Recurrent craniopharyngioma with extensive necrosis and epithelial reactive changes: Are we facing apoplexy driven by premalignant changes? Two case reports

Pituitary apoplexy is characterized by a sudden increase in pituitary gland volume secondary to ischemia and/or necrosis, usually occurring in the context of pituitary adenoma. Little is known about craniopharyngioma apoplexy. However, some cases have been reported, and it is usually an underused but necessary term in the presence of extensive necrosis and hemorrhage within Craniopharyngiomas. Here, we report two cases of craniopharyngioma apoplexy in a man aged 26 and a woman aged 30 years old, who presented this sellar tumor at an early age, both presenting recurrence and had previously undergone radiotherapy. In the previous recurrence, we observed histological findings related to extensive necrosis, fibrin thrombi, vascular damage and proliferation, inflammation, hemorrhage, fibrin foci, and epithelial reactive changes. Also, we observed pseudostratification, atypia and external epithelium pleomorphism, proliferation of the stellate reticulum with mitotic features as well. Strikingly, by immunohistochemistry, we described the overexpression of β-catenin only in loose cells found the middle of the extensive necrosis areas, displaying a high Ki67 index, found in its punctate form. Both cases showed the same histological pattern. Such findings hadn’t been described in Craniopharyngiomas; we suggest that these are related to apoplexy, post radiation changes or premalignant transformation, reason why this could be termed carcinoma in situ or high-grade intraepithelial lesion. The 2016 WHO classification for CNS tumors update does not consider new features related to malignant transformation occurring in Craniopharyngiomas.


Introduction
The term "pituitary apoplexy" (PA) is an uncommon clinical condition in which a pituitary tumor (PTs) outgrows its blood supply and a stroke overcomes [1], sometimes with considerable, abrupt hemorrhage, leading to a sudden onset of pituitary necrosis and compressive symptoms. PA is considered a neurosurgical emergency. The incidence of PA has been described in up to 10.11% of patients with pituitary macroadenoma (PMA), and in 0.36% of patients with microadenomas [2]. Precipitating factors include increase in intracranial pressure, arterial hypertension, major surgery, anticoagulant therapy, dynamic testing, high altitude, stress, or pregnancy [2]. While PA occurs mostly in adenomas; it has also been described in non-adenomatous sellar lesions including hypophysitis, sellar metastases, especially from Rathke's cleft cyst, sellar tuberculoma and craniopharyngioma [2].
Craniopharyngiomas (CPs) account for 2.5% of all intracranial neoplasms [3]. Regardless of their typical localization in the suprasellar region and adjoining structures, 10-20% of them occupy intrasellar area, but only very few grow as intrasellar cysts [3]. Symptomatic hemorrhage in cystic craniopharyngioma may mimic pituitary apoplexy; nonetheless, etiology is relatively different. Necrosis, hemorrhage and degenerative changes are neither common nor characteristic in CPs, and are usually associated with malignant transformation (MT) [3].
The aim of this paper is to present two unusual cases of aggressive craniopharyngioma that showed necrosis and hemorrhage with reactive epithelial changes that might suggest premalignant histological changes or apoplexy as a differential.

Case 1
A 30-year-old woman presents to the neurological emergency room with epistaxis. She had a history going twelve years back, when at 18 she developed persistent headache, nausea and visual disturbances (right temporal hemianopia). MRI showed a parasellar lesion, so surgical approach was performed. Tumor was removed and histopathological examination revealed an adamantinomatous craniopharyngioma, which corresponds to grade I in the WHO classification system [3]. Subsequently, she undergone radiation therapy and remained asymptomatic for 6 years, though for the following six years she'd be operated six times due to tumor recurrence. She underwent a trans sphenoidal biopsy corresponded to AdaCP by biopsy and last MRI showed extensive tumor infiltrating skull base (Figure 1a). Surgical team performed partial resection of the lesion and intra-operative study was requested, which was reported as a malignant sellar tumor. Cytopathological analysis revealed epithelial cells with prominent nucleoli and some cellular pleomorphism with necrotic background (Figures 1b and 1c).

