Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.287682
Source of Support: None, Conflict of Interest: None
Keywords: Endocrine dysfunction, Endoscopic endonasal surgery, hypophysitis, pituitary adenoma, Rathke cleft cyst, sella
Pathology of the sella and its contents has always attracted medical and neurosurgical attention. Mass lesions in this small space produce focal, local, and distant effects. Locally they compress neural structures like the pituitary gland, the optic chiasm, and the brain. With increasing mass effect, they may compress the hypothalamus and the ventricular system, rarely leading to hydrocephalus. More commonly and importantly, they may disturb the hormonal balance as the anterior and posterior pituitary gland produce and control several hormonal systems in the body.
Surgical treatment for mass lesions with the aim of decompressing neural tissue as well as correcting hypersecretion of hormones (functional pituitary adenoma) is a well-established paradigm. Tumours of this region may also cause hypofunction of the hormonal axes and in addition to the surgical decompression, they may need endocrinological support. The overwhelming majority of sellar pathology are pituitary adenomas (>90%)., Though much literature is available for this pathology, we need to be aware of the other less common sellar pathologies which need consideration during diagnosis and management. Cystic sellar lesions like arachnoid cysts, metastatic tumors, and rare pathologies like lymphoma, paragangliomas, germinoma and Langerhans cell histiocytosis (LCH) in children are well-known lesions with characteristic clinical and radiological features.,,,,,, To complete the list, vascular lesions like aneurysms and cavernous angiomas may also be rarely encountered in the sellar region.
Craniopharyngiomas can occasionally present as only a sellar lesion (10%) especially in pediatric patients. Calcification and the cystic nature of the lesion are characteristic imaging findings and in most of these entities, the pituitary gland can be separately identified. Some infrequently encountered lesions within the parenchyma of the pituitary are the Rathke's cleft cyst and hypophysitis and are discussed here.
Rathke cleft cyst
The development of pituitary gland begins in the 4th week of intrauterine life. An evagination develops from the stomodeal epithelium, the Rathke pouch. The eponymous structure was postulated by Professor Martin Rathke in 1839. The Rathke pouch meets a projection from the diencephalon, which goes on to form the posterior pituitary or the neurohypophysis. Between the sixth and eighth week of development, the Rathke pouch separates from the oral epithelium. The adenohypophysis and the pars intermedia form from the pouch. The fully developed pituitary gland is found in the sella with the stalk which is essentially an extension of the third ventricle floor. The pituitary gland itself is made of the anterior lobe or the adenohypophysis, the posterior lobe of the neurohypophysis. After the formation of the anterior and posterior lobes, the cleft between them is the Rathke cleft.
The Rathke Cleft Cyst (RCC) arises from the remnants of the Rathke cleft cells, in the pars intermedia of the pituitary gland. Incidental Rathke cleft cysts are known and several autopsy series demonstrate the presence of these. Symptomatic cysts are not too common. A meta-analysis in 2014 collected less than 2,000 symptomatic cases reported in literature till then.,
There is some variation in the types of cells lining the cyst. Ciliated cuboidal to columnar cells, which may contain goblet cells may be seen. The contents are usually mucinous in nature. Occasionally, the contents may be solid because of inspissated material. There are the occasional case reports of calcification seen within the cyst., Symptomatic cysts enlarge and compress the surrounding structures. Thus, apart from diaphragmatic stretch and compressive clinical features of the visual apparatus, endocrinologic dysfunction may also be part of the clinical picture.,,
Headache is the most common presenting symptom for symptomatic RCC (55%) Visual compromise due to direct compression of the optic nerves and chiasm is seen in many cases (34%). Endocrinological dysfunction is seen in many asymptomatic patients (46%) Presentation like pituitary apoplexy is rarely reported. However, the severity of symptoms in this scenario are milder than a pituitary apoplexy. In our review of 58 cases (27 surgically operated) of RCC, 92% presented with headaches, 26% had visual symptoms, and 48% had hormonal dysfunction.
The 3 components of sellar pathology evaluation i.e., imaging, visual examination, and endocrinological evaluation are followed for RCC as well.
The imaging modality of choice is the MRI. RCC is commonly seen as an isointense lesion on T1 and hyperintense lesion on T2 imaging. Hypointensity on T2 indicates inspissated material within the cyst. The location of the cyst may be sellar, sellar suprasellar or purely suprasellar. There is an imaging classification from Ozoner et al., which correlates the imaging characteristics viz. intensity, location of the cyst in the sagittal plane, with the possible approach needed and the outcomes. The normal pituitary is usually seen around the cyst and is identified by the enhancement pattern of the normal gland. the pituitary stalk is usually not displaced to one side as one would expect in a pituitary adenoma [Figure 1]. Contrast enhancement in an RCC wall may indicate inflammation or a squamous metaplasia. Diagnosing RCC is not always straightforward as it may be mistaken for a pituitary adenoma with apoplexy or a craniopharyngioma.,,,,,,, There are reports of coexisting pituitary adenomas and other pathology with RCC. In our experience, the imaging diagnosis was accurate in seventy percent of cases for RCC. The other possibilities included pituitary adenoma with apoplexy and craniopharyngiomas.
