Spontaneous rupture of malignant papillary craniopharyngioma with CSF seeding and metastatic deposits: A case report and literature review.

Introduction: Craniopharyngiomas are benign tumours mainly confined to the cranial cavity in the suprasellar region. Research Question and Case Description: We present a rare case of an aggressive papillary craniopharyngioma with disseminated spinal intradural disease. A 67-year-old woman presented with a 4-month history of headache, visual disturbance, acute confusion and radicular leg pain. Previous history of breast carcinoma (ER ​+ ​PR ​+ ​HER2-) was noted. The importance of histological diagnosis prior to treatment of sellar or suprasellar lesions with atypical or aggressive features is explored. Materials and methods: MRI demonstrated a partly solid and partly cystic pituitary mass lesion in the sellar and suprasellar region with chiasmal compression and hypothalamic involvement. The sella was mildly enlarged and there were no calcifications. Whole neuraxis MRI revealed intradural deposits involving the ventricular system, spinal cord and conus. Within a month, the lesion rapidly increased in size. The patient underwent a craniotomy and transventricular resection of the sellar and suprasellar mass. Cranial lesion histology favoured papillary craniopharyngioma, confirmed by BRAF V600 mutation. Lumbar puncture CSF cytology confirmed craniopharyngioma with BRAF mutation and no evidence of metastatic breast cancer.
Results: The patient remained confused postoperatively without focal neurological deficit and underwent palliative whole brain radiotherapy. She died 4 months later. A review of the literature identified 29 reports of ruptured craniopharyngioma. Discussion and
Conclusion: Ruptured craniopharyngioma presents with a suprasellar mass and drop lesions in the spinal canal, characteristics radiologically indistinguishable from metastatic disease. The importance of histological diagnoses in directing the management of these cases is highlighted. Crown

Central Nervous System

Computed Tomography

Fluid-attenuated inversion recovery

Glasgow Coma Scale

Lumbar puncture

Introduction

Craniopharyngiomas are usually rare, benign, slow-growing tumours arising from epithelial nests derived from Rathke's pouch. They constitute a small proportion (1–3%) of adult primary CNS tumours with an incidence of 1.7 per million patient years. The overall survival is 80% at 5 years (Zacharia et al., 2012). Two histological subtypes; adamantinomatous and papillary, are characterised by CTNNB1 and BRAFv600E mutations, respectively. Most craniopharyngiomas are of the adamantinomatous subtype, most common in paediatric patients. The papillary histological subtype account for 8% of all craniopharyngiomas and occur almost exclusively in adults. They have no calcifications and are characterised histologically by BRAF V600 mutations (Zoicas and Schöfl, 2012).

Craniopharyngiomas usually present with headaches, visual failure, hypothalamic dysfunction or CSF obstruction. Spontaneous rupture of the cystic components of these lesions is very rare (Karavitaki et al., 2006). It may present with the sequelae of chemical meningitis or with symptoms of neural compression such as radicular pain or neurological deficits. Malignant craniopharyngioma is a recognised entity but has not previously been described in the literature.

We present a case of a malignant craniopharyngioma with intradural drop metastases and summarise the literature on this topic. The aim of the current paper is to increase awareness of this rare presentation of aggressive craniopharyngioma and to advocate confirmation of a histological diagnosis of suprasellar lesions with cerebrospinal spread before proceeding with empirical treatment.

Case report

Clinical course of events

A 67-year-old woman presented with a 4-month history of right-sided headaches and visual disturbance. A month later she developed acute confusion, fever, vomiting and photophobia with right-sided radicular leg pain. She also reported extreme lethargy, thirst, weight loss, loss of appetite and new onset nocturia without daytime polyuria. Investigations revealed hyponatraemia.

The patient's past medical history included primary breast carcinoma, diagnosed one year earlier as a Grade 2, ER ​+ ​PR ​+ ​HER2- tumour, lymph node negative. This had been managed with wide local excision, post-operative radiotherapy and adjuvant pharmacological treatment with letrozole.

A brain MRI at presentation revealed a partly solid, partly cystic suprasellar tumour with compression of the optic apparatus. Repeat MRI one month later showed progression of the tumour with widespread metastatic lesions in the ventricular system (Fig. 1). MRI spine, performed to investigate the radicular leg pain, demonstrated an intradural extramedullary lesion at the level of L1 with equivocal pial nodules of enhancement (Fig. 2).

