Importance of initial aggressive treatment for pineal parenchymal tumor of intermediate differentiation: A case report and review of literature

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1 Practical Radiation Oncology (2013) 3, e29 e34 Teaching Case Importance of initial aggressive treatment for pineal parenchymal tumor of intermediate differentiation: A case report and review of literature Madeera Kathpal DO a,, Tina Mayer MD b, Roy Rhodes MD c, Shabbar Danish MD d, Atif Khan MD a a Department of Radiation Oncology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson University Hospital, New Brunswick, New Jersey b Department of Medical Oncology, Cancer Institute of New Jersey, New Brunswick, New Jersey c Department of Pathology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson University Hospital, New Brunswick, New Jersey d Department of Neurosurgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson University Hospital, New Brunswick, New Jersey Received 15 October 2011; revised 19 March 2012; accepted 10 April 2012 Case report A 41-year-old African-American male presented at an outside institution with complaint of progressively worsening double vision for 1 to 2 months, with dimming of vision in his left eye. Pertinent past medical, surgical, family, or social history consisted of previous tobacco, alcohol, and cocaine abuse. Magnetic resonance imaging (MRI) of the brain, with and without gadolinium, revealed a heterogeneously enhancing mass with numerous flow voids. The mass was centered in the region of the pineal gland and it was inseparable from the medullary velum. The mass was hyperintense on T1-weighted imaging suggesting hemorrhage or calcifications. There was associated hydrocephalus with no other abnormalities seen. The patient underwent a biopsy of the tumor. First, the patient had a right frontal ventriculoperitoneal shunt with a medium pressure Codman valve placed. During this procedure, it was noted that cerebrospinal fluid (CSF) Conflicts of interest: None. Corresponding author. The Cancer Institute of New Jersey, 195 Little Albany St, Rm 2013, New Brunswick, NJ address: madeeraka@gmail.com (M. Kathpal). initially drained under high pressure. A sample of CSF was sent for cytology. Once the shunt was secured, the patient was repositioned for the biopsy. The posterior fossa was targeted with an incision that extended from C1 to 3 cm above the inion. A large posterior fossa craniectomy was performed, exposing the torcula and transverse sinus. The dura was opened, the cisterns near the foramen magnum were fenestrated, and the midline of the cerebellum was followed along the floor of the tentorium until the tumor was well visualized. It was described as white and soft, and biopsies were taken of several regions of the mass. The patient had an uneventful postoperative course. Computed tomography scan of the head noted expected postoperative changes. MRI of the brain, with and without gadolinium, revealed residual tumor in the pineal region measuring approximately 4 4 cm. CSF cytology was negative for malignant cells. MRI of the axial spine was not performed. Histopathologic examination of the biopsy specimens revealed sheets of small, relatively undifferentiated tumor cells with round nuclei and scant cytoplasm. Mitotic figures were readily identified as well as scattered apoptosis. A few zones had cells arranged about small lumens. Rare, minute foci of necrosis were seen. Limited /$ see front matter. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.