Case 2
A 26-year-old man diagnosed of craniopharyngioma eleven  years prior to the current moment, having had his first surgery resection was at 15. He was treated with radiotherapy and stayed asymptomatic for 6 years, at 21 he was re-operated, and craniopharyngioma diagnosis kept unchanged. He received radiotherapy again and remained asymptomatic for 3 years. Now, he presented to the emergency room reporting rapidly progressive visual acuity decrease until bilateral amaurosis, intense headache and clinical manifestations of intracranial hypertension. MRI showed a heterogeneous tumor portraying extensive infiltration to the skull base (Figures 1d and 1e), and he underwent surgery again. Histological image changed in respect to the two previous surgeries showing a tumor with extensive necrosis and hemorrhage.

Histopathology
Both cases were initially diagnosed as adamantinomatous CP, and both showed the same histological pattern in the most recent biopsy, which drew our attention due to two particularly characteristic patterns. On the first place, most of the tumor showed coagulative necrosis ( Immunoexpression of p53 and p63 was more intense in the areas of pseudostratified epithelium. Ki67 index was also positive in nuclei, with a punctate appearance (Figure 4f and 4g). Based on the histopathological findings, adamantinomatous craniopharyngioma with extensive necrosis (apoplexy) and reactive changes were diagnosed in both cases.

