Rare Association Between Neurofibromatosis Type 1 and Adrenocortical Carcinoma

ABSTRACT

Although rare, adrenocortical carcinoma (ACC) should be considered in individuals with neurofibromatosis type 1 (NF1) presenting with adrenal incidentalomas. Despite pheochromocytoma being more prevalent in NF1, appropriate functional evaluation is important in this context to rule out adrenocortical carcinoma given its aggressive nature and poor prognosis.

Axial slice CT abdomen pelvis with portal venous contrast, revealing a well circumscribed 22 × 20 × 22 mm left adrenocortical adenocarcinoma (ACC) in a patient with neurofibromatosis type 1 (NF1).

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 genetic disorder, with incidence of between 1 in 2500 and 3000 live births [2]. Although NF1 is primarily characterized by cutaneous manifestations, there is an established association with several benign and malignant tumors, including malignant peripheral nerve sheath tumors, gliomas, and pheochromocytomas [3].

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, with annual incidence of between 1 to 2 per million and known predilection toward females [4]. Presentation with symptoms of hormone excess, particularly hypercortisolism and virilisation, 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 familial cancer susceptibility syndromes, most notably Li‐Fraumeni Syndrome and Beckwith‐Wiedemann Syndrome in childhood, and multiple endocrine neoplasia type 1 and familial adenomatous 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 followed up in our service for tumor surveillance. Her surgical history included a C3‐T8 spinal fusion secondary to kyphoscoliosis at 3 years of age, and surgical resection of two thoracic plexiform neurofibromas and a left para‐vertebral atypical neurofibromatous neoplasm. Her past medical history was otherwise 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 paroxysmal palpitations and anxiety concerning for a functional endocrine tumor.

On surveillance PET FDG assessment of a known thoracic plexiform neurofibroma, an incidental FDG‐avid left adrenal nodule was noted. Serial PET FDG eight months following revealed interval enlargement and increasing FDG‐avidity, raising 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 × 22 mm, 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 lymphadenopathy to suggest locally advanced or metastatic disease.

FIGURE 1.

Axial slice CT abdomen pelvis with portal venous contrast, revealing a well circumscribed 22 × 20 × 22 mm left adrenal lesion with homogeneous enhancement.

Further functional assessment with PET‐Dotatate was undertaken which revealed a mild‐to‐moderate avidity 21 × 19 mm left adrenal nodule (Figure 2).

FIGURE 2.

PET Gallium Dotatate Study demonstrating a mild‐to‐moderately Dotatate avid left adrenal nodule.

Preoperative serum and urine biochemistry revealed normal plasma metanephrines and urine catecholamines, with elevated morning serum cortisol of 819 nmol/L (reference range 138–650 nmol/L). 24‐hourly urinary metanephrines were normal, with mildly elevated metanephrine to creatinine ratio (0.12 mmol/mol, reference range < 0.10 mmol/mol) and 3‐methoxytyramine to creatinine ratio (0.19 mmol/mol, reference range < 0.15 mmol/mol) (Table 1).

TABLE 1.

Preoperative biochemistry.

Preoperative biochemistry
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 μmol/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 μmol/day
Metanephrine/day	0.7 μmol/day	< 1.7 μmol/day
3‐Methoxytyramine/day	1.2 μmol/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

3. Differential Diagnosis

Despite normal plasma metanephrines and urine catecholamines, pheochromocytoma remained the leading differential given the patient's history of NF1, episodic tachycardia and palpitations, imaging findings consistent with a neuroendocrine tumor, and mildly elevated metanephrine‐to‐creatinine and 3‐methoxytyramine‐to‐creatinine ratios. Low‐level catecholamine secretion was deemed consistent with an early pheochromocytoma. 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 Follow‐Up)

Given ongoing clinical suspicion for pheochromocytoma, preoperative 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 consideration 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 kyphoscoliosis, 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 postoperative 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 postoperative pain.

FIGURE 3.

Coronal and sagittal MRI imaging demonstrating severe kyphoscoliosis with a large upper thoracic meningocoele.

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 immunopositivity. CYP11B1 was weakly positive, and CYP11B2 was negative. Ki‐67 was 7%–10%. Weiss score was 3/9 (nuclear grade 3, atypical mitotic figures, clear cells < 25%). Given the histopathological and immunohistochemical findings, despite a borderline 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 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 nmol/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 ongoing to appropriately monitor for recurrence.

TABLE 2.

Postoperative biochemistry at 7 months.

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 μmol/L
Androstenedione	5.2 nmol/L	1.5–17 nmol/L
Testosterone	0.6 nmol/L	0.2–1.8 nmol/L

5. Discussion

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 diagnosis or tissue diagnosis of ACC [6, 7, 8, 9, 10, 11, 12, 13, 14]. Fraumeni and Miller [8] described the first such relationship, in which two cases of 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 ½. In 1986, Sorensen et al. [10] followed up 212 patients with NF1 to determine survival and incidence 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] reported a 5‐month‐old male with NF1 presenting in adrenal crisis following general anesthesia, with CT scan revealing a left adrenal 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 stromal 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 absence 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 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.

TABLE 3.

Summary of reported cases of NF‐1 associated ACC.

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.

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 expression 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 association supported by prior literature.

This case highlights the diagnostic challenges of adrenal incidentalomas 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 typically exceeding 4 cm [16, 17]. By contrast, the appearance in this case was small, rounded, and well‐defined, with washout features which were deemed consistent with pheochromocytoma [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 pheochromocytoma often share radiological CT features, including similar non‐contrast attenuation (typically > 20 HU) and overlapping enhancement and washout features, further confounding diagnosis [17]. Both entities commonly demonstrate FDG‐avidity, limiting the specificity of FDG‐PET in differentiating 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 symptoms of cortisol, aldosterone, or androgen hormone excess were identified. Conversely, intermittent tachycardia with associated 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 comprehensive preoperative biochemistry in this context, including assessment of cortisol and androgen excess. Approximately 60% of functional adrenal tumors demonstrate biochemical evidence 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 functional 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 secretion is common, evident in 24%–35% of patients with ACC [19, 20]. Plasma and urinary metanephrines and normetanephrines are valuable in excluding a diagnosis of pheochromocytoma 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 adjuvant 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 association, as well as guiding screening strategies for individuals with NF1.

Author Contributions

Zachary Pluim: visualization, writing – original draft, writing – review and editing. Joseph Do Woong Choi: conceptualization, supervision, writing – review and editing. Benedict Kakala: conceptualization, supervision, writing – review and editing. Jessica Wong: writing – review and editing. Roderick Clifton‐Bligh: supervision, writing – review and editing. Mark Sywak: supervision, writing – review and editing. Julie Howle: conceptualization, supervision, visualization, writing – review and editing.

Funding

The authors have nothing to report.

Ethics Statement

Local ethics approval was obtained prior to research publication.

Consent

Written informed consent was obtained from the patient based on the journal's policies.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

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.