Early-Onset Sarcoma With Germline MAX Variant: Expanding the Spectrum in Hereditary Pheochromocytoma and Paraganglioma

Abstract

Germline pathogenic variants in MYC-associated factor X (MAX) are a rare cause of hereditary pheochromocytoma and paraganglioma (PPGL) syndrome, typically presenting with pheochromocytomas (PCC). Although MAX-related PPGLs are generally characterized by an adrenergic phenotype and bilateral tumors in 67% of cases, the tumor spectrum associated with MAX pathogenic variants remains poorly understood. We present a case of a 28-year-old man with a germline MAX pathogenic variant (c.64-2A>G) who developed bilateral PCC and later, a liver sarcoma with a TP53 variant and PLEKHO2::BRAF gene fusion. The diagnosis of sarcoma in this young patient underscores a potential association between MAX pathogenic variants and an increased predisposition to sarcoma development. Our findings suggest that MAX-related PPGLs may be associated with other malignancies, including sarcoma, and support expanding surveillance guidelines to include whole-body imaging for early detection of extra-adrenal tumors. Given the rarity of MAX pathogenic variants, further studies are needed to elucidate the full spectrum of presentation and establish comprehensive evidence-based surveillance strategies.

Introduction

Germline pathogenic variants in MYC-associated factor X (MAX) are an uncommon cause of hereditary paraganglioma pheochromocytoma (PPGL) syndrome, with pheochromocytoma (PCC) being the most common presentation. The existing literature suggests a preferential paternal mode of transmission [1, 2]. In addition to risk for PPGL, case reports suggest an association between germline MAX pathogenic variants and adrenal and vertebral ganglioneuromas, neuroblastoma, parathyroid adenomas, and renal oncocytomas, many of which are diagnosed at a young age [1, 3-10]. Pituitary tumors have also been reported in at least 9 individuals with germline MAX pathogenic variants [4, 9]. Given the rarity of germline MAX pathogenic variants, knowledge of the full tumor spectrum may still be evolving. Herein we present a case of a patient with bilateral PCC associated with a germline MAX pathogenic variant who developed liver sarcoma with TP53 variant and BRAF fusion at 28 years of age.

Case Presentation

A 28-year-old man presented to his primary care physician with a rash and was found to have severe hypertension (254/178 mm Hg) and a heart rate of 104 bpm. He was treated for shingles and prescribed clonidine and nifedipine for hypertension. Three days later, he presented to the emergency department with nausea, vomiting, headaches, and diaphoresis. The physical examination was significant for an elevated blood pressure of 241/148 mmHg and heart rate of 120 beats per minute with slight respiratory distress on exam. Laboratory tests revealed hemoglobin 17.9 g/dL (179 g/L; normal reference range 13.0-17.7 g/dL, 130-177 g/L), white blood cell count 11.8 K/µL (11 800 000 cells/L; normal reference range 3.5-10.9 K/µL, 3.5-10.9 million cells/L), and elevated creatinine 2.2 mg/dL (194.48 µmol/L), baseline 0.7 mg/dL (61.88 µmol/L; normal reference range 0.7-1.2 mg/dL, 61.88-106.08 µmol/L). Electrocardiogram demonstrated sinus tachycardia with a rate of 120 beats per minute and no other evidence of cardiac injury. He was admitted for hydration and blood pressure control. A renal ultrasound identified a 3.7-cm right-sided adrenal mass. Results from adrenal hormonal evaluation were pending at the time of discharge.

