachycardia warranting a period of investigation and monitoring. She was discharged on postoperative day 7 after resolution of her tachycardia and post- operative pain.
Histopathological examination revealed a 27 ×22 ×21 mm T1 ACC within the left adrenal gland. Nuclear grade was 3, with a mitotic count of 3 per 50 HPF. There were no involved margins. Mismatch repair proteins were intact. Immunohistochemistry revealed IGF2, SF1, melan-A, and synaptophysin immunopos- itivity. CYP11B1 was weakly positive, and CYP11B2 was neg- ative. Ki-67 was 7%-10%. Weiss score was 3/9 (nuclear grade 3, atypical mitotic figures, clear cells <25%). Given the histopatho- logical and immunohistochemical findings, despite a border- line Weiss score of 3, features were deemed overall diagnostic of low-grade ACC. After discussion at the endocrine surgery multidisciplinary meeting, the patient was deemed low risk for ACC recurrence in the context of low Weiss score, small tumor size (27 mm), absence of nodal or metastatic disease, low mitotic
| Results | Values | Reference range |
|---|---|---|
| Serum | ||
| Plasma metanephrines | ||
| Normetanephrine | 430 pmol/L | < 580 pmol/L |
| Metanephrine | 80 pmol/L | < 447 pmol/L |
| Methoxytyramine | <50 pmol/L | <181 pmol/L |
| Morning Cortisol | 819 nmol/L (H) | 138-650 nmol/L |
| DHEA | 2.6 µmol/L | 2.4-13 umol/L |
| Androstenedione | 5.2 nmol/L | 1.5-17 nmol/L |
| Basal 17-Hydroxyprogesterone | 1.8 nmol/L | 0.3-3.3 nmol/L |
| Urine | ||
| Catecholamines | ||
| Noradrenaline | 243 nmol/day | 45-680 nmol/day |
| Adrenaline | 17 nmol/day | 5-80 nmol/day |
| Metanephrines | ||
| Normetanephrine/day | 1.3 µmol/day | <2.3 umol/day |
| Metanephrine/day | 0.7 umol/day | <1.7 umol/day |
| 3-Methoxytyramine/day | 1.2 umol/day | <1.3 µmol/day |
| Normetanephine/Cr | 0.20 mmol/mol | <0.25 mmol/mol |
| Metanephrine/Cr | 0.12 mmol/mol (H) | <0.10 mmol/mol |
| 3-Methoxytyramine/Cr | 0.19 mmol/mol (H) | <0.15 mmol/mol |
index, absence of vascular invasion, and Ki-67 of 7%-10%, and therefore adjuvant mitotane was not recommended.
Postoperative biochemistry at 7 months revealed normalization of serum cortisol at 414 nmol/L (reference range 138-650 nmo- l/L) (Table 2). Review and surveillance PET-FDG imaging at the 3, 6, 12 and 15-month intervals did not detect any locoregional recurrence or distant metastasis, with longer-term follow-up on- going to appropriately monitor for recurrence.
I
The authors describe a rare case of ACC in a patient with known NF1, adding to a scant literature base describing this association.
There are 8 reported cases of ACC associated with NF1, with a further 3 suspected cases lacking either confirmed NF1 diag- nosis or tissue diagnosis of ACC [6-14]. Fraumeni and Miller described the first such relationship, in which two cases of ☒ 8
ACC were found in association with extensive Café au lait spots likely representative of NF1, though no further defining features of the condition were described. Fienman and Yakovac [9] then described a case of a 2-year-old female with NF1 presenting with virilisation and a finding of ACC on laparotomy, with associated
thalamic tumor at age 4 1/2. In 1986, Sorensen et al. [10] fol- lowed up 212 patients with NF1 to determine survival and inci- dence of malignant neoplasms and identified two cases of ACC within this cohort. Wagner et al. [11] described a case in which a 3-year-old girl with diagnosed NF1 presented with Cushingoid features and virilisation, with concurrent ACC with suspected neck and paraspinous muscle metastasis. Kollurage et al. [12] re- ported a 5-month-old male with NF1 presenting in adrenal crisis following general anesthesia, with CT scan revealing a left adre- nal mass. No histopathological diagnosis was made in this case. Minkiewicz et al. [13] reported a case of a 57-year-old with NF1 who presented with synchronous ACC and gastrointestinal stro- mal tumor (GIST), with a history of endometrial cancer. Najafi- Semnani et al. [14] described a case of a 39-year-old female with diagnosed NF1 presenting with painless abdominal mass, with CT and magnetic resonance imaging (MRI) showing a large left adrenal lesion. Biochemistry revealed normal metanephrines and cortisol, and surgical resection histology confirmed ACC.