Discussion
An infrequent complication, sellar region apoplexy has been described in some rare presented cases associated to Rathke's cleft cyst and pituitary adenomas, but this event has not been  deeply analyzed in the context of craniopharyngioma. Clinical manifestations are similar to those found in pituitary tumor apoplexy. Acute headache is the most dominant presentation. Out patients' severe, sudden onset headaches, along with their individual history of CP was highly suggestive of apoplexy, causing intracranial hypertension syndrome, believed to result from the sudden expansion of the mass in the sella turcica, also, there was strong radiologic evidence of hemorrhage and acute hydrocephalus. MRI also indicated large cystic lesions causing mass effect, which was also proven by intraoperative findings before excision. Furthermore, both patients complained of acute visual acuity deterioration. PA is characterized by acute ischemic and/or necrotic infarction, in pituitary adenoma [1,2]. Apoplexy can occur in Rathke's cleft cyst as well as in CP. Clinical manifestations of the patients with RCC apoplexy are similar to those with pituitary tumor apoplexy [2]. Brain imaging is required to identify a sellar lesion which confirms the diagnosis by revealing a heterogeneous, sometimes calcified and cystic tumor with hyperintense (hemorrhagic) and/or hypo intense (necrotic) components [2]. Detailed pathophysiology is not completely understood. However, widely accepted hypotheses consider tumor vascular occlusion due to tumor rapid overgrowth, tumor blood flux reduction and tumoral aberrant vascularization. Other theories postulate acute rise in blood flow due to systemic hypertension or physical activity, reduction of vascular flux caused by surgery, radiotherapy or post intrathecal anesthesia. Molecular evidence shows abnormal expression of VEGF mRNA, coagulation disturbances such as thrombocytopenia or pharmacological anticoagulation, pregnancy, diabetes mellitus, estrogen replacement therapy, dopamine agonist therapy, sickle cell anemia, lymphocytic leukemia and head trauma in an another hang [2,6]. Differential diagnoses include meningitis, subarachnoid hemorrhage, midbrain infarction, cavernous sinus thrombosis, hemorrhagic infarction in a Rathke's cleft cyst and aneurysms [2]. Hemorrhage and necrosis are not common histological findings in CP but the etiology seems to be quite different. Minor hemorrhage may recur unless the cyst wall is totally removed. When CP walls break, the exit of the cholesterol-rich OMF can cause angiogenic, hypoxic effects, vasoconstriction and chemical meningitis, inducing vasospasm [8], inflammatory or thromboembolic complication [9]. Furthermore, radiation-induced vascular abnormalities are considered strong risk factors to malignant transformation and stroke. Early postoperative complications of CPs include evidence of hypothalamic or pituitary iatrogenic injury, hormonal insufficiency, metabolic changes, of seeding [6].
How infrequent is it for CPs, anyway, to undergo malignant transformation? The previous report considered malignant appearance as tumor cells showed moderate to severe pleomorphism, hyperchromatic nuclei, increased nuclear: cytoplasmic ratio, high mitotic activity, focal coagulative necrosis, basement membrane destruction, infiltrative growth doi: 10.7243/2055-091X-7-2 Tena-Suck et al., Journal of Histology & Histopathology 2020, http://www.hoajonline.com/journals/pdf/2055-091X-7-2.pdf and microvascular proliferation. The malignant phenotypes that have been reported in CP are the following: squamous cell carcinoma, odontogenic ghost cell carcinoma, low-grade myoepithelial carcinoma, one case amelomeloblastic carcinoma and basaloid type carcinoma. In situ carcinoma is a rare event described in CPs. The mechanisms for CP malignant transformation are still unknown. So far, these are the first reported couple of craniopharyngioma apoplexy cases with the association of radiotherapy-induced malignant transformation, and it adopts a wide arrange of histological appearances [10]. Time intervals of transformation from primary tumor to malignancy ranged from 1.2 to 35 years (average 9.7 years) in the different cases reported [10]. However, it is necessary to consider and to be prudent when differentiating radionecrosis from tumor recurrence, which represents a major issue in neurooncology.
In our cases we observed necrosis and hyalinized, glomeruloid appearance of the wall of the vessels, which has also been reported elsewhere [7]. Definitive diagnostic criteria for malignant craniopharyngioma have not been established. In this case, we could consider that the radionecrosis does not persist for more than 10 years and necrosis observed in our patient is a recent event. In these cases, not only did we see necrosis, but also abundant vessels, fibroblast proliferation, epithelial cell detritus, wet keratin, many ghost cells in the areas of necrosis and epithelial changes in cystic structures. Although these changes have not been described as premalignant changes or perhaps consider calling them as a low-grade intraepithelial lesion or just call them secondary to necrosis reactive changes. Noteworthy, we observed an increase of Ki-67, p53, and p63 immunostaining in the pseudostratified epithelium areas. This punctate pattern of Ki67 represents an interesting finding that had not been notified in Craniopharyngiomas, and its positivity indicates nucleolar activity in these same areas, which may be indicative of incipient malignant changes, and they do not correspond to necrotic nor apoptotic changes. Furthermore, transoperative cytopathological analysis showed prominent nucleoli and atypical cellular changes were appreciated and, as mentioned, these are unusual in CP. Such findings may arise whether from the mere disease mechanisms or from the effects of treatment. Intracystic bleomycin (ICB) administration represents an effective treatment strategy for cystic craniopharyngioma and rarely causes serious complications. The authors report a case of vasculopathy after ICB injection for a recurrent cystic CRP. Conventional factors that increase the risks of cardio-and cerebrovascular diseases and DM and risks for developing new intracranial tumors contributed to excess morbidity and mortality. Comorbidities such as diabetes and cardiovascular and cerebrovascular disease, as well as risks for developing new intracranial tumors contributed to excess morbidity and mortality. These studies have identified increased risk of cerebrovascular disease, including stroke and Moya-Moya syndrome. A thromboembolic origin is suggested to originate this unusual event, due to the evidence shown by studies showing inflammatory vascular involvement after an episode of aseptic meningitis.
Aberrant vascular development was described as an increase in the number and density of abnormal vessels characterized by fibroblastic proliferation and hyalinization of the wall, extensive necrosis, thrombosis and epithelial changes. Thus, we posed ourselves the question whether these findings were caused by post radiation therapy changes, radionecrosis, or if it corresponded to a spontaneous necrosis secondary to malignant transformation, or whether it corresponds to a stroke, in a persistent tumor. The aberrant membranous β-catenin expression has been correlated to poor survival in patients with craniopharyngioma, as an independent risk factor in predicting the prognosis of this disease [12].
According to the 2016 WHO classification of CNS tumors update, there are no changes related to the malignant transformation of the CPs and maybe it would be like nonendocrine sellar tumors and as other tumors arising in the sellar region [13].

Conclusion
Craniopharyngioma is rarely associated to intratumoral hemorrhage and extended necrosis. CP apoplexy is a vascular condition which may be consequence of the interaction between high relapse incidence and radiation therapy. Here, we reported rare and overlapped morphological, clinical and immunohistochemical features of highly recurrent CP, such synergistic coexistence created a clinical condition difficult to diagnose and manage. We are unaware whether the extensive necrosis and intraepithelial reactive changes are enough evidence to postulate that molecular findings and histological patterns are those of low grade intraepithelial lesion, though its highly aggressive behavior, along with its particularly elevated recurrence rate, may support its inclusion into the definition of malignancy. We hope that our detailed cases will prove to be helpful in further founding the diagnostic criteria and evaluation of biological behavior and pathophysiological mechanisms for malignant transformation.