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. Author manuscript; available in PMC: 2023 Feb 1.
Published in final edited form as: Endocr Relat Cancer. 2023 Jan 5;30(2):e220198. doi: 10.1530/ERC-22-0198

SDHx mutation and pituitary adenoma: can in vivo 1H-MR spectroscopy unravel the link?

Francesca Branzoli 1,*, Betty Salgues 2,*, Małgorzata Marjańska 3, Marie Laloi-Michelin 4, Philippe Herman 5, Lauriane Le Collen 6, Brigitte Delemer 7, Julien Riancho 8, Emmanuelle Kuhn 9, Christel Jublanc 10, Nelly Burnichon 11, Laurence Amar 12, Judith Favier 13, Anne Paule Gimenez-Roqueplo 14, Alexandre Buffet 15, Charlotte Lussey-Lepoutre 16
PMCID: PMC9885742  NIHMSID: NIHMS1860932  PMID: 36449569

Abstract

Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequently involved in pheochromocytoma/paraganglioma (PPGL) development and were implicated in patients with the “3PAs” syndrome (associating pituitary adenoma (PA) and PPGL) or isolated PA. However, the causality link between SDHx mutation and PA remains difficult to establish and in vivo tools for detecting hallmarks of SDH deficiency are scarce. Proton magnetic resonance spectroscopy (1H-MRS) can detect succinate in vivo as a biomarker of SDHx mutations in PGL. The objective of this study was to demonstrate the causality link between PA and SDH-deficiency in vivo using 1H-MRS as a novel non-invasive tool for succinate detection in PA.

Three SDHx-mutated patients suffering from a PPGL and a macroprolactinoma and one patient with an apparently sporadic non-functioning pituitary macroadenoma underwent MRI examination at 3 T. An optimized 1H-MRS semi-LASER sequence (TR = 2500 ms, TE = 144 ms) was employed for the detection of succinate in vivo. Succinate and choline containing compounds were identified in the MR spectra as single resonances at 2.44 and 3.2 ppm, respectively.

Choline compounds were detected in all the tumors (3 PGL and 4 PAs), while a succinate peak was only observed in the 3 macroprolactinomas and the 3 PGL of SDHx-mutated patients, demonstrating SDH deficiency in these tumors.

In conclusion, detection of succinate by 1H-MRS as a hallmark of SDH deficiency in vivo is feasible in PA, laying the groundwork for a better understanding of the biological link between SDHx mutations and the development of these tumors.

Keywords: pituitary adenoma, magnetic resonance spectroscopy, paraganglioma, succinate, succinate dehydrogenase

Introduction

Pituitary adenomas (PAs) are benign tumors and are most frequently sporadic, with inheritance in approximately 5% of cases. The most common familial syndromes predisposing to PAs are Familial Isolated Pituitary Adenomas (FIPA), Multiple Endocrine Neoplasia type 1 (MEN1), Carney Complex (CNC), and McCune-Albright Syndrome (MAS)X-linked Acrogigantism (X-LAG) (Tatsi and Stratakis, 2019). In addition, Xekouki et al. described an association between PA and paraganglioma (PGL) named “the three P association” (3PAs), related to succinate dehydrogenase (SDHx) pathogenic variants (Xekouki et al., 2015) in about 40 % of cases. Genes encoding SDH enzyme and its assembly factor, collectively referred to as SDHx genes (SDHA, SDHB, SDHC SDHD and SDHAF2), are the most frequently involved genes in predisposition to pheochromocytoma/paraganglioma (PPGL), rare neuroendocrine tumors derived from neural crest cells. SDHx mutations also rarely predispose to other tumors such as renal cell carcinoma (RCC) (Gill et al., 2014a), gastrointestinal stromal tumors (GIST) (Boikos et al., 2016), and PAs (Xekouki et al., 2012).

In patients carrying a germline heterozygous mutation on an SDHx gene, somatic mutation or loss of the remaining allele can induce a complete loss-of-function of SDH, an enzyme of the tricarboxylic acid (TCA) cycle that oxidizes succinate to produce fumarate, resulting in the accumulation of succinate in the tumor. Several methods to classify variants of unknown significance (VUS) are available on the tumor tissue, such as the search for loss of heterozygosity (LOH), SDHB, SDHA and SDHD with immunohistochemical analyses (Korpershoek et al., 2011; Menara et al., 2015; NGS in PPGL (NGSnPPGL) Study Group et al., 2017; van Nederveen et al., 2009), SDH activity measurement, or direct succinate quantification on frozen tumor samples with high resolution nuclear magnetic resonance or mass spectrometry (Imperiale et al., 2015; Pollard et al., 2005; Rao et al., 2015, 2013).