In addition, a further two cases through genetic analysis reported a causal association between NF1 and ACC. Gutmann et al. [ [6] described a case in which genetic analysis confirmed the ab- sence of neurofibromin expression in a 49-year-old patient with ACC, with loss of heterozygosity (LOH) within the NF1 gene. In 2014, Menon et al. [7] described a 49-year-old female presenting
| Postoperative biochemistry | ||
|---|---|---|
| Results | Values | Reference range |
| Serum | ||
| Plasma metanephrines | ||
| Normetanephrine | 280 pmol/L | <580 pmol/L |
| Metanephrine | < 50 pmol/L | <447 pmol/L |
| Methoxytyramine | < 50 pmol/L | <181 pmol/L |
| Cortisol | 414 nmol/L | 138-650 nmol/L |
| Androgens | ||
| DHEAS | 2.6 µmol/L | 2.4-13 umol/L |
| Androstenedione | 5.2nmol/L | 1.5-17 nmol/L |
| Testosterone | 0.6 nmol/L | 0.2-1.8 nmol/L |
with incidental left adrenal mass on ultrasound, without clinical features of androgen, glucocorticoid, or catecholamine excess. Biochemistry revealed mild cortisol and androgen excess [7] Histopathology confirmed ACC, and genetic analysis revealed loss of heterozygosity at the NF1 locus [7]. The reported cases of NF1-associated ACC are summarized in Table 3.
Neurofibromin is a known tumor suppressor, expressed most heavily in neural tissues, where it inhibits the RAS pathway to regulate cell division and growth [14]. Loss of neurofibromin ex- pression is responsible for tumor formation in NF1, and acquired somatic mutations have been associated with sporadic tumor
formation [15]. Tumor-specific molecular analysis, including assessment of NF1 loss of heterozygosity, was not performed in this case. As such, a direct causal relationship between NF1 and ACC cannot be established; rather, this report describes an asso- ciation supported by prior literature.
This case highlights the diagnostic challenges of adrenal inci- dentalomas in NF1, where clinical features and imaging may preferentially suggest pheochromocytoma. In 20%-30% of cases, a diagnosis of ACC is found incidentally on imaging [4]. Typical ACC CT findings include heterogeneous appearance, poorly defined contours, high attenuation values, and tumor size typ- ically exceeding 4cm [16, 17]. By contrast, the appearance in this case was small, rounded, and well-defined, with washout features which were deemed consistent with pheochromocy- toma [16, 17]. It is important to note there is a lack of consensus regarding imaging-specific features of early ACC, which can prove a diagnostic challenge [16, 17]. Moreover, ACC and pheo- chromocytoma often share radiological CT features, includ- ing similar non-contrast attenuation (typically >20 HU) and overlapping enhancement and washout features, further con- founding diagnosis [17]. Both entities commonly demonstrate FDG-avidity, limiting the specificity of FDG-PET in differenti- ating between them [16, 17]. Avidity on PET-Dotatate imaging is highly sensitive for pheochromocytoma, with uptake in ACC typically low or absent. In this case, mild-to-moderate Dotatate uptake was interpreted as initially consistent with a diagnosis of pheochromocytoma.
Approximately 60% of diagnosed ACCs present with symptoms of associated hormone excess [3]. In this case, no clear symp- toms of cortisol, aldosterone, or androgen hormone excess were identified. Conversely, intermittent tachycardia with associated
| Author (date) | Age | Sex | Presentation/hormonal status | NF-1 | Tumor genetics | Outcome |
|---|---|---|---|---|---|---|
| Fraumeni and Miller (1967) | 1-year-old | Female | Virilisation | Suspected (café au lait pigmentation) | Not assessed | NR |
| Fraumeni and Miller (1967) | 1-year-old | Female | Virilisation | Suspected (café au lait pigmentation) | Not assessed | NR |
| Fienman and Yakovac (1970) | 2-year-old | Female | Virilisation | Confirmed | Not assessed | Development of thalamic tumor age 4.5 |
| Sorensen et al. (1986) | 46-year-old | Female | NR | Confirmed | Not assessed | ACC with associated reticulosarcoma |
| Sorensen et al. (1986) | NR | NR | NR | Confirmed | Not assessed | NR |
| Gutmann et al. (1994) | 49-year-old | Female | NR | Confirmed | NF1 LOH | Surgical resection; outcome not reported |
| Wagner et al. (2005) | 3-year-old | Female | Cushingoid features and virilisation | Confirmed | Not assessed | Subtotal resection; metastatic disease during treatment; alive on chemotherapy at time of reporting |
| Menon et al. (2014) | 49-year-old | Female | Incidental imaging finding, biochemical hypercortisolism | Confirmed | NF1 LOH | Surgical resection; adjuvant mitotane; disease free at 18 months |
| Kollurage et al. (2019) | 5-month-old | Male | Adrenal crisis | Confirmed | Not assessed | Mortality related to adrenal crisis |
| Minkiewicz et al. (2020) | 57-year-old | Female | Abdominal pain and loss of weight, synchronous GIST, no hormonal biochemical abnormalities | Confirmed | Not assessed | Surgical resection; adjuvant therapy offered; disease free at 6 months |
| Najafi-Semnani et al. (2021) | 39-year-old | Female | Painless abdominal mass, no hormonal biochemical abnormalities | Confirmed | Not assessed | Surgical resection; disease free at 6 months |
Abbreviation: NR, not reported.