Fig. 1

a) Sagittal FLAIR image and one-month later b) Coronal c) Sagittal post-gadolinium T1 weighted images demonstrate the progressive sellar, suprasellar and hypothalamic heterogeneously enhancing mass and d) Comparative axial post-gadolinium images at presentation and one-month later.

Fig. 2

a) Sagittal T1 post-gadolinium image of the spine demonstrates fine nodular pial enhancement of the spinal cord with b) Axial post-gadolinium image at L1 level demonstrating a larger intrathecal enhancing lesion adjacent to the conus.

The radiological diagnosis favoured a craniopharyngioma but the rapid increase in size was not characteristic of a benign process and therefore breast metastasis and hypothalamic glioma remained in the differential diagnoses. No visceral metastatic disease was demonstrated on CT of the chest, abdomen and pelvis.

The case was discussed at the multidisciplinary team meeting and, given the diagnostic uncertainty, a stealth-guided endoscopic resection was performed. In order to establish whether the drop lesions were of the same origin or a secondary metastatic process, CSF cytology from a lumbar puncture was also obtained. The history of breast cancer was noted when making this decision.

Neuropathology

The intraoperative smear and the histology showed multiple small tissue fragments mainly composed of haphazardly arranged squamous epithelial cells with moderate pleomorphism and focal keratinisation but no wet keratin formation (Fig. 3a and b). The squamous epithelial cells were admixed with granulation tissue and chronic, predominately lymphocytic, inflammatory background (Fig. 3b). The tumour cells were strongly positive with cytokeratins (MNF116, CK7 and CK5/6), while CK20 and TTF1 were negative. MNF116 also revealed scattered small groups of cells within the granulation tissue, suggesting infiltration (Fig. 3c). The proliferation activity (Ki-67) was moderately increased but included both inflammatory and tumour cells (Fig. 3d).

Fig. 3

Cytology and histology of the suprasellar cystic lesion. a) The intraoperative smear preparation shows squamous epithelial cells with moderate pleomorphism. 3b) Sections stained by haematoxylin-eosin (H&E) show multiple small tissue fragments mainly composed of haphazardly arranged squamous epithelial cells with focal keratinisation but no lamellar or wet keratin formation (H&E). The squamous epithelial cells (left side) are admixed with granulation tissue and chronic, predominately lymphocytic, inflammatory background (right side). 3c) Immunohistochemistry for pan-cytokeratin (MNF116) is positive and also shows scattered small groups of cells within the granulation tissue, suggesting infiltration. 3d) Ki-67 demonstrates moderately increased proliferation activity but labels both inflammatory and tumour cells (compare with 3b). 3e-f) Cerebrospinal fluid (CSF) cytology specimen from lumbar puncture stained by Papanicolaou (PAP) and H&E also reveals squamous epithelial cells with focal keratinisation.

The histological features slightly favoured metastatic squamous cell carcinoma; however, the overall features were not suggestive of metastatic breast carcinoma and the primary lesion remained unclear. The sample was small and accompanied by very prominent granulation tissue formation and chronic inflammatory reaction, therefore the possibility of an atypical papillary craniopharyngioma was also considered. Molecular sequencing on the suprasellar biopsy demonstrated BRAF V600K mutation altering the diagnostic trajectory towards a papillary craniopharyngioma.

The patient subsequently underwent a lumbar puncture 4 weeks post-surgery, confirming squamous cells compatible with papillary craniopharyngioma (Fig. 3e and f). The atypical cells displayed immunoreactivity for pancytokeratin, CK7 and EMA but remained negative for breast markers GATA3, GCDFP-15, ER and PR. BRAF V600K mutation was also demonstrated in lumbar puncture specimen. CSF analysis demonstrated atypical squamous epithelial cells consistent with the cranial lesion biopsy. CSF sampling was not performed during cranial surgery. It was concluded that the biopsied suprasellar cystic lesion was an atypical papillary craniopharyngioma initiating CSF seeding or metastatic deposits. The immunoprofile and presence of non-canonical BRAF mutation in the cytology specimen proved the malignancy. The Ki67 index was difficult to assess due to the ongoing inflammatory response but more elevated than usually seen in craniopharyngioma cases.