On 309 PAs screened by immunohistochemistry, Gill et al. detected only one tumor (prolactin producing PA) with a loss of staining for both SDHA and SDHB due to biallelic somatic truncating mutations in SDHA gene (Gill et al., 2014b). Mougel et al. (Mougel et al., 2020) performed a large genetic screening of 263 patients presenting with an isolated PA and estimated that SDHx genetic variants reached 1.1% in this population. Nevertheless, lack of clear causality link between PA and SDHx mutations are major persistent pitfalls in the field and there is still an unmet medical need for in vivo tools capable of demonstrating that SDH deficiency is at the origin of such PA development.

An increase of up to 100-fold of succinate levels has been observed in SDHx-mutated compared to non-SDHx–mutated PPGL tumors (Lendvai et al., 2014; Letouzé et al., 2013). In vivo 1H-MRS allows non-invasive detection and quantification of many chemical compounds in tissues. We recently demonstrated and validated in a cohort of forty-nine patients (with 50 PPGL), the ability of 1H-MRS to detect SDHx mutations in vivo, via the detection of succinate (Lussey-Lepoutre et al., 2020, 2016) in abdominal and cervical PGL. Our findings were in accordance with the results of Varoquaux et al. (Varoquaux et al., 2015) and were confirmed thereafter by Casey et al. (Casey et al., 2018), who also successfully employed 1H-MRS for the characterization of other tumors like metastatic SDHx-related GIST and the evaluation of response to treatment in one patient. The same team studied the link between SDHB variant and PA in one patient, but no succinate peak was detected in vivo by 1H-MRS and SDHB immunostaining was positive in the resected tumor. Together, both results (no succinate accumulation and presence of the SDHB protein detected by immunohistochemistry (IHC)) are in favor of the integrity of the SDH enzyme in the PA tissue, suggesting that SDHB variant in the reported patient was not involved in the PA development.

In this study we aimed to test the feasibility of in vivo 1H-MRS as a novel non-invasive tool for succinate detection in PA and to assess the causality link between PA and SDH-deficiency in vivo.

Patients and methods

Informed consent was obtained from the four patients and the research was approved by the Ethics Committee Ile de France VI (ID RCB: 2020-A00397-32).

Case presentation

Case 1

A 40-year-old male patient with no family history of endocrine disease was referred to an endocrine unit for a right cervical mass evolving for several years. CT scan revealed an intensely enhanced right carotid bifurcation mass with splaying of the internal and external carotid arteries associated with a lesion in the sella turcica. Angio-MRI confirmed a right carotid PGL (36×28×35 mm3), which was removed, and a PA (31×25×24 mm3) with suprasellar extension and a left cavernous sinus invasion (Knosp classification grade 4).

Primary hormonal assessment revealed an elevated prolactin level (222 ng/ml; reference range: 5–15 ng/ml) with secondary suppression of gonadotrophins supporting the diagnosis of macroprolactinoma. Total urinary metanephrines were in the normal range.

Dopamine agonist (cabergoline) was introduced at 0.5 mg per week for 6 months with a partial hormonal response with a prolactin level at 55 ng/ml and almost no volume reduction. Cabergoline was then increased to 1.5 mg per week, leading after 6 months of increased dosage, to a normalization of prolactin level (22 ng/ml), but a very small PA shrinkage on control MRI. The patient has not experienced any adverse effects due to treatment allowing its continuation to date.

Case 2

A 54-year-old male patient was referred to another endocrine unit for signs of hypogonadism secondary to a prolactin macroadenoma measuring 22 mm, with suprasellaire extension but no cavernous sinus invasion (Knosp classification grade 0). He had no familial history of endocrine disease, but a personal history of a left jugulotympanic PGL at the age of 32, discovered due to front of vertigo and deafness. PGL was treated by partial surgical removal, followed by the external beam radiotherapy with no further follow-up until recently.