Ophthalmologic evaluation involves visual acuity and visual fields charting. These were affected in 26% of our patients. The most common deficit was a bitemporal hemianopia.
Hormonal evaluation is mandatory as hormonal status may be altered in many patients. In our series, forty eight percent patients had hormonal dysfunction. Though hypopituitarism was the most expected dysfunction, moderate hyperprolactinemia (probably due to stalk effect) was the most common abnormality in our patients.
Many RCC are asymptomatic and may be observed and evaluated at regular intervals. Symptomatic RCC, however, will need treatment. The principles of treatment are excision whenever possible. If the capsule is very flimsy, or very adherent, surgical decompression and adequate marsupialization of the cyst is performed to prevent recollection and recurrence as well as to avoid major pituitary dysfunction.,,
This can be achieved by the transsphenoidal approach or by a craniotomy. With recent refinements in technique, the endonasal endoscopic approach has been our preferred path for surgery. Craniotomy and deroofing is rarely required and is reserved for large suprasellar extension and was not necessary in any of our patients.
During the surgery, complete removal of the wall was thought to be an endpoint. However numerous reports now indicate that this may not be necessary from the point of alleviating the symptoms caused by the cyst. Surgical treatment brings about resolution of headache in most patients and vision improvement is seen in a sizeable number of patients.,, Endocrinological recovery is not predictable and most patients remain stable or improve. Our series showed endocrine function improvement in 46% and a deterioration in 7%. Cauterization of the cyst wall with absolute alcohol has been tried without significant benefit to prevent recurrence with increase in complications.
The chief morbidity following transsphenoidal surgical treatment of RCC is CSF leak in the postoperative period and transient, endocrine worsening. The other important sequel to watch for over a long follow up is the recurrence of the cyst. The rates of cyst recurrence can be as high as 30%. We have had only 1 recurrence in an incompletely removed cyst, 2 years after initial transsphenoidal procedure and a complete excision could be achieved during the second surgery. Certain factors like squamous metaplasia, a CSF leak at surgery and inflammation on histopathology features seem to be putative factors for reaccumulation within the cyst and recurrence.,,, The microsurgical transsphenoidal approach was found to have a higher recurrence rate (14% vs. 8%) and new endocrine dysfunction rate (25% vs. 10%) compared to the endoscopic approach. A novel method of lining the cavity with free mucosal flap has been described by Kuan et al.
The most significant factor for recurrence in a recent review has been shown to be a residual disease at follow-up scan. Thus, follow up to needs to be prolonged as recurrences are seen up to 5 years after successful surgery for the RCC, especially in this high risk group with residual cyst wall. Symptomatic lesions need to be treated with repeat surgery. Of interest is the use of drug eluting stents to prevent blocking off the opening of the opening created. There also a report of stereotactic radiation therapy given to a small cohort of patients with more than one relapse with equivocal results.
Hypophysitis may be defined as an acute or chronic inflammation of the pituitary gland with attendant pituitary hormonal dysfunction which may be associated with features of mass effect on the sellar and juxta sellar contents.
Traditionally hypophysitis has been classified according to a.) location involving the adenohypophysis, the infundibulum and posterior pituitary. The next classification paradigm has been b.) histopathology either lymphocytic/granulomatous/xanthomatous/necrotizing and more recently, the IgG4 related subtype has been added. The third paradigm is c.) etiologic classification viz. Primary hypophysitis or secondary to a systemic disease or drug administration.
Primary hypophysitides are thought to have autoimmune origins and include lymphocytic hypophysitis, the most common type reported. This is characterized by infiltration of the pituitary with lymphocytes and likely progresses to pituitary fibrosis. Several anti-pituitary antibodies have been described to initiate the process.
Xanthomatous hypophysitis is the least common variety. This is thought to be on the continuum of the autoimmune spectrum. Recently, this entity is thought to be secondary to an inflammatory process like RCC rupture. This would push this entity as a secondary hypophysitis.
Granulomatous hypophysitis may be a primary hypophysitis or secondary to another pathology. The diagnosis thus a process of exclusion. Diseases like tuberculosis, sarcoidosis, histiocytosis and syphilis may incite hypophysitis which would be a secondary form. Rarely pituitary lymphoma may present as hypophysitis., Tuberculosis as a cause of granulomatous hypophysitis is a recognized etiology, especially in the Indian subcontinent and in areas of endemicity for tuberculosis and must be considered when assessing hypophysitis.,,,,,
Newer forms of hypophysitis described are IgG4, ICI (Immune checkpoint inhibition) agents ipilimumab-related.,,, The anti pit1 antibody syndrome, a cytotoxic T-cell mediated autoimmune disease can also cause hypophysitis.
Primary hypophysitides are more common in female patients. There is association with pregnancy especially for lymphocytic varieties. Most patients are premenopausal [Figure 2]. However, more and more patients are being detected beyond the reproductive years.