Discussion

BRAF mutations may occur in a number of tumours and are particularly common (100%) in papillary craniopharyngioma, whilst extremely rare in lung adenocarcinoma (3%), head and neck squamous cell carcinoma (3%) and breast carcinoma (1%) (Alvarez and Otterson, 2019; Weber et al., 2003). The BRAF mutation was therefore felt to be diagnostic of papillary craniopharyngioma. To our knowledge, malignant transformation has only been reported in an adamantinomatous craniopharyngioma but not in a papillary craniopharyngioma (Rodriguez et al., 2007). In the current case, the histological features suggested an aggressive process. The rapid tumour progression and presence of spinal deposits detected by MRI favoured a diagnosis of drop metastases from a malignant craniopharyngioma, rather than a benign craniopharyngioma which had ruptured. This is therefore the first report of a malignant papillary craniopharyngioma with metastatic deposits.

In view of the positive BRAF V600K mutation, the case was deemed suitable for consideration of treatment with BRAF inhibitors.

There are no other cases of histologically confirmed malignant papillary craniopharyngioma with drop metastases in the literature. A literature search for reported cases of ‘ruptured craniopharyngioma’ in adults (aged above 18 years) returned results for 29 individual cases within 25 studies (Chen et al., 2016; Hadden and Allen, 2004; Hakizimana et al., 2018; John-Kalarickal et al., 2007; Kaemmerer, 1964; Krueger and Larson, 1988; Kulkarni et al., 2000; Kuzuhara et al., 1976; Lederman et al., 1987; Lloyd and Belchetz, 1977; Maier, 1985; Nishio et al., 2001; Patrick et al., 1974; Russell and Pennybacker, 1961; Satoh et al., 1993; Scully et al., 1997; Shida et al., 1998; Takahashi et al., 2003; Tena-Suck et al., 2015; Tokiwa et al., 1984; Tosaka et al., 2015; Vakharia et al., 2017; Worster-Drough et al., 1927; Yamamoto et al., 1989; Yasumoto and Ito, 2008) of which 15 had confirmed histology. The findings are summarised in Table 1. The clinical features at presentation were similar to the current case. It remains a possibility that some of these cases were indeed malignant tumours with intradural seeding.

Table 1

Existing reports of ruptured craniopharyngiomas with individual case context.