Hormonal assessment revealed hyperprolactinemia (627 ng/ml, reference range: 5–15 ng/ml), thyreotropic and gonadotropic insufficiency. No catecholamine production was detected. Cabergoline treatment at 1.5 mg per week, initiated one year before the 1H-MRS, permitted a control of the prolactinemia (24.6 ng/ml), but no PA shrinkage was observed. The size of the adenoma remaining stable over time (largest diameter under treatment: 21 mm).

Case 3

A 32-year-old patient was referred to a hypertension unit with a diagnosed hypertension. His blood pressure was 150/105 mmHg under one antihypertensive drug. He had no previous personal or family medical history of endocrine disease. The work up for secondary hypertension led to the diagnosis of a right pheochromocytoma (PCC). The plasma metanephrine and normetanephrine were normal (<0.13 nmol/l) and up to 4.5 times higher than the upper-limit (4.89 nmol/l for a normal range <1.1 nmol/l), respectively. The CT scan identified a right adrenal mass of 30 mm with a density of 37 UH. The PET-DOPA confirmed the hypermetabolism (SUVmax 39) on the right adrenal tumor without any other localization. The patient underwent surgical removal under alpha blockade treatment without complication. During the screening of secondary hypertension, the patient complained of erectile dysfunction. Hormonal assessment revealed hyperprolactinemia (356 ng/ml, reference range: 3–15 ng/ml), thyreotropic, gonadotropic and somatotropic insufficiency. Pituitary MRI showed a macroPA (16×21×24 mm3) with compression of the optic chiasm without visual impact and a probable left cavernous sinous invasion (Knosp classification grade 3). Cabergoline treatment was initiated recently.

Case 4

A 53-year-old patient was referred to a pituitary unit for a PA discovered by a CT-scan for dizziness 2 years earlier. He suffered from rheumatoid arthritis, treated by Methotrexate, and had no familial history of endocrine disease. MRI identified a macroPA (23×14.8×16.2 mm), without compression of the optical chiasma. He did not present any symptom of hypersecretion or pituitary insufficiency, hormonal assessment revealed a non-functioning macroadenoma, without surgical indication. The patient is currently under follow-up without treatment.

Genetic testing and immunochemistry

After obtaining informed consent in genetic consultation, PGL genetic testing was performed on leukocyte DNA by next generation sequencing (NGS) in cases 1 and 2, with a custom capture panel of 21 PPGL susceptibility genes (SeqCap EZ HyperCap, Roche®), including all SDHx genes (SDHA, B, C, D and AF2) and the other major (VHL, RET, TMEM127, MAX, NF1) and minor (DLST, DNMT3A, EGLN1, EGLN2, EPAS1, FH, GOT2, H3F3A, MDH2, MERTK, SLC25A11) PGL predisposition genes. In case 3, SDHx genes were tested by Sanger sequencing as previously described (Burnichon et al., 2009). Identified genetic variants were classified in accordance to ACMG and NGS in PPGL Study Group guidelines (NGS in PPGL (NGSnPPGL) Study Group et al., 2017; Richards et al., 2015). Genetic Variants were reported in accordance to HGVS Nomenclature (den Dunnen et al., 2016). No genetic testing was performed in case 4, in the absence of PGL or syndromic presentation.

SDHB protein expression was assessed on formalin-fixed paraffin embedded (FFPE) tumor samples by IHC as previously described (Korpershoek et al., 2011; Menara et al., 2015; van Nederveen et al., 2009) anti-SDHB antibody (HPA002868, Sigma-Aldrich Corp; 1:500).

1H-MRS acquisition and post-processing

The four subjects were scanned using a 3 T system (Siemens Magnetom PRISMA) equipped with a 64-channels receive-only head and neck coil.

A three-dimensional T2-weighted volumetric image (TR = 3000 ms, TE = 370 ms, resolution = 1 mm isotropic, field-of-view = 256 × 256 × 176 mm3, scan time = 3’38”) was acquired for optimal placement of the spectroscopic volume-of-interest (VOI) and tumor segmentation.