Diagnostic Assessment

Subsequently, laboratory evaluation demonstrated elevated plasma metanephrine of 839 pg/mL (4.253 nmol/L; normal reference range ≤57 pg/mL, ≤ 0.2964 nmol/L) and normetanephrine 1983 pg/mL (10.827 nmol/L; normal reference range ≤148 pg/mL, ≤ 0.8288 nmol/L; Table 1). Aldosterone was 11 ng/dL (300 pmol/L; normal reference range ≤ 21 ng/dL, ≤ 573 pmol/L) and plasma renin activity (PRA) was 25.6 ng/mL/h (0.64 pmol/L/h; normal reference range 0.25-5.82 ng/mL/h, 0.00625-0.1455 pmol/L/h). The 24-hour urine collection revealed markedly elevated metanephrine of 8240 μg/24 hours (41766.8 nmol/24 hours; normal reference range 25-222 μg/24 hours, 136.6-1212.5 nmol/24 hours) and normetanephrine 15248 μg/24 hours (83254.1 nmol/24; normal reference range 40-412 μg/24 hours, 217.8-2237.5 nmol/24 hours). He was then referred to our center for further evaluation. Adrenal protocol computed tomography (CT) showed a right adrenal nodule measuring 4.8 × 3.5 cm with an unenhanced CT attenuation of 44 Hounsfield units (HU) and a left adrenal nodule measuring 17 × 14 mm with an unenhanced CT attenuation of 34 HU. Washout characteristics for both adrenal nodules were consistent with benign adenomas. Gallium 68 dodecanetetraacetic acid-tyrosine-3-octreotate (DOTATATE) scanning demonstrated supraphysiologic uptake in the right and left adrenal gland nodules, consistent with PCC.

Table 1.

Plasma metanephrine levels during clinical course

Hormone	Initial presentation	After adrenalectomy	Second presentation
Plasma metanephrine (≤ 57 pg/mL; ≤ 0.3 nmol/L)	839 pg/mL (4.3 nmol/L)	41.4 pg/mL (0.2 nmol/mL)	< 57 pg/mL (< 0.2 nmol/mL)
Plasma normetanephrine (≤148 pg/mL; ≤ 0.8 nmol/L)	1983 pg/mL (10.8 nmol/L)	604.3 pg/mL (3.3 nmol/mL)	439.5 pg/mL (2.4 nmol/mL)

The patient reported no family history of PPGL. However, he did report pituitary adenoma in his father, skin cancers in several paternal family members, and unspecified thyroid cancer in the maternal grandmother and 2 of her sisters, which raised concern for multiple endocrine neoplasia syndrome. Germline genetic testing with a 77-gene next-generation sequencing (NGS) panel revealed a pathogenic variant in MAX (c.64-2A > G) and a variant of uncertain significance (VUS) in BARD1 (c.1055T>C, p.V352A), the latter of which was reclassified as likely benign 2 years later. The maternal half-sibling tested negative for the MAX variant. Otherwise, familial testing is pending.

Treatment

Preoperatively, the patient was started on doxazosin at 2 mg twice a day, which was titrated to 6 mg twice a day. After reviewing options of right adrenalectomy (partial right adrenalectomy was not technically feasible) with concomitant partial left adrenalectomy or right adrenalectomy alone, the patient preferred right adrenalectomy alone to minimize risk of adrenal insufficiency, understanding the need for surveillance and future partial or complete left adrenalectomy. He then underwent an uneventful robotic right adrenalectomy. Pathology confirmed a 6.1-cm PCC without atypical mitoses or lymphovascular or capsule invasion. Postoperatively, plasma metanephrines and normetanephrines were 41.4 pg/mL (0.23 nmol/mL; normal reference range ≤57 pg/mL, ≤ 0.2964 nmol/L) and 604.3 pg/mL (3.3 nmol/mL; normal reference range ≤148 pg/mL, ≤ 0.8288 nmol/L), respectively (Table 1).

Outcome and Follow-Up

Unfortunately, the patient was lost to follow-up months postoperatively. Two years later, the patient presented to another institution with abdominal pain and was found to have a 17.2-cm cystic lesion in the left hepatic lobe on CT (Fig. 1). An interventional radiology (IR)-guided drain was placed. The patient then represented to our hospital with worsening abdominal pain, increased abdominal girth, and weight loss. On presentation, plasma metanephrine levels were normalized, and plasma normetanephrine decreased from 1983 pg/mL (10 827 nmol/L) to 13.11 pg/mL (2.4 nmol/L; normal reference range ≤ 148 pg/mL, ≤ 0.8288 nmol/L; Table 1). Imaging demonstrated hemorrhagic ascites from the ruptured liver cystic lesion. IR angiogram identified a left hepatic artery branch feeding the lesion, which was embolized.

Figure 1.

