Pediatric Cushing's Disease: Dichotomy in Lateralization between Imaging and Inferior Petrosal Sinus Sampling with Review of Literature.

Inferior petrosal sinus sampling (IPSS) is a minimally invasive method done in adrenocorticotrophic hormone (ACTH)-dependent pituitary adenoma cases where magnetic resonance imaging (MRI) either gives equivocal results or fails to localize it. A 12-year-girl with cushingoid features and raised ACTH levels presented to us with two consecutive MRI's done outside showing gross change in the morphology of a left-sided pituitary adenoma. Hence, a bilateral IPSS was done which showed a higher IPS/periphery ACTH ratio on the right side as compared to left. Transsphenoidal endoscopic excision of the left pituitary adenoma along with right hemihypophysectomy was performed. ACTH levels fell postoperatively. This case stands distinct in highlighting the discordance in lateralization of pituitary adenoma on MRI and IPSS. Review of literature tells us that while IPSS is more sensitive in accurately diagnosing Cushing's disease, MRI provides better accuracy in lateralizing the site of adenoma.

INTRODUCTION

Inferior petrosal sinus sampling (IPSS) is a minimally invasive method done in adrenocorticotrophic hormone (ACTH)-dependent pituitary adenoma cases where Magnetic resonance imaging (MRI) either gives equivocal results or fails to localize the lesion. The purpose of sampling the inferior petrosal sinus (IPS) is to identify a pituitary source of excess ACTH to diagnose Cushing’s disease (CD). IPSS has its own limitations and may lead to false localization of the side of adenoma in cases of diagnostic difficulties if interpreted alone sans radiological findings. This report discusses a case of pediatric CD with dichotomy in lateralizing the site of pituitary adenoma between IPSS and MRI.

CASE REPORT

A 12-year-girl weighing 88 kg presented to the department of neurosurgery with recent onset frontal headache for 10 days and excessive weight gain for the past 2 years. On examination, she had a typical moon face with striae present on the neck. Hormonal evaluation showed raised ACTH levels of 163 pg/ml. MRI done a month ago showed a lesion of approximately 3 cm × 2 cm × 2 cm in the left sellar parasellar region encroaching upon the left cavernous sinus suggestive of a pituitary adenoma [Figure 1]. A dynamic MR imaging done 3 weeks later showed marked regression in the size of the lesion with hemorrhage seen within suggestive of pituitary apoplexy [Figure 2]. As successive MRI’s done within a relatively short frame of time before she presented to us showed gross change in the morphology and characteristic of the lesion, a basal IPSS was done to aid in diagnosis. Due to the financial constraints, corticotropin-releasing hormone (CRH) administration was not carried out during IPSS. Basal IPSS/periphery ratio on the right was 9.54 and was 3.12 on the left. These findings prompted us to repeat imaging which now showed a well-defined nodular lesion in the left sellar parasellar region encasing the left cavernous segment of internal carotid artery with the pituitary stalk pushed to the right [Figure 3]. Transsphenoidal endoscopic excision of the left pituitary adenoma was done along-with right hemihypophysectomy as the tumor could not be identified on the right side.[1] Intraoperatively, the pituitary gland was fibrotic, atrophied, and liquefied tumor tissue extruded out on incising the left half of the gland. A presellar sphenoid sinus seen on computed tomography (CT) paranasal sinuses added to the technical difficulty. Histopathology was suggestive of a pituitary adenoma on the left side and normal pituitary gland on the right. She was started on tablet hydrocortisone 2.5 mg thrice a day. Postoperative ACTH levels came down to 23 pg/ml within a fortnight.

Figure 1

Coronal sections of postcontrast magnetic resonance imaging showing a lesion of approximately 3 cm × 2 cm × 2 cm in the left sellar, parasellar region (arrow) encroaching on the left cavernous sinus suggestive of a pituitary adenoma

Figure 2

Coronal sections of a dynamic postcontrast magnetic resonance imaging after 3 weeks suggesting marked regression in the size of the lesion (arrow) with hemorrhage seen within suggestive of pituitary apoplexy

Figure 3

A well-defined nodular lesion in the left sellar, parasellar region (arrow) seen on coronal sections of a postcontrast magnetic resonance imaging which is encasing the left cavernous segment of internal carotid artery with the pituitary stalk pushed to the right