The MRS acquisition was performed in all 7 tumors using an optimized semi-LASER sequence (Klomp et al., 2009; Marjańska et al., 2012)(TR = 2500 ms, TE = 144 ms, bandwidth = 3000 Hz, number of complex points = 2024, number of transients = 64 to 512 depending on tumor size and patient compliance). The size of the VOI was adapted to the size of the tumor, and its location was chosen in order to minimize surrounding signal contamination (Figure 1 and 2). The radiofrequency power for the slice-selective 90° pulse was calibrated by determining the power that produces the maximum signal. The power for the 180° adiabatic pulses was set automatically based on the 90° calibration. Water suppression was performed using variable power with optimized relaxation delays (VAPOR) and outer volume suppression techniques (Tkác et al., 1999) to reduce contamination from unwanted signals outside the VOI. B0-shimming was performed using FAST(EST)MAP (Gruetter and Tkác, 2000). Unsuppressed-water spectra were acquired prior to the acquisition of the water-suppressed spectra for evaluation of the water line-width. VOI placement and optimization steps were repeated in case of poor shimming and/or severe lipid contamination.

Figure 1:

Figure 1:

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MR spectra acquired in the neck paraganglioma (PGL) in cases (A) 1 and (C) 2 and in the pheochromocytoma in case (E) 3 (green lines), and in the pituitary adenoma (PA) in cases (B) 1, (D) 2, and (F) 3 (red lines). The locations of the VOIs are shown on coronal or axial T2-weighted images. Spectra are shown with a line-broadening of 2 Hz. tCho: choline containing compounds; Succ: succinate.

Figure 2:

Figure 2:

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MR spectrum acquired in the pituitary adenoma (PA) of an apparently sporadic case (Case 4). The location of the VOI is shown on a coronal T2-weighted image. A line-broadening of 2 Hz was applied. Only the total choline peak is detectable. tCho: choline containing compounds.

Spectral post-processing was performed using home-made MATLAB routines. Frequency and phase corrections were performed using either the total choline (tCho) peak at 3.2 ppm or the residual water peak at 4.7 ppm. The accumulation of succinate (Succ) and tCho in the tumors was assessed visually based on the presence in the MR spectra of resonances at 2.44 ppm and 3.2 ppm, respectively.

Literature review

We searched in the Pubmed database all studies reporting coexistence of PA and the notion of an SDHx variant, including case controls, cohort studies and reviews published in English since 2000 (year of the discovery of the implication of SDHx genes in PGL predisposition).

Results

SDH deficiency

Germline variations were identified in the SDHC gene in two patients: c.224G>A, p.(Gly75Asp) for case 1 and c.160C>A, p.(Pro54Thr) for case 2 (Table 1). The c.224G>A variant (case 1) was previously described in the literature and classified as pathogenic in the SDHC LOVD database (https://databases.lovd.nl/shared/genes/SDHC). The c.160C>A variant was not previously described in the literature or in the LOVD database. SDHB immunochemistry was performed on removed PGL tissue and showed negative immunostaining in both tumors, in favor of SDH deficiency in the two PGLs, allowing to conclude that c.160C>A variant is pathogenic. In the third patient (case 3), we identified a germline variant in SDHD gene: c.170-1G>T, p.(?), previously described in the literature as pathogenic.

Table 1:

