Table 1.
Recommendations.
| Clinical overview recommendations | Strength | |
| Rec. 1 | Life expectancy in schwannomatosis is not usually affected, unlike NF2. Pain is a prominent feature, especially for people with a LZTR1 germline pathogenic variant. | Strong |
| Rec. 2 | A changing tumour, in someone with SMARCB1 germline pathogenic variant, especially one causing functional impairment, should prompt exclusion of malignant transformation. | Strong |
| Rec. 3 | LZTR1 germline pathogenic variant is associated with higher risk of unilateral vestibular schwannomas; therefore these tumours should not be considered an exclusion criterion for the diagnosis of schwannomatosis. | Strong |
| Diagnosis recommendations | Strength | |
| Rec. 1 | Germline pathogenic variant in SMARCB1 or LZTR1 should be considered diagnostic of schwannomatosis in the presence of someone with a proven schwannoma. | Strong |
| Rec. 2 |
Where possible, analysis of two tumours should be performed in sporadic cases to confirm or refute mosaic NF2. Schwannomatosis is characterised by multiple tumours harbouring independent somatic pathogenic variants in the NF2 gene which are not present in their constitutional DNA. |
Strong |
| Rec. 3 | Baseline investigations to confirm schwannomatosis should include brain and internal auditory meati MRI with at least 3 mm and preferably ≤1 mm cuts through the internal auditory meatus to rule out bilateral vestibular schwannomas (NF2). | Moderate |
| Rec. 4 | In people in whom schwannomatosis is clinically suspected and without germline pathogenic variants in SMARCB1 or LZTR1, and without the diagnostic characteristics of NF2, RNA testing should be considered (for instance, for deep intronic SMARCB1 variant associated with schwannomatosis). Due to the increased malignancy risk in schwannomatosis associated with SMARCB1 this additional step is important as when found it allows confirmation of the diagnosis and the ability to offer pre-symptomatic testing to relatives. | Moderate |
| Rec. 5 | In people with schwannomatosis at reproductive age or at transition, a discussion of the likely risks of transmission to offspring and the options for testing in pregnancy and pre-implantation diagnosis should be undertaken. | Strong |
| Rec. 6 | Affected people and at-risk offspring should be told the risk of transmission is 50% in those with germline inherited variants. In those isolated cases with no family history with negative testing of LZTR1 and SMARCB1 the transmission rate is <10%. Reduced penetrance in LZTR1 should be discussed. | Strong |
| Imaging recommendations | Strength | |
| Rec. 1 | For tumour surveillance or screening MRI should be used. PET scanning should not be used for diagnosis or surveillance of schwannomas. | Moderate |
| Rec. 2 | A baseline assessment including full craniospinal MRI and/or whole-body MRI should be carried out as soon after diagnosis as the MRIs can be conducted without general anaesthetic (typically late childhood; 12–14 years) and should be repeated in early adulthood or if symptoms evolve. | Moderate |
| Rec. 3 | The frequency of repeat MRI should be determined by clinical judgement guided by the presence of changing symptoms. | Moderate |
| Rec. 4 | It is expected that routine repeat MRI are conducted at intervals of 2–3 years. More frequent MRI should not be conducted unless the person’s symptoms change. | Moderate |
| Rec. 5 | In patients with localised pain and/or associated neurologic focal deficit, without an obvious schwannoma localised MRI should be performed using thin slices (<3 mm) in order to detect very small but functionally significant schwannomas. | Moderate |
| Rec. 6 | For targeted investigation of pain, ultrasound (in the hands of someone experienced at imaging schwannomas) may be a useful problem-solving modality. | Weak |
| Genotype specific imaging surveillance Recommendations Please consider all recommendations in imaging recommendations. | Strength | |
| Rec. 1 | SMARCB1: the following baseline investigation should be performed at diagnosis: MRI brain and spine, and whole-body MRI. | Moderate |
| Rec. 2 |
LZTR1: the following baseline investigation should be performed at diagnosis: (1). High-resolution brain MRI with fine cuts (<3 mm) through the internal auditory canal and spine MRI (2). Whole body MRI. * *Note people with LZTR1 pathogenic variants detected incidentally with no personal or family history of schwannomas and no pain or other schwannoma symptoms should not undergo MRI imaging to detect schwannomas as their risks are likely well below 1%. |
Moderate |
| Rec. 3 | If tumours are present at baseline MRI imaging, imaging should be repeated every 2–3 years, unless there is a change in symptoms or if tumours are present on brain imaging in which case an MRI at 12 months is indicated. Small (<1 cm) asymptomatic non-CNS tumours detected on whole body MRI particularly in the limbs may not require repeat imaging if no symptoms or signs develop. | Moderate |
| Rec. 4 | If there is a change in symptoms, localised MRI should be performed according to clinical manifestations, and should be repeated at an increased frequency as determined by the clinical presentation. | Moderate |
| Annual clinical assessment recommendation | Strength | |
| Rec. 1 |
At each review visit there should be: • Full assessment of pain history • Full neurological examination • Assessment of Quality of Life using a recognised tool e.g. EQ-5D • Assessment of psychological needs of the patient |
Strong |
| Non-surgical pain management recommendations | Strength | |
| Rec. 1 | Multidisciplinary pain management focusing on symptom management and targeting pain related disability using a bio-psychosocial approach should be used. | Moderate |
| Rec. 2 | Radiotherapy is likely to increase the risk of malignant transformation in people with schwannomatosis. Radiotherapy should only be considered in growing schwannomas that cannot be treated surgically or by other therapies. | Strong |
| Rec. 3 | Painful schwannomas have a significant neuropathic component, drugs such as tricyclic antidepressants and gabapentinoids should be used first line, and SSRI or other ASD (Topiramate, Carbamazepine, Oxcarbazepine) second line. | Moderate |
| Rec. 4 | Chronic use of opioids is not recommended due to their poor effect on neuropathic pain and associated tolerance, dependency and hyperalgesia. | Strong |
| Rec. 5 | Transient Receptor Potential Vanilloid 1 (TRPV1) antagonists [capsaicin and some cannabinoid receptor ligands] may be effective in intractable pain because of Schwann cell expression of nerve growth factor. | Weak |
| Surgical intervention recommendations | Strength | |
| Rec. 1 | For those with painful schwannomas, if surgery is possible without neurological deficit, then early surgical intervention should be offered. | Strong |
| Rec. 2 | If surgery is performed on symptomatic schwannomas, it should be by surgeons with experience resecting nerve sheath tumours. | Strong |
| Rec. 3 | Some lesions are not surgically removable, and operations are linked to increased morbidity. So, assessment of the likelihood of success and the risks of neurological deficit should include assessment by a surgeon with significant experience resecting nerve sheath tumours | Strong |
| Rec. 4 | The use of intraoperative neurophysiological monitoring should be considered and is essential for surgery on critical nerves. | Moderate |
| Rec. 5 | If surgery fails to relieve local pain or symptoms, repeated surgeries to the same symptomatic area should be avoided as they offer diminishing benefit to pain control and may contribute to worsening of the schwannomatosis pain syndrome. | Moderate |
| Rec. 6 | Use of spinal cord stimulation is an emerging therapeutic option and should be considered by multidisciplinary teams on an individual basis. | Weak |
| Non-surgical intervention recommendation | Strength | |
| Rec. 1 | Bevacizumab probably should be actively considered along with all other treatment options in the multidisciplinary team review, specifically in patients with multiple rapidly enlarging tumours, which are symptomatic in terms of pain and/or neurological deficit, and for those which are inoperable. | Weak |