2 e30 M. Kathpal et al Practical Radiation Oncology: January-March 2013 microcalcifications and few foci of prior hemorrhage were seen. The astrocytic component of the pineal tissue had scattered Rosenthal fibers. There was no pineocytoma component in this specimen. Immunohistochemistry revealed a strong, uniform staining of the tumor cell cytoplasm for synaptophysin. There was a patchy but often strong staining for chromogranin-a. Most of the tumor cells also stained strongly for neurofilament protein. The tumor cells were negative for glial fibrillary acidic protein and neuronal nuclear protein. Ki-67 mitotic labeling index was 30%. The tumor was initially classified as pineal parenchymal tumor of intermediate differentiation (PPTID), WHO grade 2-3. The specimen was sent for consultation with a final diagnosis of PPTID, high grade (3) variant being made. The patient was referred to radiation oncology 10 days postoperatively. He was still experiencing double vision and was wearing a patch over his right eye. He received 3-dimensional conformal treatment with 5 coplanar fields utilizing 6-MV photon energy targeting the gross tumor volume surrounded by a 2-cm margin to the block edge. He was treated to 5000 cgy in 25 fractions, delivered 5 days a week (Fig 1). He tolerated this treatment well, maintaining a good appetite and energy level. He had no complaints of nausea, vomiting, or headaches. The patient did well for 10 months with improvement of his double vision until he developed right facial nerve palsy. Four months later he started to develop gait instability and return of his double vision. Three weeks after that he experienced lower extremity paresthesia, left greater than right, paresthesia significantly noted in the anal region, and weakness in his lower extremities. He also complained of tenderness to palpation along the cervical and thoracic spine. He presented to the outside institution's emergency department. Computed tomography of the head showed no acute findings. MRI of the cervical, thoracic, and lumbar spine, with and without gadolinium, revealed spinal drop metastasis within C1 to C4 and C6 to C7 with diffuse disease involving the thoracic spine with cord compression at levels T1 to T4 and disease in L2 and S1 to S3. The patient underwent palliative radiation consisting of 3000 cgy in 10 fractions from C7 to T5 and L5 to the sacrum using 15-MV photon energy with separate AP-PA (anterior-posterior-posterior-anterior) fields with a 1.5-cm margin from lateral edge of the vertebral body to the block edge. He once again tolerated the radiation well, with some improvement in his symptoms. He did well for the next 4 months until he lost his hearing bilaterally and experienced acute bilateral lower extremity weakness, left greater than right, which escalated to inability to bear weight on his left leg and to descend stairs. At the time of his admission to our institution, he complained of numbness in his toes, dysphagia, and constipation for the previous week. His Eastern Cooperative Oncology Group performance status was a 2. He had horizontal nystagmus in the left eye, and 4 out of 5 strength in his right upper extremity compared with 5 out of 5 strength in his left. His left lower extremity strength was 1 out of 5 compared with 2 out of 5 in his right. He had bilateral facial nerve palsy as well as bilateral sensorineural deafness. MRI of the brain, with and without gadolinium, showed bilateral cerebellopontine angle masses, right larger than left (Fig 2). There was extensive leptomeningeal metastatic disease along the medulla and upper cervical spinal cord with cord compression. Spinal MRI showed extensive intradural, extramedullary enhancement from T5 to T10 and multiple intradural enhancing nodules from T12 to L3. There were also post radiation changes in the vertebral bodies and soft tissues from T1 to T4. Debulking of the right cerebellopontine mass was undertaken. Tissue diagnosis of the removed tumor confirmed metastatic disease from the pineal tumor when the 2 were compared (Figs 3 and 4). Palliative radiation therapy was given to T7 to L3 to 2400 cgy in 8 fractions using 15-MV photon energy with an AP-PA field configuration planned to 1.5 cm from lateral vertebral body to block edge, with intent to later Figure 1 Axial, sagittal, and coronal views of the isodose distribution of the patient's initial 3-dimensional conformal treatment with 6-MV photon energy to the pineal region and margin to 5000 cgy in 25 fractions.

3 Practical Radiation Oncology: January-March 2013 Initial aggressive treatment for PPT e31 Figure 4 Histopathologic examination of the metastatic cerebellopontine angle tumor demonstrating tumor cells staining strongly for neurofilament protein. Figure 2 Axial view of a T1-weighted MRI sequence with gadolinium demonstrating bilateral cerebellopontine angle tumors. treat him to 1000 cgy to his entire brain and spine. Unfortunately, the patient had a decline in mental status and decided to go on hospice prior to further treatment. He died less than a month later. No autopsy was performed. Discussion Two main discussion points come from this case. First, this patient should have been treated with craniospinal irradiation immediately after biopsy. Because of the high-grade features and subsequent aggressive nature of our patient's tumor, we argue that he should have been treated initially as a pineoblastoma. Second, the unusual histology guided the treating physician's decision making; however, there is no consensus on how to grade this tumor. The classification of grading for PPTID according to the WHO states that while this tumor corresponds to grade 2 or 3, no established grading criteria exists. Macroscopic appearance is similar to pineocytoma, although transitional cases consisting of pineocytomatous areas associated withadiffusepatternarealsoseen in PPTID. Grade 2 tumors may be differentiated from grade 3 by mitotic activity and immunoreactivity to neurofilament protein. There is a potential for aggressive behavior although the mean Ki-67 labeling index is only 3% to 10%. Survival from PPTID is negatively affected Figure 3 (A) Histopathologic examination of the metastatic cerebellopontine angle tumor demonstrating sheets of small, relatively undifferentiated tumor cells with round nuclei and scant cytoplasm. (B) Histopathologic examination of the metastatic cerebellopontine angle tumor demonstrating infiltration into cranial nerve VII.