Article information			Patient demographics		Clinical symptoms	Initial diagnosis	Intervention/management	Approach	Outcome/post-operative status					Radiation therapy	Histological findings
Authors	Year and number of case reports		Age (years)	Sex					Re-presentation with complications within 30 days	Repeat management within 30 days		Repeat management within 1 year
										Surgical	Conservative	Surgical	Conservative
Chen et al.,	2016	1	65	F	Diplopia, fatigue, bitemporal hemianopsia.	CP with mass effect on optic chiasm and tracts.	Image-guided surgical decompression.	Endoscopic, trans-sphenoidal, trans-sellar.	Yes	Yes	Yes	Yes	Yes	Yes	Papillary CP.
Hadden et al.,	2004	1	34	M	Headache.	Chemical meningitis following CP cyst rupture.	Previous decompression.EVD insertion following rupture.	Trans-frontal subtotal resection.	Yes	No	Yes	No	No	No	Subacute inflammatory reaction at necropsy.
Hakizimana et al.,	2018	1	53	M	LUTS, febrile, headache. Depression and paranoid personality. disorder.	Suprasellar cystic lesion with heterogeneous contrast enhancement. Hypophysitis.	Cyst drainage and washout.	Sub-frontal.	Yes	No	Yes	Yes	Yes	No	Papillary CP.
John-Kalarickal et al.,	2007	1	61	F	Headache, visual disturbance.	Cystic CP.	Biopsy and drainage of cystic lesion followed by surgical resection.	Trans-sphenoidal biopsy.Bifrontal resection.	No	No	No	Yes	No	No	Histological confirmation of CP.
Kaemmerer et al.,∗	1964	1	46	M	Chemical meningitis.	CP.	Conservative management.	-	-	-	-	-	-	-	Histological confirmation of CP.
Krueger et al.,	1988	1	73	M	Recurrent fever, chills, frontal headache, meningismus, muscle cramping, confusion. Coma.	Leaking CP.	Contrast CT scan.Antibiotics and steroid treatment.	Trans-sphenoidal.	No	No	No	No	No	No	Sterile persistent neutrophilic pleocytosis. Normal glucose and protein.
Kulkarni et al.,	2000	1	38	F	Chemical ventriculitis.	Intraventricular rupture of CP cyst.	Non-contrast CT. EVD. Craniotomy and partial cyst excision.	-	Yes	Yes	No	No	No	Yes	Histological confirmation of CP.
Kuzuhara et al.,∗	1976	1	46	M	Aseptic meningitis.	CP.	Carotid angiography. Surgical resection.	-	-	-	-	-	-	-	-
Lederman et al.,	1987	1	82	F	Visual disturbance, panhypopituitarism, altered mental status.	Pituitary adenoma, CP and metastatic tumour.	CT scan. Surgical resection.	Trans-sphenoidal.	No	No	No	No	No	Yes	Basaloid-type epithelial cells. Abundant eosinophilic cytoplasm. Consistent with CP.
Lloyd et al.,	1977	1	29	F	Chemical meningitis.	Pituitary apoplexy.	Skull x-ray.Sub-total resection.	Trans-cortical.	-	-	-	-	-	-	-
Maier et al.,	1985	1	30	M	Erosion and drainage into nasopharynx. Headache, polydipsia, polyuria.	Pituitary tumour, CP.	Skull x-ray. Conservative management.	-	No	No	No	No	No	Yes	Pure cholesterol crystals in drainage material. Tissue fragments consistent with CP.
Nishio et al.,∗	2001	1	50	F	Febrile, headache, nausea.	Chemical meningitis.	CT.Contrast-MRI. Surgical resection.	-	-	-	-	-	-	-	-
Patrick et al.,	1974	1	21	M	Chemical meningitis.	Ruptured CP cyst.	Pneumoencephalogram. Conservative management.	-	Yes	Yes	No	No	No	No	-
Russell & Pennybacker,	1961	1	67	F	Chemical meningitis. Memory lapse, hypersomnia.	Cystic CP.	Skull x-ray. Conservative management.	-	No	No	No	No	Yes	No	Infiltration with polymorphs and chronic inflammatory cells at necropsy.
Satoh et al.,	1993	4	1) 252) 363) 644) 54	1) M2) M3) F4) M	1) Headache, nausea.2) Meningism.3) Improvement in visual disturbance. 4) Febrile, altered consciousness, hypopituitarism., visual disturbance.	1-4) Cystic CP	2-4) CT or MRI.2) Cerebral angiography. Partial surgical resection.3) Partial surgical resection.4) Surgical resection.	2) Fronto-temporal.4) Trans-sphenoid and trans-cranial.	1,2,4) Yes	No	No	No	No	2, 3, 4) Yes	1) –2) Adamantinomatous CP.3) Adamantinomatous CP.4) Squamous cell CP.
Scully et al.,	1997	1	60	M	Meningism.	-	Conservative management.	-	-	-		-	-	-	-
Shida et al.,	1998	1	36	F	Pre-natal: headache, pollakiuria. Ante-natal: visual disturbance, aphasia, loss of consciousness. Diabetes insipidus. Motor and sensory disturbance.	CP.Symptomatic vessel narrowing secondary to CP cyst rupture.	Subtotal surgical resection.	Bifrontal.	No	No	No	No	No	Yes	Histological confirmation of CP.
Takahashi et al.,	2003	2	1) 702) 69	1) F2) F	1) Headache, visual disturbance.2) Visual disturbance.	1) CP. Dermoid cyst.2) Cystic CP.	1,2) Cyst evacuation.1) Tube of an Ommaya reservoir insertion.	2) Trans-cranial.	1) No2) No	1) No2) No	1) No2) No	1) Yes2) Yes	1) Yes2) Yes	1) No2) Yes	1,2) CP with adamantinomatous pattern.
Tena-Suck et al.,	2015	1	36	F	Headache, nausea, visual disturbance.	Pituitary adenoma.CP.	Total surgical resection.	Trans-sphenoidal.	No	No	No	Yes	No	No	Piloide gliosis.Xanthogranulomatous hypophysitis.
Tokiwa et al.,∗	1984	1	43	M	Visual disturbance, altered consciousness.	Cystic CP.	CT. Surgical resection.	-	No	No	No	No	No	No	Histological confirmation of CP.
Tosaka et al.,	2015	1	69	M	Headache, gait and visual disturbance, progressive hearing loss.	Superficial siderosis of CNS secondary to CP haemorrhage.	Surgical resection.	Antero-basal hemispheric. Bi-coronal and trans-lamina terminalis craniotomy.	No	No	No	No	No	No	Haemorrhagic papillary CP. Positive stain: CAM5.2. Negative stains: GFAP, S-100 protein, CK20, and EMA. MIB-1 LI: 3.4%.
Vakharia et al.,	2017	1	75	F	Chemical ventriculitis. Acute hydrocephalus. Panhypopituitarism. Visual disturbance.	Ruptured CP cyst.	EVD. Ommaya reservoir. VPS.	Endoscopic, intra-cystic.	No	No	No	No	No	No	Proteinaceous material, blood, histiocytes, hemosiderin on aspirate cytopathology.
Worster-Drought et al.,	1927	1	19	F	Chemical meningitis.	CP.	-	-	-	-	-	-	-	-	-
Yamamoto et al.,	1989	1	59	F	Sciatica, headache, nausea.	SAH secondary to CP haemorrhage.	CT. Cerebral angiography. Subtotal resection.	Fronto-temporal.	No	No	No	No	No	No	Adamantinomatous pattern of peri-dermoid tissue. Consistent with CP.
Yasumoto et al.,	2008	1	47	M	Asymptomatic.	Cystic CP.	VPS. MRI. Subtotal resection.	-	No	No	No	Yes	No	No	-