Radiological imaging of bilateral PCC and sarcoma. Gallium-68 DOTATATE positron emission tomography/ computed tomography (PET/CT) image from initial presentation showing increased uptake in right (A) and left (B) adrenal gland (arrow). Contrast enhanced coronal (C) and axial (D) CT from second presentation showing large heterogeneous hypodense mass along the anterior left hepatic lobe measuring 17 × 14 × 16 cm (arrow).

Due to persistent hemorrhage, the patient subsequently underwent exploratory laparotomy, lysis of adhesions, partial hepatectomy, and cyst fenestration, revealing a giant bleeding lesion, suspected to be a hepatic adenoma. Surprisingly, the initial pathology of the liver lesion demonstrated malignant epithelioid and spindle cell neoplasm. Based on these findings, the differential diagnosis included metastatic PCC with sarcomatoid transformation and de novo unclassified sarcoma. Immunohistochemical stains were positive for vimentin, CD56, valretinin (focal), desmin, smooth muscle actin; focally positive for glypican3; and negative for pancytokeratin-AE1/3, MNF-116, Cam5.2, WT1, D2-40, Arginase1, CD31, ERG, DOG1, CD117 (cKIT), myogenin, MDM2, synaptophysin, chromogranin, INSM1, S100, SOX10, GATA3, and inhibin. SDHB staining was retained, and the Ki-67 proliferative index was estimated at approximately 30% to 40%. The previous adrenalectomy specimen was reviewed in tandem with the liver specimen and was found to be morphologically different.

Comprehensive tumor genomic profiling showed a pathogenic TP53 variant (c.844C>T, p.R282W) at a variant allele fraction (VAF) of 80.2% by NGS and a PLEKHO2::BRAF gene fusion by RNA fusion panel. Copy number analysis demonstrated chr 1p36 amplification. The germline MAX pathogenic variant was present at a VAF of 85%, indicating loss of heterozygosity. These findings led to a final pathologic diagnosis of high-grade unclassified spindle cell sarcoma with PLEKHO2::BRAF gene fusion and peritoneal carcinomatosis.

The patient continued to have hemorrhagic ascites, which could not be controlled by surgical or IR involvement. Therefore, medical oncology deemed the patient ineligible for palliative chemotherapy. After discussions with his family and palliative care, the patient pursued inpatient hospice care and passed away in 3 weeks.

Discussion

PPGLs are classified into 3 distinct clusters based on their underlying germline or somatic mutations: pseudohypoxia-related clusters 1A and 1B, kinase signaling-related cluster 2, and Wnt signaling-related cluster 3 [3]. MAX-related PPGLs fall under cluster 2 tumors and the prevalence of MAX-related PPGLs is 1% in patient groups without other known susceptibility mutations. These tumors are bilateral in 67% of cases and estimated metastatic risk is ∼10%. In contrast to tumors in cluster 1, which exhibit heterogeneous characteristics with variable locations in sympathetic or parasympathetic ganglia, and occasionally in adrenal gland, cluster 2-related PCCs are predominantly characterized by an adrenergic phenotype, indicating that these tumors likely originate from fully differentiated chromaffin cells. An exception to this pattern is seen in MAX-related PCCs, where the absence of MAX leads to a failure in the induction of phenylethanolamine-N-methyltransferase by glucocorticoids.

Although the penetrance of MAX-related PCCs is not well established, recent screening in 2 families indicated 92% penetrance for these tumors [9]. Furthermore, prior studies suggested that germline MAX variants cause tumor predisposition when paternally inherited [1]. Our patient's father, who had a pituitary adenoma, may be the proband and supports this theory.

Germline MAX pathogenic variants are uncommon, leading to an absence of robust data regarding tumor penetrance and the possible associated tumor spectrum. While the risk for PCC is well-recognized, literature regarding other associated risks is supported by case reports of rare tumors at young ages in individuals with germline MAX variants. The presence of sarcoma at 28 years of age in our proband raises concern for the contribution of germline MAX pathogenic variants to hereditary sarcoma predisposition. Furthermore, the high VAF of the germline MAX variant in the sarcoma suggests loss of the normal MAX allele and provides evidence of a possible contribution. The germline MAX VAF was 85%, higher than the somatic TP53 VAF, which was 80%. Together these data suggest MAX loss of heterozygosity occurred earlier in the tumorigenic process than TP53 mutation. Further studies are necessary to clarify potential interactions between the MAX variant and the TP53 variant or PLEKHO2::BRAF fusion.