Patients with pituitary adenoma (PA) and SDHx variant

Patient number PA cell type Associated PGL Familial history* Mutated gene Genetic variants Variants classification SDHB IHC in PA LOH or somatic mutation in PA
1 - No Yes SDHB c.761dup, p.(Lys255Ter) Pathogenic - -
2 PRL Yes No SDHC c.253_255dup, p.Phe85dup Likely pathogenic - -
3 GH Yes Yes SDHD c.298_301del, p.(Thr100Phefs*34) Likely pathgenic Positive (patchy) Yes
4 NF No Yes SDHA c.1873C>T, p.(His625Tyr) VUS Negative No*
5 PRL Yes Yes SDHD c.242C>T, p.(Pro81Leu) Pathogenic - -
6 NF No No SDHA ** c.726_737del, p.Ser243_Arg246del c.988_989dup, p.Ala331Thrfs*18 Likely pathogenic Negative Yes
7 GH Yes Yes SDHD c.274G>T, p.(Asp92Tyr) Pathogenic Negative Yes
8 PRL Yes - SDHD c.274G>T, p.(Asp92Tyr) Pathogenic Positive Yes
9 PRL Yes Yes SDHB c.18C>A, p.(Ala6=) Benign - -
10 PRL Yes - SDHA c.91C>T, p.(Arg31Ter) Pathogenic Negative -
11 PRL No Yes SDHB c.(540+1_541-1)_(*159_?)del, p.(?) Likely pathogenic Negative Yes
12 NF Yes No SDHB c.587G>A, p.(Cys196Tyr) Pathogenic Dubious Yes
13 PRL Yes Yes SDHB c.298T>C, p.(Ser100Pro) Likely pathogenic - Yes
14 PRL No Yes SDHB c.298T>C, p.(Ser100Pro) Likely pathogenic - -
15 PRL Yes No SDHA c.91C>T, p.(Arg31Ter) Pathogenic - -
16 GH Yes - SDHAF2 c.−52T>C, p.(?) VUS - -
17 PRL Yes - SDHB c.423+1G>A, p.(?) Pathogenic - -
18 PRL Yes Yes SDHC c.380A>G, p.(His127Arg) Pathogenic - -
19 NF Yes Yes SDHA c.969C>T, p.(p.Gly323=) Likely benign Positive No
20 GH Yes Yes SDHB c.689G>A, p.(Arg230His) Pathogenic - -
21 PRL Yes Yes SDHB c.642+1G>A, p.(?) Likely pathogenic - -
22 PRL Yes Yes SDHD c.242C>T, p.(Pro81Leu) Pathogenic - -
23 PRL Yes Yes SDHB c.(?_−151)_(72+1_73-1)del Pathogenic - -
24 PRL No Yes SDHB c.5C>T, p.(Ala2Val) VUS - -
25 PRL No Yes SDHB c.24C>T, p.(Ser8=) Benign - -
26 PRL No Yes SDHC c.403G>C, p.(Glu110Gln) VUS - -
27 GH No No SDHC c.403G>C, p.(Glu110Gln) VUS Positive -
28 PRL Yes Yes SDHB - - - -
29 NF carcinoma Yes No SDHB c.587G>A, p.(Cys196Tyr) - Negative -
30 PRL No Yes SDHB c.298T>C, p.(Ser100Pro) Likely pathogenic Positive No
31 NF No Yes SDHB c.380T>G, p.(Ile127Ser) Likely pathogenic Positive -
32 NF Yes Yes SDHD c.(315-?_480+?)del Likely pathogenic - -
33 PRL No Yes SDHC c.405+1G>T, p.(?) Pathogenic Positive No
34 PRL No Yes SDHA c.1753C>T, p.(Arg585Trp) Pathogenic Positive No
35 PRL No No SDHA c.757_758del, p.(Val253Cys*67) Likely pathogenic - -
36 PRL PGL Yes SDHC c.224G>A, p.(Gly75Asp) Pathogenic - -
37 PRL PGL No SDHC c.160C>A, p.(Pro54Thr) Pathogenic - -
38 PRL PCC No SDHD c.170-1G>T, p.(?) Pathogenic - -
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Familial history including history of SDHx mutation and/or PPGLand/or GIST and/or RCC and/or PA; PGL: paraganglioma; PCC: pheochromocytoma; PRL: prolactine; NF: nonfunctional PA; GH: Growth hormon; IHC: immunohistochemistry; LOH: loss of heterozygotity in the tumor

“-”: not available or not performed

*

: loss of the mutated allele

**

: somatic mutations only; Genetic Variants were reported in accordance to HGVS Nomenclature; bold: patients from our study

Succinate detection by 1H-MRS

Voxel sizes were 12 × 15 × 15 mm3 (PGL) and 10 × 10 × 9 mm3 (PA) for case 1, 14 × 14 × 14 mm3 (PGL) and 11 × 11 × 11 mm3 (PA) for case 2, 14 × 14 × 12 mm3 (PGL) and 10 × 9 × 9 mm3 (PA) for case 3 (Figure 1) and 9 × 9 × 8 mm3 for case 4 (Figure 2). Number of transients were 512 for both PGL and PA in case 1, 64 and 128 for PGL and PA, respectively, in case 2, 256 and 192 for PCC and PA, respectively, in case 3, and 224 for PA in case 4.