DISCUSSION

Cushing’s syndrome (CS) is a disorder caused by dysfunction of the hypothalamus–pituitary–adrenal axis leading to excess exposure to cortisol, whereas CD is the presence of an ACTH secreting pituitary adenoma responsible for the raised cortisol. CD is the most common cause of endogenous CS. CD is a life-threatening condition occurring rarely in the pediatric population who present with typical cushingoid features.[2] It poses a diagnostic and therapeutic challenge due to the complexity in identifying and localizing the lesion and the young age group involved. Noninvasive methods of differentiating between pituitary and ectopic source of raised ACTH include CRH stimulation test, urinary cortisol levels, sonography of the abdomen, and high-dose dexamethasone suppression test which is considered the primary noninvasive diagnostic test.[3] The detection rate of pituitary adenomas for pediatric CD varies from 52% to 75% on CT and/or MR scans.[4] However, because of the high prevalence of non-functioning pituitary incidentalomas (10%–20%),[5] finding of a pituitary lesion on imaging does not definitively diagnose CD. Most of the pituitary ACTH secreting adenomas are <4 mm and they possess image intensity similar to that of the normal pituitary gland which makes accurate detection difficult.[36]

The pituitary gland is drained by hypophyseal veins that drain into the surface plexiform venous network which in turns empties laterally into the cavernous sinuses. The cavernous sinus then empties into the superior and the IPS. Pituitary venous drainage is usually unilateral despite wide intercavernous communication.

IPSS was introduced in 1977 by Corrigan et al.[7] In 1984, Doppman et al. suggested simultaneous sampling from both IPSs to avoid false-negative results. This procedure was termed bilateral IPSS (BIPSS).[8] IPSS confirms the presence of a hormonally active pituitary microadenoma when imaging alone has been insufficient or inconclusive. The diagnosis of CD is confirmed by a baseline IPSS/peripheral ratio ≥2 or CRH-stimulated IPSS/peripheral ratio ≥3.[9] BIPSS for ACTH levels before and after stimulation with CRH is considered to be the most sensitive test for differentiating CD from ectopic ACTH secreting syndromes.[10] In a meta-analysis of 21 studies, the overall sensitivity and specificity of BIPSS in such cases was found to be 96% and 100%, respectively.[11] False-positive results are possible in patients with mild CS when cortisol levels are minimally elevated or in cases where there is an ectopic CRH secretion.[12] When the site of ACTH-secreting pituitary microadenoma is ipsilateral to a hypoplastic IPS, a false-negative reading is obtained.[13] Transsphenoidal excision with contralateral hemihypophysectomy is the recommended surgical treatment. Postoperative complications are more damaging for children than adults as their growth is ongoing.[1415]

Wind et al.[16] evaluated 501 patients of CD and found that IPSS correctly predicted the side of the tumor in 273 patients (69%), whereas the tumor was located contralaterally in 123 patients (31%). Mamelak et al.[17] performed venous angiography of the cavernous and IPSs followed by bilateral simultaneous venous sampling of ACTH of 23 patients with proven CD. Venous drainage was found to be bilaterally symmetrical in 14 patients (61%) and asymmetrical in 9 (39%). IPSS correctly lateralized the tumor in 12 cases of symmetrical drainage, but in only 4 cases of asymmetric drainage. Incorrect lateralization in cases of asymmetric venous drainage was probably due to shunting of blood toward the side of dominant venous drainage. Colao et al.[18] performed a retrospective study of the diagnostic accuracy of basal and post-CRH IPSS, MRI, and CT in distinguishing pituitary from the ectopic ACTH secretion in 97 CS patients: 74 with CD and 10 with ectopic ACTH secretion. The sensitivity and diagnostic accuracy of IPSS (86%) was significantly higher than MRI (50%) and CT (40%). However, IPSS was less reliable in identifying the adenoma site found at surgery than MRI or CT (65% vs. 75% and 79%). There is a higher frequency of right-sided predicted lateralization and the higher accuracy in left-sided predicted lateralization which may be attributed to the more frequent right-sided dominance of pituitary venous drainage.[16]

Pituitary gland does not behave as right and left half either anatomically or functionally. The discrepancy in lateralization between imaging and IPSS can be explained either by intercavernous venous mixing or by dominant pituitary venous drainage seen in approximately 40% of healthy individuals. Another plausible explanation is the presence of epicenter of lesion on one side with extension to contralateral side. Rarely, there may also be a double adenoma, wherein the one visualized on imaging may be an incidentaloma, and the functional nonvisualized one may be responsible for the IPSS gradient.[19]

Understanding venous anatomy, intraprocedural heparin administration, proper catheter positioning and procedural technique and careful sample handling are essential to maximize the IPSS success rates. Although BIPSS is more accurate than other diagnostic tests; it is not performed frequently since it is invasive and costly. However, consensus indicates that BIPSS should be performed ideally when noninvasive diagnostic tests yield equivocal results.[320]

CONCLUSION

This case stands distinct in highlighting the discordance in lateralization of pituitary adenoma on MRI and IPSS. Review of literature tells us that IPSS is more sensitive in diagnosing CD, whereas MRI provides better accuracy in lateralizing the lesion. This necessitates the need for a thorough surgical approach in such cases.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.