∗English abstract only; foreign language article.

CP: craniopharyngioma; CNS: Central Nervous System; CSF: Cerebrospinal Fluid; CT: Computed Tomography; EMP: epithelial membrane antigen; ICU: Intensive Care Unit; IV: Intravenous; F: female; GFAP: glial fibrillary acidic protein; LI: labelling index; LP: Lumbar Puncture; LUTS: Lower Urinary Tract Symptoms; M: male; MRA: Magnetic Resonance Angiography; MRI: Magnetic Resonance Imaging; PMH: Past Medical History; ICA: Internal Carotid Artery; MCA: Middle Cerebral Artery; SAH: Sub-arachnoid haemorrhage; VPS: ventriculoperitoneal shunt.

In the majority, the presenting complaint was notable for chemical meningitis in addition to those symptoms which are commonly seen in non-ruptured craniopharyngiomas (n ​= ​11). The sub-arachnoid space was the most prevalent site of rupture (n ​= ​18). Surgical intervention was indicated in 22 cases for diagnosis and decompression of neural structures with sub-total resection via a trans-sphenoidal approach as the most popular technique. A similar proportion of cases were treated with conservative management (n ​= ​4) or radiotherapy (n ​= ​3) without biopsy. Length of follow-up was variable (range: 1 day–6 years; mean: 65.7 weeks) with no recurrence (remission or absence of regrowth) reported in 7 cases beyond 1-year follow-up (mean: 19.6 months).

Conclusion

We report an atypical presentation of an aggressive, malignant papillary craniopharyngioma associated with CSF seeding along the neuraxis. This is the first report of such a case in the literature. The importance of histological diagnosis prior to treatment is emphasised. We advocate a low threshold for obtaining a histological diagnosis with sellar or suprasellar lesions, particularly in cases with atypical or aggressive features.

Compliance with ethical standards

The authors declare that they have no competing interests.

No funding contributed to this work.

Author contributions

A.B.M, E.C.M, S.B. and N.T. conceptualised the study. M.A., A.B.M., I.B. and E.M. drafted the manuscript. M.A. and C.M. contributed to the table and literature review. M.R.H. performed the CSF cytology. I.B. and Z.R. reported on the biopsy findings and prepared the histopathological figures and legends. S.C. prepared the radiological images. All authors revised and approved the manuscript for intellectual content.

Consent

Consent was obtained from the patient's next of kin for the inclusion of fully anonymised, non-identifiable patient material.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.