Water linewidths were 6 Hz (PGL) and 10 Hz (PA) for case 1, 6 Hz (PGL) and 16 Hz (PA) for case 2, 10 Hz (PGL) and 17 Hz (PA) for case 3, and 15 Hz (PA) for case 4. Succinate and total choline were identified as singlet resonances at 2.4 and 3.2 ppm, respectively, in the MR spectra acquired in both PGL and PA of all three patients with an SDHx mutation (Figure 1), while only total choline was detectable in the apparently sporadic case 4 (Figure 2).

Data collection from the literature

Thirty-five SDHx-mutation carriers with PA were described in 19 articles listed in Table 1 and Supplementary Table 1 (Benn et al., 2006; Casey et al., 2018; De Sousa et al., 2017; Dénes et al., 2015; Dwight et al., 2013; Efstathiadou et al., 2014; Gill et al., 2014b; Gorospe et al., 2017; Guerrero Pérez et al., 2016; Lemelin et al., 2019; López-Jiménez et al., 2008; Maher et al., 2018; Mougel et al., 2020; Niemeijer et al., 2015; Papathomas et al., 2014; Tufton et al., 2017; Varsavsky et al., 2013; Xekouki et al., 2015, 2012). PA identified in SDHx-mutation carriers were classified for 34 among the 35 (no description of PA was provided for 1 patient) as follows: prolactinoma in 22 cases (63%), GH-secreting in 5 cases (14%), and non-functioning in 7 patients (20%) including one pituitary carcinoma (Table 1). Genetic variants were identified in the five SDHx genes: 7 (20%) on SDHA, 16 (46%) on SDHB, 5 (14%) on SDHC, 6 (17%) on SDHD and one (3%) on SDHAF2. In silico predictions classified these variants as pathogenic in 17 cases and as likely pathogenic in 11 cases. The causality link between SDHx variants and PA development was studied by SDHA, SDHB or SDHD IHC in 15 of the 35 previously described cases, and the search for LOH in tumors was performed in 12 cases. IHC demonstrated SDH loss in 6 out of 15 cases (3 SDHA, 2 SDHB, 1 SDHD, Table 1). LOH was found in 4 additional cases (2 SDHB, 2 SDHD), but with positive or dubious SDHB IHC in 3 of them.

Discussion

In this pilot study, we detected a succinate peak, characteristic of SDH deficiency, in all six tumors of SDHx-mutated patients under investigation, but not in the control patient, thereby demonstrating, for the first time in vivo, the causality link between SDHx mutations and PA development.

The description of the association between PA and PPGL is not novel, as it was first reported by Iversen in 1952 (Iversen, 1952), but it was not until the mid-2000s and the discovery of SDHx genes that the hypothesis of a genetic cause was raised. In 2006, Benn et al. described the onset of a PA in a 15-year-old SDHB mutation carrier (Benn et al., 2006). In 2012, Xekouki et al. was first to raise the hypothesis of a causality link between a SDHD pathogenic variant and a GH-producing macroadenoma. Nevertheless, IHC performed in the PA showed a negative SDHD immunostaining and a positive SDHB immunostaining in a large part of the tumor. According to other reports, these results are in favor of preserved SDH enzyme activity ((Menara et al., 2015)(van Nederveen et al., 2009)). Moreover the LOH at the SDHD locus (chromosome 11) described in the previous study is frequent in PA (Pack et al., 2005).

The discovery of endocrine tumors like PA and PGL in the same patient legitimately raises the question of a common genetic origin involving genes predisposing to PGL such as SDHx genes, MYC-associated factor X (MAX), and the classical PA-predisposing MEN1 gene (Mougel et al., 2020). Nevertheless, while PGL is a very rare tumor (prevalence 1-9/1,000,000), this is not the case for PA (prevalence between 1/1,000 to 1/1,300). Thus, a better understanding of the causality link between SDHx mutations and tumor development represents a crucial challenge as this may involve a change in patient care. Indeed, the question of the systematic search for an SDHx mutation in the presence of a PA or, conversely, the systematic search for a PA in a patient with an SDHx mutation remains debated. Robust methods are needed to demonstrate SDH deficiency in the tumor, in order to link a PA tumor development to an SDHx pathogenic mutation in a patient, but also to classify VUS in case of large genetic screening of patients with PA. In the 35 cases from the literature, the link between SDHx mutations and PA development appears well established for 7 tumors among the 35 described, and no tumor tissue was available for 19 PA (54%). LOH in the tumor tissue was not linked with SDH deficiency in three cases and its reliability can legitimately be questioned. This might be explained by a relatively high frequency of allelic losses in these tumors, particularly at loci that may contain the SDHx genes (Pack et al., 2005). Indeed, complete or partial loss of chromosomes 1 or 11, containing SDHB or SDHD loci in PA, was described in 12 to 58 % of cases and in 14 to 38%, respectively (Neou et al., 2020; Pack et al., 2005).

