Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Apr;8(4):367-377.
doi: 10.1530/EC-19-0004.

AIP-mutated Acromegaly Resistant to First-Generation Somatostatin Analogs: Long-Term Control With Pasireotide LAR in Two Patients

Affiliations
Free PMC article

AIP-mutated Acromegaly Resistant to First-Generation Somatostatin Analogs: Long-Term Control With Pasireotide LAR in Two Patients

Adrian F Daly et al. Endocr Connect. .
Free PMC article

Abstract

Acromegaly is a rare disease due to chronic excess growth hormone (GH) and IGF-1. Aryl hydrocarbon receptor interacting protein (AIP) mutations are associated with an aggressive, inheritable form of acromegaly that responds poorly to SST2-specific somatostatin analogs (SSA). The role of pasireotide, an SSA with affinity for multiple SSTs, in patients with AIP mutations has not been reported. We studied two AIP mutation positive acromegaly patients with early-onset, invasive macroadenomas and inoperable residues after neurosurgery. Patient 1 came from a FIPA kindred and had uncontrolled GH/IGF-1 throughout 10 years of octreotide/lanreotide treatment. When switched to pasireotide LAR, he rapidly experienced hormonal control which was associated with marked regression of his tumor residue. Pasireotide LAR was stopped after >10 years due to low IGF-1 and he maintained hormonal control without tumor regrowth for >18 months off pasireotide LAR. Patient 2 had a pituitary adenoma diagnosed when aged 17 that was not cured by surgery. Chronic pasireotide LAR therapy produced hormonal control and marked tumor shrinkage but control was lost when switched to octreotide. Tumor immunohistochemistry showed absent AIP and SST2 staining and positive SST5. Her AIP mutation positive sister developed a 2.5 cm follicular thyroid carcinoma aged 21 with tumoral loss of heterozygosity at the AIP locus and absent AIP staining. Patients 1 and 2 required multi-modal therapy to control diabetes. On stopping pasireotide LAR after >10 years of treatment, Patient 1's glucose metabolism returned to baseline levels. Long-term pasireotide LAR therapy can be beneficial in some AIP mutation positive acromegaly patients that are resistant to first-generation SSA.

Keywords: AIP; FIPA; acromegaly; lanreotide; octreotide; pasireotide; pituitary adenoma; resistant; somatostatin analog; thyroid cancer.

Figures

Figure 1
Figure 1
Genealogic trees of Patient 1 and Patient 2. The nephew of Patient 1 who was positive for an AIP mutation is unaffected by pituitary or other diseases; deceased members in the kindred of Patient 1 died for reasons unrelated to pituitary or endocrine diseases. The AIP mutation positive father of Patient 2 is unaffected by pituitary or other endocrine conditions.
Figure 2
Figure 2
Panel A shows hormonal responses over 24 years from diagnosis to last follow-up in November 2018 in Patient 1. IGF-1 and HbA1c levels are shown in response to octreotide/lanreotide depots and then with pasireotide LAR beginning in 2006, until withdrawn 18 months ago. The normal range for IGF-1 is outlined in grey in the lower part of the graph. The postoperative tumor residue is shown in panel B (arrow) and the shrinkage of the tumor in panel C after about five years of pasireotide therapy. Panel D shows the MRI after >12 months off all somatostatin analogs.
Figure 3
Figure 3
Trends in growth and shrinkage of the pituitary adenoma in Patient 2. A T1-weighted gadolinium-enhanced (T1Gd) MRI image of the tumor at diagnosis (2008) is shown by the arrow. At that time, it was a microadenoma and prolactin hypersecretion had been established. Slow progression until the 2009 MRI is in marked contrast with the MRI in 2011, when a T2-weighted image shows a large, invasive pituitary macroadenoma had developed, in association with frank signs and symptoms of acromegaly and increased height. Postoperatively, a sizable residue in seen from 2012, but this shrank progressively when the patient was on pasireotide LAR therapy up until the 2016 and 2018 MRI images where there remains evidence of only a small potential tumor residue (arrow).
Figure 4
Figure 4
AIP immunostaining in tumors from Patient 2 and family. Panel A shows normal thyroid tissue with strong positivity for AIP (brown) from the AIP mutation-positive sister of Patient 2 who had a 2.5 cm follicular thyroid carcinoma at a young age. In panel B the AIP staining of the follicular thyroid carcinoma is generally negative or scant. Panel C shows the absent or low AIP immunostaining in the somatotropinoma of Patient 2 at 20× and 40× resolutions.
Figure 5
Figure 5
Somatostatin receptor (SST) immunohistochemistry in the pituitary adenoma from Patient 2 and control acromegaly case. Panels A, B and C show the SST2, SST3 and SST5 staining in the somatotropinoma from Patient 2. Staining of two tumor samples for SST2 and SST5 are shown in panels A and C (surgery 1 inset; surgery 2 main picture), demonstrating negative SST2 staining and variably positive SST5 staining, predominantly membranous. SST3 staining (panel B) was strongly positive. For comparison purposes, panels D, E and F show examples of SST2, SST3 and SST5 staining, respectively in tumor from a representative octreotide-responsive AIP mutation-negative adult acromegaly patient.

Similar articles

See all similar articles

Cited by 1 article

References

    1. Caputo M, Ucciero A, Mele C, De Marchi L, Magnani C, Cena T, Marzullo P, Barone-Adesi F, Aimaretti G. Use of administrative health databases to estimate incidence and prevalence of acromegaly in Piedmont Region, Italy. Journal of Endocrinological Investigation 2018. [epub]. (10.1007/s40618-018-0928-7) - DOI - PubMed
    1. Gruppetta M, Mercieca C, Vassallo J. Prevalence and incidence of pituitary adenomas: a population based study in Malta. Pituitary 2013. 16 545–553. (10.1007/s11102-012-0454-0) - DOI - PubMed
    1. Gatto F, Trifirò G, Lapi F, Cocchiara F, Campana C, Dell’Aquila C, Ferrajolo C, Arvigo M, Cricelli C, Giusti M, et al. Epidemiology of acromegaly in Italy: analysis from a large longitudinal primary care database. Endocrine 2018. 61 533–541. (10.1007/s12020-018-1630-4) - DOI - PubMed
    1. Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A. High prevalence of pituitary adenomas: a cross-sectional study in the province of Liège, Belgium. Journal of Clinical Endocrinology and Metabolism 2006. 91 4769–4775. (10.1210/jc.2006-1668) - DOI - PubMed
    1. Petrossians P, Daly AF, Natchev E, Maione L, Blijdorp K, Sahnoun-Fathallah M, Auriemma R, Diallo AM, Hulting AL, Ferone D, et al. Acromegaly at diagnosis in 3173 patients from the Liège Acromegaly Survey (LAS) database. Endocrine-Related Cancer 2017. 24 505–518. (10.1530/ERC-17-0253) - DOI - PMC - PubMed
Feedback