palpitations, anxiety, and mildly elevated metanephrine- to-creatinine and 3-methoxytyramine-to-creatinine ratios supported a diagnosis of pheochromocytoma [18]. Though a diagnosis of pheochromocytoma was deemed most likely, this case underscores the importance of appropriate and compre- hensive preoperative biochemistry in this context, including assessment of cortisol and androgen excess. Approximately 60% of functional adrenal tumors demonstrate biochemical ev- idence of hormone secretion, though only 40% of these present with symptoms associated with this hormonal excess [19]. This may represent hormone secretion at a subclinical level [20]. Of the functional tumors, hypercortisolism is most common at 30%-40%, followed by androgen excess at 20%-30% and less commonly aldosterone or estrogen excess [19]. In this case, an elevated serum cortisol level was noted on preoperative func- tional evaluation, and all other screening tests were normal. This raised suspicion for functional adrenocortical tumor with hypercortisolism, although confirmatory testing-including dexamethasone suppression testing, urinary free cortisol, late- night salivary cortisol, and ACTH-was not performed prior to surgery. As such, stress-related hypercortisolaemia could not be definitively excluded. Presentation with mixed hormone se- cretion is common, evident in 24%-35% of patients with ACC [19, 20]. Plasma and urinary metanephrines and normetaneph- rines are valuable in excluding a diagnosis of pheochromocy- toma and were normal in this case [21].
This case is notable for describing an early-stage, low-grade ACC diagnosed incidentally on surveillance imaging, with minimal hormone excess. It reinforces that ACC may mimic pheochromocytoma both clinically and radiologically, with early recognition allowing for curative resection without ad- juvant therapy.
ACC represents a rare endocrine malignancy, though there is mounting literature suggesting an association between NF1 and ACC. It is important to consider these entities together, especially in the context of an adrenal incidentaloma where early diagnostic features are non-specific [17]. Appropriate initial functional evaluation is essential to rule out a diagnosis of pheochromocytoma which is much more prevalent within this population group [3]. Recognition of this relationship and early diagnosis is important given the aggressive nature and potentially poor prognosis of ACC, with a five-year survival rate of between 15% and 47% [20]. Further genetic analyses reinforcing a causative relationship between NF1 and ACC would be beneficial in both increasing awareness of this asso- ciation, as well as guiding screening strategies for individuals with NF1.
Zachary Pluim: visualization, writing - original draft, writing - review and editing. Joseph Do Woong Choi: conceptualization, supervision, writing - review and editing. Benedict Kakala: concep- tualization, supervision, writing - review and editing. Jessica Wong: writing - review and editing. Roderick Clifton-Bligh: supervision, writing - review and editing. Mark Sywak: supervision, writing - re- view and editing. Julie Howle: conceptualization, supervision, visual- ization, writing - review and editing.
Open access publishing facilitated by Western Sydney University, as part of the Wiley-Western Sydney University agreement via the Council of Australasian University Librarians.
The authors have nothing to report.
Local ethics approval was obtained prior to research publication.
Written informed consent was obtained from the patient based on the journal’s policies.
The authors declare no conflicts of interest.
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
1. J. M. Friedman, “Neurofibromatosis 1: Clinical Manifestations and Diagnostic Criteria,” Journal of Child Neurology 17, no. 8 (2002): 548-554.
2. R. E. Ferner and D. H. Gutmann, “Chapter 53 - Neurofibromatosis Type 1 (NF1): Diagnosis and Management,” in Neurofibromatosis (El- sevier, 2021), 561-578.
3. E. J. Petr and T. Else, “Pheochromocytoma and Paraganglioma in Neurofibromatosis Type 1: Frequent Surgeries and Cardiovascular Cri- ses Indicate the Need for Screening,” Clinical Diabetes and Endocrinol- ogy 4, no. 1 (2018): 15.
