Primary Central Nervous System Lymphoma of the Cerebellopontine Angle: Epidemiological Characteristics and Imaging Features may be Helpful for Making an Accurate Preoperative Diagnosis

Purpose Primary central nervous system lymphoma (PCNSL) of the cerebellopontine angle (CPA) is rare, thus the preoperative diagnosis is still a challenge. Methods We searched the database at our institution and performed a search of English literature in PubMed and Google Scholar. Keywords used were as follows: “primary central nervous system lymphoma”; “cerebellopontine angle”; “lymphoma”. Only cases in the English language that were located in the CPA and contained adequate clinical information pertinent to the analysis were included. Results 297 cases of pathologically conrmed PCNSLs were recorded between January 2009 and October 2020 at our institution. 6 cases were located in the CPA, accounting for 2.0% of all PCNSLs. 26 cases meeting the above criteria were found in the literature. Including ours, a total of 32 patients were analyzed. Females were more frequently affected (F/M ratio, 2.2:1). There was a preponderance of left-sided lesions in the PCNSLs of the CPA (L/R ratio, 1.5:1). On CT, 80.0% of them presented as hyperdense lesions. On T1-weighted image, 66.7% appeared isointense. While on T2-weighted image (T2WI), 68.4% appeared isointense/hypointense. After contrast administration, 86.2% presented intense homogeneous enhancement.


Materials And Methods
The neurosurgical database at the Second A liated Hospital of Zhejiang University School of Medicine, was searched for all surgical cases of primary central nervous system lymphomas between January 2009 and October 2020. A retrospective chart review was then performed with research ethics board approval. The age, sex, image presentation, location, preoperative diagnosis, surgical management and pathological examination were recorded.
All patients underwent computed tomography (CT) or magnetic resonance imaging (MRI) for diagnosis and surgical planning. Postoperative clinical information and neuroradiological presentation were evaluated.
Additionally, for the review, a search was conducted of the English literature in PubMed and Google Scholar for every case report, series, letter to the editor, original article and literature review related to PCNSL of the CPA. In addition, the reference lists of the obtained articles and previous reviews were examined. Keywords used were as follows (single word or combination): "primary central nervous system lymphoma"; "cerebellopontine angle"; "lymphoma". Only cases in the English language that were located in the CPA and contained adequate clinical information pertinent to the analysis were included.

Statement of human and animal rights
All procedures performed involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal patient consent is not required. Ethical approval for this study was obtained from the Ethics Committee of the Second Affiliated Hospital, Zhejiang University School of Medicine (ID: 0182/2021).

