Patient Initials: MSClincopathologic Conference (CPC)

8/7/15

Jennifer Nichols, PGY3

HistoryHPI: Patient is a 58y/o female with PMH significant for recurrent GBM initially diagnosed in 2012, GERD, DVT 2/2015 on warfarin, who presented as a t/f from OSH with generalized weakness altered mental status.

Patient reports that since her chemotherapy tx 2 weeks prior she has felt weak with increased fatigue. She follows with Dr. Drappatz in addition to a local oncologist in WV where she resides. She was taken to OSH by her mother (who she lives with) because she felt patient was less communicative and was unable to ambulate the bathroom. At OSH, VSS except mild tachycardia, she had unremarkable bloodwork and normal UA.

She had a CXR c/f PNA (RUL infiltrate) so she was started on levofloxacin. She did report occasional 4/10 R sided pleuritic CP for a few days prior to admit. Given her hx of GBM and AMS (decreased ability to communicate) she was t/f to SHY.

Per her daughter, who was present at time of SHY admission, responses were slowed from pt’s baseline but she did not seem confused or otherwise altered.

Pt denies any headache, pain, vision changes, numbness, tingling, difficulty swallowing, changes in bowel or bladder function, rashes, or difficulties with cognition. Denies cough, edema, N/V, abdominal pain, dyspnea. She notes that she has some baseline left-sided weakness, which she feels is improving.

History cont…• Past Medical/Surgical History:• PAST ONCOLOGIC HISTORY: GBM, R frontal• 1. Diagnosed 2/2012 after she developed headaches• 2. R frontal craniotomy at OSH; MGMT +• 3. Received radiation plus temodar on trial with cedrianib v. placebo through 4/2013, later

determined to be on placebo arm; later observation• 4. 9/2014 slight progression on imaging and 12/2014 imaging showed recurrent R frontal

tumor; underwent debulking with Dr. Amankulor 12/10/14• -post op course c/b neglect and lethargy, hyponatremia and UTI• 5. 1/2015 developed AMS, balance problems, urinary control difficulty; imaging showed acute

hydrocephalus and VP shunt placed 1/5/15• 6. 3/2015 follow up MRI showed marked tumor progression along the falx into the corpus

callosum; initiated Avastin 2/13/15 and lomustine; lomustine has been held since initial dose on 3/6/15 due to concerns of toxicity

• Medical History• 1. DVT 2/2015• 2. GERD• 3. Urinary incontinence• 4. Migraine• 5. Hysterectomy• 6. Hyperlipidemia

History Cont…• All: NKDA• Meds on Admission:

– Atorvastatin 40mg PO QHS– Keppra 500mg PO BID– Levofloxacin 750mg PO daily– Naproxen 500mg PO BID prn– Oxybutynin 5mg PO TID prn– Pantoprazole ER 40mg PO qAM– Sumatriptan 50mg PO daily prn– Coumadin 3mg PO daily

• SocHx: Lives in WV with her mother. Denies EtOH, tobacco, illicits• FamHx: Non-contributory

Examination• VS: T 36.7, BP 128-152/86-106, P95, RR 20, 93% SpO2 on RA• General: No acute distress. • HEENT/Neck: NCAT, MMM, normal conjunctiva/sclera, neck supple.• Respiratory: Respirations are non-labored. • Cardiovascular: RRR, normal peripheral perfusion. No edema.• Gastrointestinal: NT/ND, +BS.• Integumentary: Warm, Dry, Intact. • Neurologic: • Mental Status: Awake, alert and oriented to person and place ("UPMC“). Oriented to year and month but not

date or day of week. Not oriented to situation. Cooperative with normal comprehension of most simple commands and fluent speech. Repetition and naming intact. Recall intact to recent and remote memory and 3/3 with memory challenge. Able to follow complex multistep commands. Deficits in attention - becomes distracted frequently during line of questioning and stared, but easily redirectable

• Cranial Nerves: Full visual fields by confrontation. Unable to visualize discs through undilated pupil. EOMI, no nystagmus. Pupils equal, round, and reactive to light and accommodations. Normal facial sensation bilaterally. No facial weakness or asymmetry. Normal expression. Hearing grossly normal. Palate elevates symmetrically. Normal strength of the trapezii and sternocleidomastoid muscles, no atrophy. Tongue protrudes in midline; no fasciculations or atrophy.

