Nine adenomas demonstrated less intense but still recognizably positive staining on the TMA sections. Staining of these adenomas was confirmed to be unequivocally diffusely positive when repeated on whole mount sections (Fig. 3).
The patient is currently well with no evidence of recurrence 45 months after surgery.
A clinical phenotype of SDH-deficient pituitary neoplasia is now emerging. Including this case, of the 9 pituitary adenomas reported in association with confirmed SDH mutation, the mean age has been 45 years (range, 30 to 62 y), and 6 have occurred in men. Seven have had hormone production documented clinically or by IHC, of which 6 have been prolactin-producing macroadenomas21,24,26 and 1 a growth hormone–secreting macroadenoma.25 In addition, the clinically nonfunctioning pituitary macroadenoma arising in the setting of germline SDHA mutation, which we recently described,23 also demonstrated positive IHC staining for prolactin (previously unreported data).
Taken together the findings suggest that SDH-deficient pituitary adenomas may occur at a young age, may commonly be macroadenomas, may more commonly produce prolactin (on the basis of clinical or IHC findings), and may show a slight male predisposition. However, prolactin-producing adenomas in male patients tend to be larger at presentation than in female patients, and prolactinomas in general do not usually come to surgery unless they are large or not responsive to medical therapy. Furthermore, relatively few SDH-deficient pituitary tumors have been reported to date. Therefore, more cases will need to be identified before a strong phenotype-genotype correlation for SDH-deficient pituitary tumors can emerge to further investigate this suggestion that prolactin-producing macroadenomas in young male patients are more likely to be SDH deficient.
The very low incidence of SDH deficiency in pituitary adenomas has important implications for the development of surveillance guidelines for individuals known to carry SDH mutations. Currently, we recommend annual physical examination with blood pressure documentation and fasting fractionated plasma metanephrine and normetanephrine as well as a third yearly MRI from the base of the skull to the coccyx, including kidneys and adrenal glands.23 Because this field of imaging does not encompass the pituitary, we have considered extending the field to include the sellar region in patients already scheduled for an MRI scan. However, given the high incidence of clinically insignificant pituitary incidentalomas,28 the benefits of this approach will have to be carefully weighed against the risk of overdiagnosing and overtreating clinically insignificant incidental pituitary adenomas. In the interim, we recommend that the possibility of pituitary disease, particularly associated with hyperprolactinemia, be specifically considered in the annual history and physical examination for patients with known SDH mutation.
In conclusion, it appears that pituitary adenomas are a legitimate albeit very rare component of the hereditary syndromes associated with SDH mutation, and therefore the possibility of pituitary neoplasia should be considered clinically in patients with SDH mutation who are under surveillance. SDH-deficient pituitary adenomas may be more frequently large and prolactin producing, may show a slight male sex preponderance, and may more commonly occur at a younger age. However, the issue of whether these associations represent a strong phenotype-genotype correlation awaits confirmation in further cases. Although somatic inactivation of the SDH genes in the absence of a germline mutation does occur in pituitary adenomas, it appears to be a rare event, and IHC for SDHA and SDHB can be used to triage formal genetic testing in pituitary adenomas when clinical suspicion of hereditary disease arises.
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