Results
Two hundred and ninety-seven cases of pathologically con rmed primary central nervous system lymphoma were recorded between January 2009 and October 2020 at our institution. Six of them were located in the CPA, accounting for 2.0% of all PCNSLs in the present study. They comprised two men and four women with an average age of 60.8 years (range 51-69 years). Headache and vomiting were the most common presenting symptoms, and were seen in four cases. Other symptoms and signs included hearing loss, dizziness, dysphagia, hoarseness, facial palsy and facial hypoesthesia. PCNSL of the CPA was frequently found on the left than on the right side (L/R ratio, 2:1). In two patients, tumors were resected via suboccipital retrosigmoid craniotomy. In the other four patients, stereotactic biopsy was performed.
The English medical literature in the PubMed and Google Scholar databases was reviewed, and 26 cases of CPA PCNSLs meeting the above-mentioned criteria were included. The characteristics of the 26 cases were summarized in Table 1. Including our six patients, a total of 32 cases were analyzed. The reported age range was between 21 and 82 years, with a median age of 56.5 years. Females were more frequently affected (F/M ratio, 2.2:1). Regarding the locations of PCNSLs of the CPA, 18 cases (56.3%) were in the left side, 12 cases (37.5%) were in right side, and 2 cases (6.3%) were bilateral. The most frequent initial symptom of CPA PCNSL was hearing disturbance (64.5% of all the patients), and cerebellar signs (ataxia and unsteady gait) were the second most common symptom (41.9% of all the patients). Facial palsy, headache and vomiting were also common symptoms.
Cerebrospinal fluid (CSF) cytology was used to diagnose pathologically in one patient. One patient was diagnosed at autopsy. Most of the preoperative diagnoses were schwannoma and meningioma, other preoperative diagnoses included metastatic tumor, hemagioma and tuberculosis meningitis. Only three cases were accurately diagnosed preoperatively. Diffuse large B-cell lymphoma was the most common type of PCNSLs of the CPA. Routine hematological parameters including tumour markers were within normal limits, and the serology tests for HBV, HCV, and HIV were negative.
CT scan revealed a slight hyperdense mass in the left CPA (Fig. 1). No adjacent bony abnormality was present.
The lesion was isointense on T1WI and T2WI (Fig. 2a, b). The fourth ventricle and adjacent brainstem were mildly compressed by the lesion. Perifocal edema was detected on the T2WI (Fig. 2b). Contrast-enhanced MRI demonstrated a well-enhanced mass lesion in the left CPA, extending into the left internal auditory canal (Fig. 2ce). FDG-PET/CT examination showed an intensely hypermetabolic lesion in the left CPA (Fig. 3), thus excluding the possibility with systemic tumor. Lumbar puncture was performed, CSF analysis revealed an increased protein level (protein 321.8 mg/dL), with a normal glucose level and a pleocytosis with a preponderance of lymphocytes (98% lymphocytes). Additionally, CSF IgG was signi cantly elevated (377.0 mg/L). No bacteria, acid-fast bacilli, or fungal organisms were seen on smears or cultures. CSF cytology revealed no malignant cells. On the basis of these imaging ndings, a malignant pathology such as high-grade glioma, metastatic tumor or lymphoma were considered preoperatively. We recommended craniotomy or stereotactic biopsy with pathological examination.
Finally, the patient and his family chose stereotactic biopsy. No steroid treatment before the surgery was provided.
Stereotactic biopsy was carried out to obtain tumor tissue. The frozen section was suggestive of a lymphoma.

Haematoxylin and eosin (H&E) staining showed diffuse in ltration of large anaplastic cells with irregular nuclei
and scanty cytoplasm, with frequent mitoses and apoptosis (Fig. 4a). The immunohistochemical study yielded positive results for CD20 and CD79a, and negative results for CD3, CD43 and glial fibrillary acidic protein (GFAP) (Fig. 4b). These findings were compatible with primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system.
Postoperatively, the patient's hearing loss and facial palsy were unchanged and no additional neurological deficits were developed. He was then transferred to the hematology department for chemotherapy.

