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Anne Thiel, Anna-Carinna Reis, Matthias Haase, Gerald Goh, Matthias Schott, Holger S Willenberg, and Ute I Scholl

Objective

Cortisol excess due to adrenal adenomas or hyperplasia causes Cushing's syndrome. Recent genetic studies have identified a somatic PRKACA L206R mutation as a cause of cortisol-producing adenomas. We aimed to compare the clinical features of PRKACA-mutant lesions with those of CTNNB1 mutations, and to search for similar mutations in unilateral hyperplasia or tumors co-secreting aldosterone.

Design, patients, and methods

In this study, 60 patients with cortisol excess who had adrenalectomies at our institution between 1992 and 2013 were assessed, and somatic mutations were determined by Sanger sequencing. A total of 36 patients had overt Cushing's syndrome, the remainder were subclinical: 59 cases were adenomas (three bilateral) and one was classified as hyperplasia. Four tumors had proven co-secretion of aldosterone.

Results

Among cortisol-secreting unilateral lesions without evidence of co-secretion (n=52), we identified somatic mutations in PRKACA (L206R) in 23.1%, CTNNB1 (S45P, S45F) in 23.1%, GNAS (R201C) in 5.8%, and CTNNB1+GNAS (S45P, R201H) in 1.9%. PRKACA and GNAS mutations were mutually exclusive. Of the co-secreting tumors, two (50%) had mutations in KCNJ5 (G151R and L168R). The hyperplastic gland showed a PRKACA L206R mutation, while patients with bilateral adenomas did not have known somatic mutations. PRKACA-mutant lesions were associated with younger age, overt Cushing's syndrome, and higher cortisol levels vs non-PRKACA-mutant or CTNNB1-mutant lesions. CTNNB1 mutations were more significantly associated with right than left lesions.

Conclusions

PRKACA L206R is present not only in adenomas, but also in unilateral hyperplasia and is associated with more severe autonomous cortisol secretion. Bilateral adenomas may be caused by yet-unknown germline mutations.

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Fatemeh Majidi, Samuela Martino, Mustafa Kondakci, Christina Antke, Matthias Haase, Vasileios Chortis, Wiebke Arlt, Cristina L Ronchi, Martin Fassnacht, Claire Laurent, Jean-Michel Petit, Olivier Casasnovas, Amir Mouhammed Habra, Aleem Kanji, Roberto Salvatori, An Thi Nhat Ho, Ariadni Spyroglou, Felix Beuschlein, Diego Villa, Wasithep Limvorapitak, Björn Engelbrekt Wahlin, Oliver Gimm, Martina Rudelius, Matthias Schott, Ulrich Germing, Rainer Haas, and Norbert Gattermann

Purpose:

We sought to refine the clinical picture of primary adrenal lymphoma (PAL), a rare lymphoid malignancy with predominant adrenal manifestation and risk of adrenal insufficiency.

Methods:

Ninety-seven patients from 14 centers in Europe, Canada and the United States were included in this retrospective analysis between 1994 and 2017.

Results:

Of the 81 patients with imaging data, 19 (23%) had isolated adrenal involvement (iPAL), while 62 (77%) had additional extra-adrenal involvement (PAL+). Among patients who had both CT and PET scans, 18FDG-PET revealed extra-adrenal involvement not detected by CT scan in 9/18 cases (50%). The most common clinical manifestations were B symptoms (55%), fatigue (45%), and abdominal pain (35%). Endocrinological assessment was often inadequate. With a median follow-up of 41.6 months, 3-year progression-free (PFS) and overall (OS) survival rates in the entire cohort were 35.5% and 39.4%, respectively. The hazard ratios of iPAL for PFS and OS were 40.1 (95% CI: 2.63–613.7, P = 0.008) and 2.69 (95% CI: 0.61–11.89, P = 0.191), respectively. PFS was much shorter in iPAL vs PAL+ (median 4 months vs not reached, P = 0.006), and OS also appeared to be shorter (median 16 months vs not reached), but the difference did not reach statistical significance (P = 0.16). Isolated PAL was more frequent in females (OR = 3.81; P = 0.01) and less frequently associated with B symptoms (OR = 0.159; P = 0.004).

Conclusion:

We found unexpected heterogeneity in the clinical spectrum of PAL. Further studies are needed to clarify whether clinical distinction between iPAL and PAL+ is corroborated by differences in molecular biology.