Genetic Testing Results

January 24, 2012:  Zoe does NOT have the germline mutation, which means that the chromosomal deletion that helped give rise to the ATRT tumor is present only in the cancer cells and not in all the cells of her body, and that means that neither I nor Cam need to have genetic testing to gauge the propensity for ATRT brain cancer.  



We celebrate this and thank the Lord this is the case.  Now, we just need to make sure we eliminate all those cancer cells.  At the end of February, Zoe will undergo a series of tests to see how effective this course of treatment has been against her cancer.

January 2012 Medical Update

After the resection, Zoe's brain had difficulty regulating her respiratory rate, heart rate, urine content and function, and temperature.  She was diagnosed with Diabetes Insipidus, but, upon beginning Chemotherapy (at which point she needed to stop taking DDAVP so that the chemicals would be frequently eliminated from her bladder), it was discovered that her brain had healed and this condition no longer applied.

Zoe still has hypothyroidism and may, indeed, have hypothyroid obesity.

Since her diagnosis, Zoe's vocabulary has tripled and the speed at which she learns has increased.  She successfully transfers knowledge from one area to another, and her thirst for learning is unquenchable.  

Her ability to use her right hand was severely hampered by tonal issues, even to the point of needing to wear a brace on her wrist, but, five months later, her wrist is relaxed and she is able to grasp utensils, block puzzle pieces, and turn board book pages.  

Her legs continue to be markedly weak, somewhat due to neurological and physiological conditions, but primarily due to being bedridden for nearly all of the last five months.  She is often either connected to continuous chemotherapy infusions, violently ill from the side effects, or too vulnerably neutropenic to be outside of her hospital room.  She is also on "precautions" a great deal, which has meant that she has not been able to play with other children throughout her extended time in the hospital.  We expect that after Cycle 6 in February, this pattern will change and we will be seeing Zoe's strength and coordination improve.

She still needs to have a neuro-opthalmological exam as there is concern about her optic nerves, her right eye muscles, and frequent double vision.  We believe this double vision is at least partly responsible for her psychological resistance to walk.  She presently has very little confidence in walking or shifting position.

We sent a blood sample to learn more about her INI-1 deletion.

Our loving, bright, physically agile 2 year old daughter began showing signs of lethargy, dizziness, right-sided weakness, vision changes, and coordination difficulties in the summer of 2011. On August 19th, both a CT scan and MRI conveyed a 3-cubic inch tumor in the thalamic region of her brain. A total resection was performed by Dr. Lilian Goumnerova at Children's Hospital Boston and Zoe is currently undergoing the Dana-Farber Cancer Institute protocol (DFCI IRB Protocol 02-294) to treat AT/RT, although there is not a consensus of her diagnosis.

She is also part of an INI-1 gene study as she has the INI-1 deletion.

Complications: After the August 23, 2011 resection, Zoe's brain had difficulty regulating heart rate, respiratory rate, temperature, and blood oxygenation levels. All of these functions returned to normal within six weeks post-op. Zoe also developed Diabetes Insipidus as the surgery likely put pressure on the pituitary gland. She was treated with DDAVP. Because her chemotherapy drugs can destroy the bladder, she was removed from the DDAVP and it was found that her brain had healed itself of the Diabetes Insipidus.

At five weeks post-op, we noticed that Zoe was again increasingly tired and seemed to regress in her ability to walk. An MRI on September 30th showed hydrocephalus; an external ventricular drain was placed, but was proven to be ineffective, so a shunt operation was performed on October 13th.

Her mucositis after the first round of chemotherapy was so painful that the pain management team had to get involved and Zoe needed increasing amounts of morphine and one dose of Dilodid to capture her pain. Six days later, Zoe did not need any further pain medication, but is expected to experience the same condition with round II due to Doxorubicin.

Zoe still suffers from dizziness, coordination difficulties, and vision problems, but is able to walk, speak, hear, and learn at this stage in her treatment. A neurocognitive and neuropsychology test will be performed in anticipation of radiation treatment in Massachusetts General Hospital's Proton Beam Radiation Therapy program.

