Internal Medicine: Day 29

Tuesday was the longest day in clinic ever. My scheduled 9-12 turned into a nonstop 9-7, which meant that my lunch I quickly and sneakily had at 5pm consisted of this:

I got home after work and felt like I needed to eat a stick of butter to make up for not eating all day. I was actually so hungry that I nearly passed out in clinic (irony - I have been working in a syncope clinic). After I turned pale and then diaphoretic, my attending allowed me to leave. I thought the days of long hours without any lunch were for the surgery clerkship?!



I will be presenting my first case report tomorrow morning, and it is about a hereditary disease called von Hippel-Lindau. If you're a Grey's Anatomy fan, you might recognize this disease as Henry was diagnosed with it (he also had the associated pheochromocytoma and neuroendocrine pancreatic neoplasms).

In case you are interested, here's the report (any possible patient identifiers have been modified to protect privacy):

XQ is a 41 year old African American female seen in the Cancer Center Clinic for genetic counseling and testing regarding von Hippel-Lindau. XQ was diagnosed with Clear Cell Renal Cancer a few months prior to her encounter at our clinic. For this, she underwent a Davinci-assisted right nephrectomy, with a biopsy which showed Renal Cell Carcinoma, Clear Cell Type, Grade 2, 3.5cm (multifocal), limited to kidney with negative margins. With localized disease, surgical resection is considered curative. XQ also has a history of brain hemangiomas, cervical spine cysts, and anxiety. Family history is significant for Renal Cancer in her mother; pathological records are to be obtained from the corresponding hospital. XQ’s most recently obtained vital signs are as follows: BP = 126/71, HR = 117, T= 98.2F, BMI = 20.2. 

Assessment:      Clear Cell Renal Cancer

                                Von Hippel-Lindau

Discussion:         

Von Hippel-Lindau (VHL) is an inherited, autosomal dominant syndrome manifested by a variety of benign and malignant tumors. The prevalence of this genetic disorder is approximately 1:36,000.  The manifestations of VHL may occur at any time during life, with an average age of initial presentation of 26 years. These manifestations of VHL-associated tumors include hemangiomas of the cerebellum and spine, retinal angiomas, clear cell renal cell carcinomas, pheochromocytomas, endolymphatic sac tumors of the middle ear, serous cystadenomas and neuroendocrine tumors of the pancreas, and papillary cystadenomas of the epididymis and broad ligament. There are two types of VHL disease. Type I disease have a substantially lower risk of developing pheochromocytomas, although they are at high risk for other VHL-associated lesions. The most common mutations in Type I include nonsense and frameshift mutations. Type II disease are at high risk for developing pheochromocytoma, and are again subdivided into groups based upon the risk of developing renal cell carcinoma. The most common types of mutations in Type II disease is missense mutation.

The pathogenesis of VHL has been mapped to chromosome 3p25, whose gene product (pVHL) functions as a tumor suppressor protein. As such, VHL is a “two-hit” disease in which a germline mutation inactivates one copy of the VHL gene in all cells followed by a loss of expression of the second, normal allele through either somatic mutation or deletion of the second allele, or through hypermethylation of its promoter.  The pathogenesis of pVHL is that it normally targets several proteins for proteasomal degradation, thus regulating their levels within the cell. pVHL also forms a stable complex as well as also functioning as a receptor for target molecules which covalently bind to ubiquitin, which facilitates degradation by proteasomes. In tumor tissues, both copies of the gene are inactivated, and proteasomal degradation does not occur as normal. A major protein which is regulated by pVHL is Hypoxia-inducible factor-1 (HIF-1), which induces transcription of mRNA coding for erythropoietin and other growth factors, thus resulting in the production of abnormal factors which would normally be produced during conditions of physiologic hypoxia. HIF-1 also induces a physiologic angiogenic response, which is theorized to create an autocrine loop which provides an uncontrolled growth stimulus consistent with highly vascular CNS tumors found in VHL patients.

Diagnosis is based upon clinical suspicion followed by detection of a germline mutation in the VHL gene via genetic testing. Genetic testing is typically performed on peripheral blood leukocytes, with DNA sequencing and qualitative as well as quantitative Southern blot analysis of the VHL gene. The sensitivity and specificity of these methods is near 100%.  Rarely, a patient may have the clinical features of VHL without a detectable mutation, attributed to mosaicism for the VHL mutation. Patients suspected of having VHL disease should be referred to specialized centers for genetic counseling. The criteria are summarized in Table 1 below.

Table 1: Criteria for referral to Massachusetts General Hospital VHL Clinic:

                Any blood relative of an individual diagnosed with VHL disease

                Any individual with TWO VHL-associated lesions:

                                Hemangioblastoma
                                                Clear cell renal carcinoma

                                Pheochromocytoma

                                Endolymphatic sac tumor

                                Epididymal or adnexal papillary cystadenoma

                                Pancreatic serous cystadenoma

                                Pancreatic neuroendocrine tumors

                Any individual with ONE or more of the following:

                                CNS Hemangioblastoma

                                Pheochromocytoma or paraganglioma

                                Endolymphatic sac tumor

                                Epididymal papillary cystadenoma

                Any individual with:

                                Clear cell renal carcinoma diagnosed at age <40 years

                                Bilateral and/or multiple clear cell RCCs

                                >1 Pancreatic serous cystadenoma

                                >1 Pancreatic neuroendocrine tumor

                                Multiple pancreatic cysts + any VHL associated lesion

Surveillance strategies are an important part of caring for individuals with VHL, which allows for the detection of small, asymptomatic tumors before the development of metastasis or other complications arise.  Surveillance has focused primarily on the three manifestations which most often result in severe disability or death: hemangioblastomas, renal cell carcinomas, and pheochromocytomas. The recommendations for each patient vary in response to the presence of previously diagnosed asymptomatic disease as well as disease manifestations in other members of the family. There is some controversy regarding how best to screen VHL patients; a suggested protocol is listed below, in Table 2.

Table 2: A Proposed Surveillance Protocol for VHL Patients

                Infants and children up to age 11: Annual examinations including:

                                Retinal examination including dilation of pupils for retinal angiomas

                                Plasma catecholamines (epinephrine, norepinephrine, metanephrine,

normetanephrine, and DOPA) for pheochromocytoma

                Adolescents ages 11-19: Annual examinations listed above plus:

                                Ultrasound of abdomen (kidney, pancreas, and adrenals)

                                                If abnormal, MRI or CT of abdomen (unless pregnant)

                                MRI of the brain and entire spine with gadolinium for hemangioblastoma

                Adults: Annual examinations listed above plus:

                                MRI for RCC every other year

                                                Baseline ear, nose, and throat examination including audiometry; retest if any

symptoms of ringing, tinnitus, pain, or change of auditory acuity occur

and order appropriate imaging.