4 e32 M. Kathpal et al Practical Radiation Oncology: January-March 2013 Table 1 Grade classifications of pineal parenchymal tumor of intermediate differentiation (PPTID) WHO grade Ref [ 1 ] Jouvet classification Ref [ 2 ] Our patient [This study] Grade 1 (pineocytoma) Low cellularity No mitosis Positive staining for NF Grade 2 (intermediate) Pineocytomatous rosettes Low to moderate cellularity Mild nuclear atypia Low mitotic activity Positive NF staining b6 mitoses per 10 fields Positive staining for NF Grade 3 (intermediate) Grade 4 (pineoblastoma) Moderate to high cellularity Moderate nuclear atypia Moderate to high mitotic activity Negative NF staining High cellularity High mitotic activity Necrosis NF, neurofilament; WHO, World Health Organization. b6 mitoses per 10 fields with negative or weak NF staining 6 mitoses with positive NF staining Mixed pineocytoma/pineoblastoma 6 mitoses with no or weak NF staining Readily seen mitosis Positive staining for NF No pineocytoma component Minute foci of necrosis by the presence of necrosis, high mitotic index, and absence of neurofilament protein staining. 1 Jouvetetal, 2 in 2000, developed their own grading system based on prognostic factors affecting overall survival, event-free survival, and local control of pineal parenchymal tumors (PPTs). Grade 1 corresponds to pineocytoma. PPTID is divided into 2 grades. Grade 2 has b6 mitosisandisneurofilament (NF)-positive. Grade 3 is either NF-negative with b6 mitosis or NF-positive with 6 mitosis. Grade 3 also includes mixed pineocytomas and pineoblastomas. Grade 4 is a pineoblastoma (Table 1). 2 According to their analysis of 66 patients with PPTs, grade 2 disease had a recurrence rate of 26%. Grade 2 disease was also found to have a 5- and 10-year eventfree survival 87.5% and 57%, respectively. These authors correlate their grade 2 disease to WHO grade 2 disease. Our patient, however, had no pineocytomatous component, which makes it difficult to classify by WHO grading criteria. Therefore, our patient's tumor is more closely related to a Jouvet grade 3 which had a higher propensity for recurrence at 56% and a lower 5- and 10-year event-free survival of 65% and 23%, respectively. 2 Jouvet et al 2 also calculated the relative risk (RR) of death or recurrence using specific histologic findings. They determined that the presence of necrosis significantly worsened overall survival with a RR of 2.54, while the presence of neurofilaments was protective with a RR of Necrosis and mitosis correlated strongly with poor event-free survival with RRs of 4.96 and 4.33, respectively. Fauchon et al 3 reviewed 76 patients with PPTs that were initially graded by WHO grade and then re-graded using the Jouvet classification. Using the WHO classification, 19 patients had pineocytoma, 28 had intermediate type, and 29 had pineoblastoma. Using the Jouvet classification, 11 were grade 1, 27 were grade 2, 20 were grade 3, and 18 were grade 4. They found a 10% discrepancy between original diagnosis and final diagnosis. Age less than 20, a diameter of the tumor of 4cmon computed tomography, grading classification, and use of chemotherapy all had a negative effect on overall survival and disease-free survival. There was a trend toward increased disease-free survival, but not overall survival with complete resection. Using the Jouvet classification, the authors mention that response to radiation is worse for grade 3 tumors than grade 2. The site of relapse is also closely related to tumor grade. Nearly 60% of patients who relapsed did so in the spine. No grade 1 tumors relapsed whether radiation was given or not. Grade 2 tumors are more likely to recur locally, while grade 3 tumors have the potential for metastatic spread. 3 Stoiber et al 4 published a retrospective review of a single institution's experience of treating PPTs with radiation to analyze overall survival, local control rates, patterns of failure, and possible prognostic factors. Ages ofthepatientsrangedfrom13to57yearsold.ofthe 14 patients analyzed, 1 had PPTID and 9 had pineoblastoma. Two patients with pineoblastoma were treated with craniospinal irradiation (CSI) plus a local boost for tumor recurrence after initial treatment with brachytherapy. Both these patients died within 18 months. The patient with PPTID was treated to 5400 cgy in standard fractionation to the gross tumor volume but she had a pineocytoma component to her tumor, unlike our