• Motor: Normal muscle bulk and tone in all 4 extremities. No tremor or bradykinesia. Mild L pronator drift. Strength 5/5 throughout on R. On L, 4+/5 shoulder abduction/adduction, elbow flexion/extension, hand grip, hip flexion, ankle dorsi-/plantar flexion

• Reflexes: 2+ and symmetric in biceps, triceps, brachioradialis, patellar, and achilles tendons. Plantar responses flexor. No pathological reflexes.

• Sensory: Intact to light touch, temperature, vibration throughout. No extinction to double simultaneous stimulation.

• Coordination: Normal finger-to-nose and heel-to-shin. • Gait: Deferred.

Hospital Course• Unfortunately, brain MRI during admission demonstrated significant disease

progression. This was likely the cause of her cognitive/overall decline. Neurosurgery and Neuro-Oncology as well as Radiation Oncology agreed that there was no role for further chemotherapy or XRT. She was started on decadron while inpatient (initially 4mg IV q6 transitioned to 4mg PO q6 on discharge). EEG performed during admission revealed independent bilateral temporal sharp waves R>L as well as focal R sided slowing superimposed on generalized moderate slowing. Therefore, keppra was increased from 500mg PO BID to 750mg PO BID.

• Given tumor progression and no further treatment options, code status was re-addressed with patient and family and decision was made to pursue hospice at a local facility.

• She was to complete Levofloxacin course (started at OSH) for PNA; her pleuritic CP was noted to have improved. Lovenox was continued for hx of DVT with expectation that it would likely be tapered off while in hospice.

• She died in hospice care about a month later.

Radiology• MRI Brain w/ and w/o:

– 3/25/15: Increasing masslike T2 hyperintensity, heterogenous enhancement in the medial R frontal lobe crossing the anterior corpus collosum into the L frontal periventricular WM c/w tumor progression. Improving cytotoxic edema (peri-resection cavity) in the anterior lateral right frontal lobe demonstrated by less enhancement/T2 hyperintensity. Stable gyriform enhancement in the R temporal lobe.

– 5/22/15: Increasing edema, enhancement, and mass effect in the frontal horn of the L lateral ventricle. Progressive edema and enhancement along the genu of the corpus callosum is c/w tumor progression.

– 6/11/15: Increasing extent of mass-like T2 hyperintensity and enhancement in the genu of the corpus callosum extending to the L frontal lobe with increasing mass effect. Also increased mass effect and enhancement in the R frontal lobe. These findings are c/w tumor progression.

Radiology Continued

T2 Flair

Radiology Continued

T1 + Contrast

Glioblastoma Multiforme (GBM)• Arises from astrocytes. Highly malignant; reproduces quickly and supported

by a large network of blood vessels. • Found in cerebral hemispheres generally, but can be found anywhere in

brain or spinal cord. • Contain a mix of cell types (cystic mineral, calcium deposits, blood vessels,

mixed grade of cells). Dead cells may be seen, especially towards the center. Glioblastoma rarely metastasizes outside of the CNS.

• Due to their rapid growth, the most common symptoms are usually caused by increased pressure in the brain, including headache, N/V, drowsiness. Mass effect can also lead to focal deficits.

• Represents about 15.4% of all primary brain tumors and about 60-75% of all astrocytomas

• They increase in frequency with age, M>F• Very difficult to completely remove because they have “finger-like”

tentacles. Difficult to treat with chemo and radiation because there are so many different types of cells that respond variably

• Median survival: 2-3 years. <2 years if more aggressive. Generally longer survival (can be up to 5 years) in children

Pathology• R frontal lobe excision:

– Diagnosis: Recurrent, residual Glioblastoma• Cortex and WM: some areas show infiltrating tumor cells. • A portion of the cortex shows extensive secondary structuring

by tumor cells around neurons with scattered mitoses seen only in this area. No necrosis, necrosis with pseudopalisading or endothelial proliferation.