To our knowledge, this is the second report of early-onset sarcoma in a patient with a germline MAX pathogenic variant and first report of abdominal sarcoma. Seabrook et al identified a patient with a MAX pathogenic variant (c.22G>T, p.Glu8*) who presented with multiple tumors including a thoracic chondrosarcoma diagnosed at 34 years of age [4]. Table 2 summarizes tumors observed in patients with underlying germline MAX mutations including our case [9].

Table 2.

Clinical characteristics of patients with germline MAX variants

	N = 110a
Female gender	41.8% (46)
PCC/PG	92.7% (102)
Bilateral	54.5% (60)
Metastatic	17.2% (19)
Other neuroendocrine tumors	19.0% (21)
Pituitary adenoma	8.1% (9)
Primary hyperparathyroidism	3.6% (4)
Neuroblastoma	1.8% (2)
Adrenal ganglioneuroma	1.8% (2)
C cell hyperplasia	0.9% (1)
Ganglioneuroblastoma	0.9% (1)
Ganglioneuroma	0.9% (1)
Pancreas neuroendocrine tumor	0.9% (1)
Other tumors	9% (10)
Breast cancer	0.9% (1)
Lung adenocarcinoma	0.9% (1)
Papillary thyroid carcinoma	0.9% (1)
Prostate cancer	0.9% (1)
Renal cell carcinoma	0.9% (1)
Renal oncocytoma	1.8% (2)
Squamous cell carcinoma of the tongue	0.9% (1)
Sarcoma	1.8% (2)
Chondrosarcoma of chest	0.9% (1)
Sarcoma of liver	0.9% (1)

Abbreviations: PCC, pheochromocytoma; PG, paraganglioma.

^a Data compiled from Lian et al [9] with the addition of our reported patient.

Current recommendations suggest that patients with a history of a TMEM127- or MAX-related PCC should undergo surveillance similar to other cluster 2 tumor patients such as RET- and NF1-mutation carriers. Such screening includes yearly clinical and biochemical evaluations, as well as abdominal and pelvic magnetic resonance imaging (MRI) every 5 years [11]. Current surveillance guidelines from the National Comprehensive Cancer Network (NCCN) on Neuroendocrine and Adrenal Tumors recommend annual measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines and cross-sectional imaging of skull base to pelvis, preferably with whole-body MRI, every 2 to 3 years in patients with hereditary PPGL [12]. The cumulative reports of extra-adrenal tumors and malignancies in patients with germline MAX pathogenic variants support annual measurement of metanephrines, whole-body MRI every 2 years, and strong consideration of pituitary hormones based on annual clinical assessment.

Learning Points

• Germline MAX pathogenic variants are a rare cause of hereditary PPGL syndrome, with bilateral PCC being the most common presentation.

• MAX-related PPGLs are typically characterized by an adrenergic phenotype, but the tumor spectrum associated with MAX variants may extend beyond PPGLs, including other endocrine neoplasia and sarcomas.

• Comprehensive surveillance for patients with germline MAX variants should include annual metanephrines, whole-body imaging (eg, MRI) to detect extra-adrenal tumors every 2 years, and strong consideration of pituitary hormonal evaluation based on annual clinical assessment.

• New lesions identified in a patient with a germline MAX pathogenic variant should be evaluated as a potential malignancy, such as sarcoma.

• Genetic counseling and family testing in MAX-related PPGL can uncover other associated mutations and guide clinical management and family risk assessment.

Contributors

All authors made individual contributions to authorship. P.B. and P.D. were involved in the diagnosis and management of the patient and manuscript submission. A.E. was involved in manuscript preparation and review of the literature. All authors reviewed and approved the final draft.

Abbreviations

CT

computed tomography

IR

interventional radiology

MAX

MYC-associated factor X

NGS

next-generation sequencing

PCC

pheochromocytoma

PPGL

pheochromocytoma/paraganglioma

VAF

variant allele fraction

Funding

P.D. was supported by Department of Defense W81XWH-22-PRCRP-CDA-SO.

Disclosures

None declared.

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient's relatives or guardians.

Data Availability Statement

Original data generated and analyzed during this study are included in this published article.