2018 NPA-06

This case was originally published in 2018. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A 67-year-old man presented with visual deterioration. A detailed ophthalmological evaluation identified bitemporal hemianopsia. MRI revealed a lesion in the sella turcica, extending into the suprasellar area and elevating the optic chiasm (Image A and Image B). At surgery, the neurosurgeon described a bulging cystic structure. When it was incised, a yellow fluid oozed out. The cavity contained no mass or nodule, and a plane of dissection was not identified around the cavity. A fragment of the cyst dome was submitted for pathologic diagnosis.

Tissue Site
Sella turcica

The whole slide image provided is an H&E stained slide of pituitary area from a biopsy.

Rathke cleft cysts, occasionally called pars intermedia cysts, are derived from the epithelial remnants of the Rathke pouch, an early embryological diverticulum of the dorsal stomodeum that becomes incorporated into the developing pituitary gland. Such cysts are most often microscopic structures seen in the pituitary gland between the adeno- and neurohypophysis. Rathke cleft cysts are nonneoplastic, although in rare situations true neoplasms such as craniopharyngiomas may arise in them.

Rathke cleft cysts represent only about 2% of sellar region masses. Many Rathke cleft cysts are asymptomatic and are discovered incidentally during evaluation of unrelated problems or at autopsy. The clinical problems caused by Rathke cleft cysts are variable and include headache, visual problems, and/or pituitary hormonal abnormalities. If the cyst compresses the pituitary stalk, hyperprolactinemia may occur. If the cyst extensively compresses the pituitary gland, panhypopituitarism can develop. Diabetes insipidus, although uncommon, can occur. The visual abnormalities vary from decreased acuity, bitemporal hemianopsia or chiasmatic syndrome, and optic atrophy. No clinical presentation is specific for Rathke cleft cysts.

Rathke cleft cysts may have a variable appearance on MRI studies. In its most basic form the Rathke cleft cyst is a distinct, sharply delineated, nonenhancing, cystic structure located in the sella and/or the supersellar area (Image A and Image B). They have a round, oval, or dumbbell shape. Typically, Rathke cleft cysts change little over time and may ultimately decrease in size. Frequently, they contain an intracystic nodule having high signal intensity on T1-weighted images and low signal intensity on T2-weighted images. This nodule within the cyst represents aggregated mucin. Rathke cleft cysts do not enhance after contrast administration. However, if the cyst ruptures or if hemorrhage occurs, then the distinct nature of the cyst can be replaced by an ill-defined, heterogeneously enhancing mass that may show high signal intensity on T1 images.

Rathke cleft cysts are usually thin walled and vary in size from less than a millimeter to four centimeters. They typically contain a yellow, thick, viscous fluid. The cyst wall consists of fibrovascular stroma lined by a layer of epithelium (Image C). The epithelial lining can be of three types: a) cuboidal or columnar ciliated cells (Images D), b) nonciliated cells, and c) mucus secreting cells. The presence of abundant mucin in association with the cystic lesion strongly supports the diagnosis of Rathke cleft cyst. Squamous metaplasia is a common alteration. This can raise the diagnostic possibility of a squamous neoplasm or a craniopharyngioma.

If the cyst ruptures or undergoes focal degeneration, the tissue in the lesion can become inflamed and/or necrotic with xanthogranulomatous reaction and formation of cholesterol laden debris. However, careful inspection of the resected material will reveal remnants of the typical epithelium or metaplastic squamous cells. The wall of Rathke cleft cysts may contain fragments of anterior or posterior pituitary gland.

The IHC profile of Rathke cleft cysts can vary, yet certain specific markers permit distinction from alternative diagnoses. Lining epithelium is positive with a spectrum of cytokeratin (CK) markers (Image E and Image F). While it used to be generally accepted that all Rathke cleft cyst epithelium was positive for CK20, more extensive experience has shown that the epithelium may be negative, as in the current case (Image G). There are a number of markers that together help to delineate Rathke cleft cysts from other lesions. Rathke cleft cyst epithelium is reliably negative for nuclear expression of beta-catenin (Image H). The epithelium is positive for EMA (Image I) and is often positive for S100 (Image J), while GFAP is typically negative (Image K).

One critical differential diagnosis between cystic lesions of the sellar region is the distinction of Rathke cleft cyst and craniopharyngioma. This is often difficult when the lesion contains squamous epithelium; however, there are multiple features that help to make this distinction. Rathke cleft cysts do not contain “wet keratin” found in most cases of the latter lesion. Rathke cleft cysts are often CK20 positive, whereas craniopharyngiomas are not. Rathke cleft cysts do not exhibit nuclear positivity for beta-catenin, whereas adamantinomatous craniopharyngiomas do; currently this appears to be the best differentiating IHC stain. In addition, papillary craniopharyngiomas are positive for the BRAF V600E mutations, while Rathke cleft cysts are negative.

Cystic pituitary adenomas typically retain some staining for pituitary hormones and/or chromogranin. Also, there might be areas with remaining histologically recognizable adenoma. While incidental Rathke cleft cysts may stain weakly for pituitary hormones, those that are clinically symptomatic are typically negative. The lining of ependymal cysts is consistently positive for GFAP and S100. Arachnoid cysts are positive for EMA, but are negative for GFAP and S100.

• Rathke cleft cysts are nonneoplastic masses that are most frequently detected as incidental findings at autopsy.
• Rathke cleft cysts derive from embryological remnants in the sella and/or supersellar area.
• The diagnosis depends on finding the cyst lining cells including foci of squamous metaplasia.
• The clinical presentation of Rathke cleft cysts is similar to other mass lesions in the sella.
• There is no single IHC stain that differentiates Rathke cleft cyst from the other cystic lesions of the sella.

1. Hofmann BM, Kreutzer J, Saeger W, et al. Nuclear beta-catenin accumulation as reliable marker for the differentiation between cystic craniopharyngiomas and rathke cleft cysts: a clinico-pathologic approach. Am J Surg Pathol. 2006;30:1595-603.
2. Kleinschmidt-DeMasters BK, Lopes MBS, Prayson RA. An algorithmic approach to sellar region masses. Arch Pathol Lab Med. 2015;139:356-72.
3. Le BH, Towfighi J, Kapadia SB, et al. Comparative immunohistochemical assessment of craniopharyngioma and related lesions. Endocr Pathol. 2007;18:23-30.
4. Schweizer L, Capper D, Hölsken A, et al. BRAF V600E analysis for the differentiation of papillary craniopharyngiomas and Rathke’s cleft cysts. Neuropathol Appl Neurobiol. 2015;41:733-42.
5. Seunggu JH, Rolston JD, Jahangiri A, et al. Rathke’s cleft cysts: review of natural history and surgical outcomes. J Neurooncol. 2014;117:197-203.