The most common symptom is headache and endocrine dysfunction. Other symptoms may include visual compression.
The most common endocrinologic dysfunction is the adrenal insufficiency and hyperprolactinemia, seen in lymphocytic hypophysitis. Adrenocorticotropic hormone deficiency is almost always seen in lymphocytic hypophysitis. Granulomatous hypophysitis defects include posterior pituitary dysfunction in addition to headache. In the xanthomatous variety, gonadotrophic and growth hormone deficiencies are also seen. The IgG4 variant shows diabetes insipidus (DI) in nearly half of the patients.
In secondary hypophysitis endocrinologic presentation depends on the specific etiology. Langerhans cell histiocytosis (LCH) presents with diabetes insipidus and a mild anterior pituitary dysfunction.
The imaging modality of choice is the MRI with gadolinium enhancement. MRI shows an enlarged gland, which enhances variably. The thickened, enhancing, non-displaced pituitary stalk is the commonest feature. In patients with DI, the posterior bright spot is lost. The pituitary gland cannot be seen separately. Even so, in a significant number of cases, hypophysitis is misread as a pituitary adenoma. The MRI scoring system developed by Gutenberg et al. shows a high specificity and sensitivity to distinguish these entities. Their group found that the pregnant state, pituitary volume, gland symmetry, the signal intensity and homogeneity on contrast, the posterior pituitary bright spot, enlargement of the stalk, and sphenoidal mucosal swelling as significant factors for predicting hypophysitis over a pituitary adenoma. These were assigned a signed number based on statistical analysis that ranged from -13 to + 8. Scores of -13 to -2 were suggestive of hypophysitis, while scores of -2 to -8 suggested non-secreting pituitary adenomas.
The sine qua non of diagnosis is histopathology. Lymphocyte infiltration, presence of macrophages, foamy histiocytes, (xanthomatous variety), multinucleated giant cells. This necessitates surgical exploration. Even before this, other diagnostic modalities include imaging, visual examination, and hormonal evaluation.,, [Figure 3].
Treatment is directed toward reducing the inflammatory/immune response and the symptomatic mass effect caused due to the disease. Management of hormonal imbalances is an important component of treatment. Glucocorticoids play an important role to suppress and control the inflammatory process. Other immune suppressing agents like azathioprine and agents like rituximab have been used for treatment., Surgical treatment is reserved for those patients who do not respond to medical therapy, when the diagnosis is in doubt or when there is significant mass effect on the visual apparatus. Surgery usually involves a transnasal transsphenoidal approach and biopsy and decompression when needed.
Experience with hypophysitis in a neurosurgical unit
We have had the occasion to treat thirty eight cases of hypophysitis in the past twenty two years (1998-2020). Of over a 1,000 cases of sellar suprasellar pathology reviewed, 38 cases of hypophysitis were identified. Of these, 21 were treated conservatively. A total of 17 cases underwent surgical procedures. Of the operated cases, a vast majority (13/17) were female, and 9 of these 13 were premenopausal. The main indications for surgery here were optic apparatus compromise (9/17), progression of lesions despite medical treatment, persistent headaches (12/17) and uncertain diagnosis [Table 1].
Endocrine dysfunction [Table 2] was found in 13 of 17 patients. Adrenal axis hypofunction was seen in 8/13 patients, while diabetes insipidus was seen in 7/13 of these patients. Three patients had panhypopituitarism.
Interestingly, neuroimaging findings [Table 3] showed 7 patients as hypophysitis, while 10 were diagnosed as having a pituitary adenoma. The reason for this may be greater awareness and the long period of the study where radiological understanding and codification has improved in the latter half of the study period.
All surgeries were done via the transnasal route [Table 4]. Three were done by endoscope assisted microsurgery, in the earlier part of the series. Of the operated cases, 10 were lymphocytic variety, while 7 were granulomatous. Of the granulomatous variety, 2 were tuberculous granulomas. No xanthomatous variant was encountered [Figure 4].
Postoperative results showed significant relief of headache (91.6%), and improvement in vision in 88% of patients. Hormone function improved in 6 of the 13 patients. There was worsening in 2 patients, while 5 had unchanged hormone functions. CSF leak was seen in 3 postoperative patients. Two of these needed a lumbar drain inserted for 2 days to control the leak. To summarize our experience, as well as the evidence from literature, surgical exploration has specific indications and can be done safely via the trans sphenoid endoscopic method. In our setting, it is especially important to look for tuberculous hypophysitis.
Although the most common sellar pathology is the pituitary adenoma, attention must be drawn to the other possibilities. This can be due to odd history, atypical hormonal disturbance or atypical imaging features. A detailed interaction with endocrinologist is necessary and medical treatment can relieve this condition in most of these patients. Surgery has a limited role only for proper diagnosis and decompression may become necessary in a few cases. The outcomes from treatment, especially surgical treatment, would depend on high index of suspicion (as non-adenoma lesions) and recognition early during the surgery, resulting in appropriate management.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]