• WM shows decreased cellularity and some gliosis with focal pallor, consistent with treatment effects. Some pleomorphic nuclei in these areas may represent residual tumor, infiltrating new tumor, or radiation effect on reactive astrocytes.

• In summary, at least some portions of this tumor appear to be recurrent. No areas of radiation-related necrosis were seen.

Pathology Continued• EGFR (epidermal growth factor receptor) staining is strongly, diffusely positive. EGFR

amplification is the most common alteration in glial tumors, 34-54%. EGFR is a common hallmark of GBM and promotes pro-proliferative signal. It is crucial in the early stage of tumor development, sustaining tumor growth, promoting infiltration, and mediating resistance to therapy

• GFAP (glial fibrillary acid protein) strongly stains the tumor cell processes. This is a stain for reactive astrocytes, astrocytes damaged by ischemia, and swollen astrocytes in areas with vasogenic edema

• IDH (isocitrate dehydrogenase) 1 and 2 mutations negative. IDH1 or IDH2 gene mutations are in 70-90% of astrocytomas, 69-94% oligodendrogliomas, 78-100% oligoastrocytomas, and 82-88% glioblastomas.

• IDH1 and 2 are involved in signal transduction, lipid synthesis, oxidative stress, and oxidative respiration. IDH mutations are a prognostic advantage.

• ATRX (α-thalassemia/mental-retardation-syndrome-X-linked) normal/no nuclear staining. ATRX loss is found in anaplastic tumors including astrocytomas > oligodendrogliomas, oligoastrocytomas. Often seen with IDH mutations and 1p/19q codeletion.

• Tumors with ATRX loss have a significantly better prognosis; it identifies a subgroup of astrocytic tumors with a favorable prognosis

Pathology Continued• Ki-67 proliferation is 8% in the most cellular areas, which is low. Ki-67 proliferation is

used to predict tumor recurrence and overall prognostic outcome.

• 1p/19q deletions: NegativeIf present, these deletions have a strong association with oligodendroglial tumors and is present in 80-90% of oligodendrogliomas and 60% of anaplastic oligodendrogliomas

• Co-deletion of 1p/19q is associated with enhanced chemosensitivity and overall longer survival.

• BRAF (proto-oncogene) mutation negative. Common in a wide spectrum of tumors (multiple types of astrocytomas, as well as gliomas, gangliogliomas) and is more common in peds. Found in less than 2% of adult gliomas.

• MGMT (O(6)-methylguanine-DNA methyltransferase) Promotor methylation was identified; this is a positive feature for the majority of tumors as this usually indicates a better response to treatment and longer overall survival in glioma patients treated with alkylating agents

• MGMT (10q26) encodes a DNA repair protein that removes alkyl groups from guanine (06 position); these alkyl groups are commonly produced by chemotherapeutic alkylating agents. Methylation turns off the protein, making the tumor more responsive to Temodar and radiotherapy

Pathology Continued• EGFR vIII mutation negative. It is an oncogenic, constitutively active mutant

form of EGFR that is commonly expressed in glioblastoma.• Interestingly, it has been shown to sensitize tumors to EGFR tyrosine kinase

inhibitors when the tumor suppressor protein PTEN is intact.

• Deletions of 9p (P16/CDKN2a) and 10q (PTEN aka phosphatase tensin homolog) were both negative. These deletions are most frequently found in high grade astrocytic lesions and associated with anaplasia and short survival.

• PTEN regulates cell proliferation, apoptosis, and tumor invasion and is common in GBMs.

• CDKN2A loss (cyclin-dependent kinase inhibitor 2A) is frequently found in tumors. The gene codes for p16INK4a, which is a tumor suppressor (regulates cell progression from G1 to S phase)

• Deletion of TP53 (17p13) is negative. Deletion is frequently found in glioblastomas, with inverse correlation with EGFR amplification and is associated with a more protracted clinical course