A particular histological phenotype was described, characterized by intracytoplasmic vacuoles and stigmata of aggressiveness (Dénes et al., 2015; Tufton et al., 2017) and a relative resistance to dopamine agonist for prolactinomas, resulting, as in our cases, in normalization of secretion, but a poor shrinkage (Gorospe et al., 2017; Maher et al., 2018). Most of SDH-associated PA are thus macroprolactinomas. Our results are in accordance with the literature (Loughrey et al., 2022) as the first two patients (cases 1 and 2) examined in this study were both followed for a macroprolactinoma relatively resistant to medical treatment (hormonal control with poor tumor shrinkage).

Surgery is not the only recommended treatment, especially for prolactinomas, which are well controlled with dopamine agonist, or for aggressive PA, which can benefit from radiotherapy. Therefore, an in vivo biomarker of SDHx mutations is essential to identify this sub-group of tumors. In vivo 1H-MRS allows detecting and quantifying many chemical compounds in tissue, noninvasively. In the last decade, 1H-MRS has shown a great potential for the identification of specific tumor genetic subtypes in vivo, providing added value to other neuroimaging methods for noninvasive diagnosis, prognosis and prediction of early response to treatment in cancer (Andronesi et al., 2016, 2012; Branzoli et al., 2019; Casey et al., 2020, 2018; Choi et al., 2012; Di Stefano et al., 2022). Notably, 1H-MRS has been shown to significantly improve the noninvasive diagnosis of gliomas (Branzoli et al., 2018). The majority (50–86%) of gliomas diagnosed in younger adults (<45 years) have recurrent somatic mutations in one of the genes encoding isocitrate dehydrogenase (IDH1 and IDH2), leading to the overproduction of 2-hydroxyglutarate (2HG) (Dang et al., 2009), which is thus a specific marker of IDH mutations, detectable in vivo by 1H-MRS. The spectroscopic pattern of succinate, characterized by a single peak at 2.44 ppm, does not overlap with other neurochemicals possibly present in the tumor.

In PPGL, 1H-MRS has been shown to detect SDH-related tumors with a sensitivity of 87% and a specificity of 100% (Lussey-Lepoutre et al., 2020, 2016). In the present study, we showed that succinate can also be visually identified also in the in vivo MR spectra acquired in PA, thanks to the spectroscopic pattern of this metabolite, characterized by a single peak at 2.44 ppm, which does not overlap with other neurochemicals possibly present in the tumor.

Nevertheless, it should also be stressed that 1H-MRS has a limited sensitivity, which depends on the size of the tumor, the patient’s compliance and the absence of necrotic areas in the tumor. Indeed, the small size of the PA analyzed in this study was at the origin of low signal-to-noise ratio associated with the spectra acquired in these tumors, especially for case 2.

In conclusion, using 1H-MRS, we demonstrated that the causality link between PA and SDHx can be established in vivo. In vivo 1H-MRS will improve genetic testing in apparently sporadic PA and in PA associated with PGL (“3PAs”). Moreover, by assessing the link between SDHx mutations and PA development in a patient with an already known SDHx mutational status, 1H-MRS results can improve treatment and guide surveillance of patients bearing a potentially more aggressive tumor pattern compared to non-SDHx mutated tumors. Our proof-of-concept study lays the groundwork for a better understanding of the biological link between SDHx mutations and the development of PA.

Supplementary Material

01

Acknowledgments

The authors would like to thank Edward J. Auerbach, Ph.D. for implementing MRS sequences on the Siemens platform.