4. T. Else, A. C. Kim, A. Sabolch, et al., “Adrenocortical Carcinoma,” Endocrine Reviews 35, no. 2 (2014): 282-326.
5. T. Else, “Association of Adrenocortical Carcinoma With Familial Cancer Susceptibility Syndromes,” Molecular and Cellular Endocrinol- ogy 351, no. 1 (2012): 66-70.
6. D. H. Gutmann, J. L. Cole, W. J. Stone, B. A. Ponder, and F. S. Collins, “Loss of Neurofibromin in Adrenal Gland Tumors From Patients With Neurofibromatosis Type I,” Genes, Chromosomes & Cancer 10 (1994): 55-58.
7. R. K. Menon, F. Ferrau, T. R. Kurzawinski, et al., “Adrenal Cancer in Neurofibromatosis Type 1: Case Report and DNA Analysis,” Endocri- nology, Diabetes & Metabolism Case Reports 2014 (2014): 140074.
8. J. F. Fraumeni, Jr. and R. W. Miller, “Adrenocortical Neoplasms With Hemihypertrophy, Brain Tumors, and Other Disorders,” Journal of Pe- diatrics 70, no. 1 (1967): 129-138.
9. N. L. Fienman and W. C. Yakovac, “Neurofibromatosis in Child- hood,” Journal of Pediatrics 76 (1970): 339-346.
10. S. A. Sorensen, J. J. Mulvihill, and A. Nielsen, “Long-Term Fol- low-Up of Von Recklinghausen Neurofibromatosis, Survival and Malignant Neoplasms,” New England Journal of Medicine 314 (1986): 1010-1015.
11. A. S. Wagner, J. M. Fleitz, and B. K. Kleinschmidt-Demasters, “Pe- diatric Adrenal Cortical Carcinoma: Brain Metastases and Relationship
to NF-1, Case Reports and Review of the Literature,” Journal of Neuro- Oncology 75 (2005): 127-133.
12. U. A. Kollurage, R. V. S. Jayawikrama, A. D. K. S. N. Yasawardana, and N. Atapattu, “Adrenal Crisis in Metastatic Adrenal Cortical Carci- noma in an Infant With Neurofibromatosis Type 1,” Sri Lanka Journal of Child Health 48, no. 1 (2019): 74-76.
13. I. Minkiewicz, E. Wilbrandt-Szczepańska, J. Jendrzejewski, K. Sworczak, A. Korwat, and M. Śledziński, “Co-Occurrence of Adreno- cortical Carcinoma and Gastrointestinal Stromal Tumor in a Patient With Neurofibromatosis Type 1 and a History of Endometrial Cancer,” Acta Endocrinologica (Bucharest) 16, no. 3 (2020): 353-358.
14. M. Najafi-Semnani, M. Rajabi-Moghaddam, and H. Abbaszadeh, “Adrenocortical Carcinoma in a Patient With Neurofibromatosis Type 1: A Case Report,” Caspian Journal of Internal Medicine 12, no. 4 (2021): 613-617.
15. M. Bergoug, M. Doudeau, F. Godin, C. Mosrin, B. Vallée, and H. Bénédetti, “Neurofibromin Structure, Functions and Regulation,” Cells 9, no. 11 (2020): 2365.
16. R. Ambrosini, F. Bertagna, F. Dondi, A. D’Amario, T. Falcone, and L. Grazioli, “Imaging in Adrenocortical Carcinoma and Malignant Pheo- chromocytoma,” in Primary Adrenal Malignancies. Updates in Surgery, ed. G. A. M. Tiberio (Springer, 2024), 31-45.
17. M. Barat, A .- S. Cottereau, S. Gaujoux, et al., “Adrenal Mass Charac- terization in the Era of Quantitative Imaging: State of the Art,” Cancers 14, no. 3 (2022): 569.
18. N. Reisch, M. Peczkowska, A. Januszewicz, and H. P. Neumann, “Pheochromocytoma: Presentation, Diagnosis, and Treatment,” Jour- nal of Hypertension 24, no. 12 (2006): 2331-2339.
19. Y. Nakamura, Y. Yamazaki, S. J. Felizola, et al., “Adrenocortical Car- cinoma,” Endocrinology and Metabolism Clinics of North America 44, no. 2 (2015): 399-410.
20. L. Ng and J. M. Libertino, “Adrenocortical Carcinoma: Diagnosis, Evaluation and Treatment,” Journal of Urology 169, no. 1 (2003): 5-11.
21. R. Libé and O. Huillard, “Adrenocortical Carcinoma: Diagnosis, Prog- nostic Classification, and Treatment of Localized and Advanced Disease,” Cancer Treatment and Research Communications 37 (2023): 100759.