Emergency Department Documentation  8/19/2011

Neurological Findings:  Developmentally delayed.  Right sided upper and lower extremities hemiparesis (UE started over two months ago; LE started one week ago); LE:  clonus, babinski positive; DTR hyperreflexia; right sided facial paralysis (middle and lower branches paralysed, upper branch normal)

Medical Decision Making

Differential Diagnosis:  right sided hemiparesis and right sided facial paralysis

Rationale:   See Neurological Findings; one episode of right arm focal seizure yesterday

DD Left Sided Brain Tumor, Thalamic Tumor: high grade glioma, ATRT

- CT first to assess for hydrocephalus

- MRI with contrast and spectro to evaluate tumor size and character further

MRI Findings:  Large heterogeneous mass lesion is seen centered in the left basal ganglia and thalamus appearing hypointense on T1, isointense on T2 with few areas of T2 hyper and hypointensity interspersed between it.  The mass measures approximately 4.7cm AP x 4.5cm transverse x 3.2cm CC.  Few cystic areas are seen within the mass.  The mass appears to be bright on diffusion wieghted sequences suggesting high cellularity.  On postcontrast studies, avid contrast enhancement is seen.  The lesion is causing mass effect on the lateral and third ventricles with obstruction of the foramina Monro.  Moderate dilation of the lateral ventricles and posterior third ventricle is seen.  Fourth ventricle is normal.  Extensive perifocal edema is seen extending to the adjacent frontal temporal lobes, midbrain, pons, cerebellum and right basal ganglia.

Imaging features favor ATRT, PNET, or high-grade astrocytoma.  Choroid plexus papilloma/carcinoma seems to be unlikely.

Pathology Reports:

1.  Surgical Pathology Final Report, Children's Hospital Boston MA

Dr. Antonio Perez-Atayde at CHB and Dr. David Louis of Massachusetts General Hospital are of the opinion that this primary brain tumor best fits in the category of ATRT.  Dr. C. Fletcher of Brigham and Women's Hospital has diagnosed this tumor as myoepithelial carcinoma.

Note:  This is a highly malignant tumor which has features of ATRT and also of the recently-described entity "myoepithelial carcinoma" (not hitherto known to arise in the brain; see references).

Reference:  Loss of INI-1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma.  (Hornick, Dal Cin, Fletcher.  Am J Surg Pathol.  2009 April; 33(4):542-50

Myoepithelial carcinoma of soft tissue in children: an aggressive neoplasm analyzed in a series of 29 cases.  Gleason, Fletcher. Am J Surg Pathol.  2007 Dec; 31(12):1813-24.

Microscopic Description

The sections showed the heterogenous tumor cells with epithelioid and spindle differentiation forming nexts and solid sheets in a myxoid and hyalinized stroma with brisk mitotic activity.  Chondroid differentiation can be seen throughout the specimen (best seen in block 3B).  In some areas, tumor has an undifferentiated round cell appearance.  Areas of necrosis are identified.

2.  Dr. Johnathan A Fletcher, Brigham and Women's Hospital, Boston MA offers the following interpretation:  A deletion involving the 5' region of the EWSR1 locus on chromosome 22 was identified in 70% of cells.  Deletions of this 22q region are typical in ATRT.  However, because the deletion breakpoint is in the EWSR1 gene region, the alternate possibility of an unbalanced rearrangement targeting EWSR1 should also be considered.  Karyotype: nuc ish(EWSR1x2) (3' EWSRx1) [35/50]

3.  Dr. Fausto Rodriquez, Johns Hopkins Reference Laboratories, Baltimore MD offers the comment:  The histologic sections demonstrate epithelioid cells with rhabdoid features, focal spindled areas, and brisk mitotic activity.  Immunohistochemical studies performed at Johns Hopkins Hospital show loss of INI-1 in the tumor cells, while being preserved in the associated vasculature.  These findings support the ATRT diagnosis.

4.  Dr. Umberto deGirolami, Department of Anatomic Pathology, Children's Hospital Boston MA, writes: Immunostaining performed and reviewed at CHB revealed that the tumor showed focal and partical positivity for SMA (block 3D).  CD34 highlighted the rich vasculature (block 3D).

The deletion analysis for 22q11.2 was consistent with two overlapping deletions in the SMARCB1/INI 1 locus, which resulted in homozygous loss of the first two exons of the gene.  Probes that map proximal to SMARCB1 in 22q11.2 as well as to distal regions of chromosome 22 showed alternating gain and loss.  These results suggest that there is a complex rearrangement or multiple deletions in chromosome 22.  One possibility is an inversion followed by a deletion.  This could be investigated further with a high resolution SNP array or standard cytogenetic and FISH studies.

In light of the patient's age and tumor location, these results are most consistent with an ATRT.  Genetic counseling to discuss the possibility of performing peripheral blood studies to rule out a germline deletion in the SMARCB1 gene is recommended.

EEG Report

1.  The presence of sleep activated right temporal parietal sharp waves.

2.  The presence of intermittent rhythmic slowing in the bilateral posterior quadrants.

3.  The presence of asymmetries throughout the recording with decreased voltage activity and sleep elements on the left.

This EEG is indicative of a decreased seizure threshold of a focal mechanism of onset from the right temporal region.  The biposterior slowing is indicative of cortical dysfunction.  This EEG is indicative of a structural or functional abnormality over the left hemisphere; suggestive of encephalopathy of nonspecific etiology.