Fundings

This work has received funding from the French endocrine society, the Paradifference Foundation, the European Union’s Horizon 2020 research and innovation program under grant agreement No 633983, by the Institut National du Cancer and the Direction Générale de l’Offre de Soins (PRT-K 2014, COMETE-TACTIC, INCa-DGOS_8663) and the Cancer Research for Personalized Medicine - CARPEM project (Site de Recherche Intégré sur le Cancer - SIRIC). The Paris Cardiovascular Research Center (PARCC) team is supported by the Ligue Nationale contre le Cancer (Equipe Labellisée). Genetic and immunohistochemical studies were granted by the Institut National du Cancer and the Direction Générale de l’Offre de Soins (PRT-K 2014, COMETE-TACTIC, INCa-DGOS_8663).

FB received support from Investissements d’avenir [grant number ANR-10-IAIHU-06 and ANR-11-INBS-0006].

MM acknowledges support from the following National Institutes of Health grants: BTRC P41 EB027061 and P30 NS076408, and the Fulbright Fellowship.

Footnotes

Declaration of interests

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported

Contributor Information

Francesca Branzoli, Paris Brain Institute - Institut du Cerveau (ICM), Center for Neuroimaging Research (CENIR), F-75013, Paris, France; Sorbonne University, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, F-75013, Paris, France.

Betty Salgues, Sorbonne University, nuclear medicine department, Pitié-Salpêtrière Hospital, Assistance -Publique Hôpitaux de Paris; Paris Cardiovascular Research Center (PARCC), Inserm U970, Paris, France.

Małgorzata Marjańska, Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN 55455, USA.

Marie Laloi-Michelin, Endocrinology department, Lariboisière Hospital, Assistance -Publique Hôpitaux de Paris, 75010 Paris, France.

Philippe Herman, ENT unit, Lariboisière Hospital, Assistance -Publique Hôpitaux de Paris; Paris-Cité University, INSERM U1141, 75010 Paris, France..

Lauriane Le Collen, Inserm/CNRS UMR 1283/8199, Pasteur Institute of Lille, EGID, University of Lille, Lille, France; Department of Endocrinology Diabetology, University Hospital Center of Reims, Reims, France; Department of Genetic, University Hospital Center of Reims, Reims, France.

Brigitte Delemer, Department of Endocrinology Diabetology, University Hospital Center of Reims, Reims, France; CRESTIC EA 3804, University of Reims Champagne Ardenne, UFR Sciences Exactes et Naturelles, Moulin de La Housse, BP 1039, 51687, Reims Cedex 2, France..

Julien Riancho, AP-HP, Hôpital Européen Georges Pompidou, Hypertension Unit, and Reference centre for rare adrenal diseases F-75015 Paris, France.

Emmanuelle Kuhn, Pituitary Unit, Pitié-Salpêtrière Hospital APHP, Sorbonne University, Paris, France..

Christel Jublanc, Pituitary Unit, Pitié-Salpêtrière Hospital APHP, Sorbonne University, Paris, France..

Nelly Burnichon, Département de médecine génomique des tumeurs et des cancers, AP-HP, Hôpital Européen Georges Pompidou, F-75015 Paris, France; Université Paris Cité, Inserm, PARCC, F-75015 Paris, France.

Laurence Amar, AP-HP, Hôpital Européen Georges Pompidou, Hypertension Unit, and Reference centre for rare adrenal diseases F-75015 Paris, France; Université Paris Cité, Inserm, PARCC, F-75015 Paris, France.

Judith Favier, Université Paris Cité, Inserm, PARCC, F-75015 Paris, France.

Anne Paule Gimenez-Roqueplo, Département de médecine génomique des tumeurs et des cancers, AP-HP, Hôpital Européen Georges Pompidou, F-75015 Paris, France; Université Paris Cité, Inserm, PARCC, F-75015 Paris, France.

Alexandre Buffet, Département de médecine génomique des tumeurs et des cancers, AP-HP, Hôpital Européen Georges Pompidou, F-75015 Paris, France; Université Paris Cité, Inserm, PARCC, F-75015 Paris, France.

Charlotte Lussey-Lepoutre, Sorbonne University, nuclear medicine department, Pitié-Salpêtrière Hospital, Assistance -Publique Hôpitaux de Paris; Paris Cardiovascular Research Center (PARCC), Inserm U970, Paris, France.

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