Approach to von Hippel Lindau, Cowden disease, and other inherited conditions

Case. An adult female presents on referral for gait instability. She was diagnosed with vHL disease as a teenager. Her mother also had vHL but she has no other siblings with the disease. She has multiple hemangioblastomas of the central nervous system (CNS) including both the brain and spinal cord. Over the years, she has undergone multiple craniotomies including suboccipital craniotomy and spinal laminectomies, as well as Gamma Knife stereotactic radiation treatments, for management of these hemangioblastomas. In addition, she has had renal lesions and undergone bilateral radiofrequency ablations for multiple renal cell carcinomas. Several years ago she was found to have an enlarging pancreatic cyst that required a distal pancreatectomy and splenectomy. She is blind in the right eye due to complications from a retinal hemangioblastoma. After spinal surgery for tumor resection at T11 1 year ago, she reports that she has never regained full feeling in her legs and has persistent gait imbalance, near falls, and reduced sensation in her lower extremities. Imaging of her cerebellar and spinal cord shows stable residual hemangioblastomas without fourth ventricular compression or evidence of radiographic progression.

Teaching Points. vHL is tumor-predisposition syndrome characterized by neoplasms of the nervous system, kidneys, and other organs. This case highlights a number of key features of vHL including the (1) neurological manifestations which include hemangioblastomas of the cerebellum, spinal cord, and retina; (2) that management of vHL-associated tumors requires coordination across a multidisciplinary treatment team; and (3) that neurological complications of these tumors and their treatment contribute to patient morbidity.

Cerebellar, spinal, and retinal hemangioblastomas are the most common nervous system manifestations. Extranervous features including renal cysts, clear-cell renal cell carcinoma (RCC), pheochromocytoma, endolymphatic sac tumors, epididymal cystadenomas, and broad ligament cystadenomas. Cerebellar hemangioblastomas are benign, slow-growing, highly vascular, cystic WHO grade I neoplasms. They rarely occur sporadically, and approximately 30% of patients who present with such a lesion will have vHL. In vHL, cerebellar hemangioblastomas tend to be multiple and present at a younger age (mean age 33 years) compared to sporadic cerebellar hemangioblastomas (mean age 43 years).

As in this case, management of vHL-associated tumors is best conducted by a multidisciplinary team familiar with this condition including a neurosurgeon, radiation oncologist, geneticist, urologist, gastrointestinal or general surgeon, and ophthalmologist among others. When CNS lesions are symptomatic or growing rapidly, surgery is the treatment of choice. Lesions that cannot be completely resected or are not amenable to surgery are often treated with radiation therapy. Research on the efficacy of nonsurgical interventions such as systemic therapy (e.g., vascular endothelial growth factor [VEGF] and fibroblast growth factor receptor inhibitors) is promising; however, these treatments are not currently approved for use. ^,

Neurological complications of these tumors and their treatment are not uncommon and may include symptoms arising from (1) direct compression of the tumor on surrounding structures (e.g., myelopathy, cerebellar dysfunction, increased intracranial pressure, or vision loss), (2) side effects of treatment (e.g., stroke, intracranial hemorrhage, CNS infection), or (3) a combination of these. Fortunately, the risk of spontaneous intracranial hemorrhage from the cerebellar tumor is low.

Von Hippel Lindau Disease. vHL is an autosomal dominant tumor syndrome affecting 1 in 31,000 live births. Patients are predisposed to multiorgan cystic and neoplastic lesions of the kidneys, spinal, cerebellum, and other organs. Both benign and malignant tumors may occur. The VHL gene is a tumor suppressor gene located on chromosome 3p25. This gene encodes the von Hippel Lindau protein (pVHL), which is a chaperone protein that ushers two important cytoplasmic transcription factors, hypoxia-inducible factors 1 alpha and 2 alpha (HIF1a and HIF2a) to the proteasome for degradation. HIF1a and HIF2a participate in the cellular response to hypoxia. When active, they increase expression of genes involved in cell proliferation and angiogenesis including transforming growth factor (TGF)-alpha, VEGF, and platelet-derived growth factor (PDGF)-beta. HIF1a and HIF2a also play an important role in erythropoietin (EPO) regulation. In vHL patients, loss of pVHL results in the inability to degrade HIF1a and HIF2a, which leads to activation of pro-growth pathways and tumor formation.