Discussion
Primary central nervous system lymphoma is a rare and aggressive extranodal non-Hodgkin lymphoma that restricted entirely to the brain, leptomeninges, spinal cord or eyes, without systemic involvement [28,33]. PCNSL accounts for approximately 1-4% of all primary brain tumors [32,40], but its incidence has been increasing over the past 20 years in both immunocompetent and immunocompromised individuals [14,36]. Diffuse large B-Cell Lymphomas are the most common type (~90%), while the remaining 10% are poorly characterized by Burkitt's lymphomas, T-Cell lymphomas and low-grade lymphomas [5,12,15,33]. PCNSL most commonly locates in the cerebral hemispheres (38%), thalami/basal ganglia (16%), corpus callosum (14%), periventricular region (12%), or cerebellum (9%) [21,25], while it rarely occurs in the CPA. We reviewed 32 cases of PCNSLs of the CPA, including the reported cases in the English literature and six patients in our hospital, trying to gure out the accurate preoperative diagnosis of this rare disease. Given that CPA PCNSLs can be very non-specific with the presenting symptoms, accurate preoperative diagnosis of the lesion is mainly based upon imaging. On computed tomography (CT) scan, PCNSLs of the CPA generally present as hyperdense lesions with homogenous enhancement after contrast administration [12,22,28,32]. Bony erosion and expansion of the internal auditory canal is rare in the PCNSL of CPA, which can be differentiate from acoustic neurinoma [28]. In the present study, we found that 80.0% of all the CPA PCNSLs presented as hyperdense lesions on CT scans. On MRI, PCNSLs of the CPA are typically homogeneously isointense on T1WI [19,36,38], and homogeneously isointense/hypointense with mild perifocal edema on T2WI [11,28,32]. After contrast administration, they show an intense homogeneous enhancement [22,35]. In a review of the MRI appearance of CPA PCNSLs in the present study, 66.7% appeared isointense on T1WI, and 68.4% appeared isointense/hypointense on T2WI. After contrast administration, 86.2% presented an intense homogeneous enhancement.
Accurate preoperative diagnosis of CPA PCNSLs can be very di cult due to the rarity and clinical similarities to other common CPA tumors. However, increasing experience with CT and MRI studies allow greater accuracy in the preoperative differential diagnosis [10]. The common differential diagnosis includes schwannoma (70%-90%), meningioma (5%-10%), epidermoid cyst (5%-7%), metastatic tumors and glomus jugulare tumors [2,6,10,11,19,21]. Kendall et al analyzed 208 cases of CPA tumours and found bony erosion of the internal auditory canal in 98 cases on CT scan, with 93.9% of the of these being acoustic neuromas [24]. However, bony erosion and expansion of the internal auditory canal is rarely observed in CPA PCNSLs, which can be differentiate from acoustic neurinomas [28]. Characteristic T2-wighted MRI may play an important role in the preoperative differential diagnosis [11,28,38]. In the present study, we found that 68.4% of all the CPA PCNSLs appeared as isointense to hypointense on T2WI, which is in contrast to most other CPA lesions [16,32]. This signal intensity is attributable to the high cellularity and high nuclear to cytoplasmic ratio of the PCNSL, which also correspondingly explains the high signal intensity of PCNSLs usually observed on diffusion-weighted imaging (DWI) [3,32]. In our study, we found that only three case were accurately diagnosed preoperatively, and all the three cases were identi ed at our institution. The accurate preoperative diagnosis is mainly because of the accumulated experience from the previous surgery cases of CPA PCNSLs.
When PCNSL of CPA is suspected by CT/MRI, conclusive diagnosis should be made by histological or cytological examination of tumour [12,22,27]. CSF sampling by lumbar puncture can be performed at the time of initial assessment [12,22]. If CSF cytology is successful to establish a de nitive diagnosis of malignant lymphoma, surgery can be avoided [7,22]. However, the positive rate of CSF cytology is low. Balmaceda et al. reported that the initial CSF cytological studies were positive in only 15% [8]. Serial CSF samples may result in increased diagnostic sensitivity [12]. If CSF cytology failed to con rm the diagnosis, tumor excision or biopsy should be performed. The aim of the surgery is to obtain a frozen section of CPA PCNSL during surgery [19,37]. Since radical tumor resection has no advantage on survival and may cause more neurologic de cits, radical decompression should be discouraged [19,36,37]. It is advisable to proceed with stereotactic biopsy for brain lesions with a radio-graphic appearance consistent with PCNSL [15]. Once the diagnosis of CPA PCNSL is established, more effective treatment should be delivered. However, the optimal treatment of PCNSL has yet to be de ned [15]. High-dose methotrexate (HD-MTX)-based induction chemotherapy is considered standard for newly diagnosed PCNSL [15].
Through review of the literature and our cases (Tables 1, 2), CSF cytology was used to diagnose pathologically in only one patient, tumor resection was performed in 80.6% of the patients, and stereotactic biopsy was achieved in only 13.8% of the patients.

Conclusion
In conclusion, PCNSL of CPA is extremely rare lesion, accounting for 2.0% of all PCNSLs in the present study.
There is a preponderance of females and left-sided lesions in the PCNSLs of CPA. Contrast-enhanced MRI with T2WI is very helpful in the preoperative diagnosis of the CPA PCNSL. Although rare, lymphoma should be included in the differential diagnosis of CPA lesions.    a Hematoxylin and eosin staining (magni cation ×200) showed diffuse in ltration of large anaplastic cells with irregular nuclei and scanty cytoplasm, with frequent mitoses and apoptosis. b CD-20 immunohistochemistry staining (magni cation ×200) demonstrating positivity.