Neurologic Manifestations

Hemangioblastomas are the most common tumor in patients with vHL and are seen in 60–84% of cases. These are benign, highly vascular tumors that do not metastasize or invade surrounding tissue. On neuroimaging, they appear as cystic enhancing lesions often with a cyst with mural nodule appearance on T1-weighted gadolinium enhanced sequences ( Fig. 18.1A ). Tumors are frequently scattered throughout the cerebellar cortex. In the spine, spinal hemangioblastomas avidly enhance but may lack a clear cystic component ( Fig. 18.1B ). These lesions can hemorrhage or compress neighboring structures resulting in morbidity and rarely mortality. Although they commonly occur in the cerebellum and spinal cord, clinicians should be aware that they may also develop in the retina and contribute to vision loss.

Retinal capillary hemangioblastomas in vHL are often multiple, bilateral, and can cause vision impairment or blindness due to retinal traction and/or detachment, retinal edema, and glaucoma. They are present in up to 70% of vHL patients by age 60 years. Because of the high prevalence, any patient presenting with a retinal capillary hemangioblastoma should receive genetic testing for vHL germline mutations, and patients with vHL should undergo routine ophthalmologic examination for surveillance. First-line treatment for these lesions includes laser photocoagulation and cryotherapy. Typically, these lesions require only one treatment, as the success rate is approximately 70%. Other treatment options include photodynamic therapy, external beam radiotherapy, and surgical resection.

Evaluation of hemangioblastomas is best conducted by a team familiar with this syndrome. Studies have shown that about half of hemangioblastomas do not grow during a patient’s lifetime and can be observed with surveillance imaging. Asymptomatic patients are often followed clinically and with brain MRI with and without contrast every 2–3 years. In the remaining patients, growth can be step-wise, linearly, or exponential, and thus monitoring with imaging is important to determine the growth trajectory to guide treatment decisions.

Case. A healthy woman presents for evaluation of 1 year of progressively worsening headaches. She was initially diagnosed with a ganglioneuroblastoma of the spine and base of the brain as a child and treated with chemotherapy. Later, she was found to have a thyroid goiter and diagnosed with Graves disease, for which she underwent a thyroidectomy. Additional cancers include prior diagnosis of endometrial cancer, for which she underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. About 1 month ago she underwent a colonoscopy for abdominal pain and was found to have multiple polyps in the proximal transverse colon. Biopsy was negative for adenomatous epithelium. There is a strong family history of early-onset cancer, including breast cancer in her mother and grandmother and colon cancer in an uncle, all prior to age 40 years. She was recently referred to genetic counseling and underwent genetic testing showing a pathogenic mutation in the PTEN gene, and she was diagnosed with Cowden syndrome/PTEN hamartoma tumor syndrome. Following evaluation, the patient was referred for brain MRI with and without contrast, which revealed a hyperintense lesion on T2-weighted and fluid- attenuated inversion recovery (FLAIR) sequences that was consistent with a dysplastic gangliocytoma of the cerebellum.

Teaching Points. Cowden syndrome is a rare autosomal dominant disorder affecting 1 in 250,000 live births. The syndrome results from germline mutation in the phosphatase and tensin homolog ( PTEN ) gene on chromosome 10 (10q22-23). This case highlights several important principles for clinicians who encounter patients with Cowden syndrome including: (1) the importance of being familiar with tumors associated with this syndrome so that prompt genetic counseling referral can be made, and (2) the association with dysplastic gangliocytoma of the cerebellum.

Cowden syndrome is associated with a variety of benign and malignant tumors. Neurologic manifestations in Cowden syndrome frequently include benign CNS tumors such as men ingiomas, macrocephaly, heterotopias, vascular abnormalities, and developmental delay. Extranervous manifestations include tumors of the skin and mucous membranes, breast, thyroid, genitourinary tract, gastrointestinal tract (including tumors and polyps in the stomach and colon), and defects in immune function.

The most common CNS neoplasm is the dysplastic gangliocytoma of the cerebellum which, when present, is known as Lhermitte-Duclos disease (LDD). In adults, LDD is pathognomonic for Cowden syndrome. LDD is characterized by the presence of benign, slow-growing hamartomatous enlargement of the cerebellar folia. The majority of patients present with slowly progressive cerebellar ataxia, elevated intracranial pressure due to fourth ventricular compression, or headache, as was present in this patient’s case. Imaging shows non-enhancing enlargement of the cerebellar cortex that often has a striated or tiger-striped appearance on T2-weighted imaging sequences. Given the progressive nature of this lesion, asymptomatic patients should be followed with serial imaging. Symptomatic patients are considered for surgical resection. Radiotherapy is often delayed until recurrence.