5 Practical Radiation Oncology: January-March 2013 Initial aggressive treatment for PPT e33 patient. She was 25 years old at time of diagnosis and was disease-free for 7 years. Of the 7 patients with primary pineoblastoma, 3 received only irradiation to the whole brain and the other 4 received CSI, with doses from 3000 to 4000 cgy with a boost to the tumor to a total dose of 5000 to 6000 cgy. All 4 patients treated with CSI for primary pineoblastoma experienced local recurrence; 3 in the pineal region, 2 of these with concurrent spinal failure and 1 with spinal failure alone. 4 The authors concluded that exact histologic grading is paramount when deciding extent of treatment. Open biopsy is preferred over stereotactic biopsy because small sample size may miss less differentiated cells. 4 Schild et al 5 reported the Mayo Clinic experience with PPTs. Thirty patients were included in this study; 21 diagnosed by biopsy or resection and 9 diagnosed at autopsy. Classification of the tumors was performed by the same neuropathologist and revealed 4 groups. Nine patients were diagnosed as pineocytoma, containing cytologically benign, mature-appearing cells arranged in sheets or ill-defined irregular lobules. Homer Wright-like rosettes were often seen as well as an occasional tumor giant cell. Fifteen patients were diagnosed with pineoblastoma consisting of smaller, mitotically, poorly differentiated cells with scant cytoplasm and processes, disposed in patternless sheets. Occasional Homer Wright and Flexner-Wintersteiner rosettes were seen. Four patients with PPTID were seen to have cytologic features between pineocytoma and pineoblastoma. Lastly, 2 patients were diagnosed with mixed PPT, which exhibited features of both pineocytoma and pineoblastoma. The ages of the patients ranged from 11 months to 77 years. The paper discussed staging workup, treatment options, and patterns of failure. The authors concluded that after a diagnosis of any pineal parenchymal tumor, staging workup should consist of MRI of the spine or myelogram and CSF cytology. They also concluded that it is easier to predict tumors with seeding capability than those that will fail locally. They reported no local failures in patients treated with N5000 cgy to the primary tumor. All patients who experienced leptomeningeal spread had persistent or recurrent local disease. They noted that all tumor types except pineocytoma had seeding potential and that these tumors had improved tumor control with the use of craniospinal radiation. Lutterbach et al 6 retrospectively analyzed 101 patients with PPTs. Thirty-seven patients had PPTID and 64 patients had pineoblastoma based on 3 different grading systems chosen by the geographic location of the treatment center. Forty-five patients received definitive radiation therapy and 56 received postoperative radiation therapy. As initial treatment, a total of 56 patients received craniospinal irradiation with a boost to the tumor and 22 patients underwent treatment to the tumor itself, like our patient. The median dose to the pineal tumor was 5400 cgy and the median dose to the spine was 3600 cgy. Thirty-four patients received chemotherapy. One to 8 different agents were used. While cyclophosphamide was often used alone, combinations of drugs most often included platinum with etoposide. All but 3 patients with disseminated disease at presentation received chemotherapy. Significantly more patients with pineoblastoma received chemotherapy when compared with patients with PPTID. 6 Patients with major residual disease after initial treatment had a significantly reduced overall survival compared to patients with no residual disease or minor residual disease. Extent of disease (local vs disseminated) and histology (PPTID vs pineoblastoma) were found to be significantly different in terms of overall survival when residual disease was not included in the analysis. The median progression-free survival was also significantly decreased with pineoblastoma when compared with patients with PPTID. 6 From the evidence provided in previous studies and our own experience, a few key points should be considered when deciding how to treat high-grade pineal parenchymal tumors in the adult population. First, a biopsy that provides sufficient tissue in order to make an accurate diagnosis is vital. An aggressive surgical resection should be attempted for it provides better local control and increased overall survival. 4-6 Cerebral spinal fluid cytology and MRI of the entire neuraxis should be performed prior to the initiation of any postoperative treatment. 5,7 If disseminated disease is present, the use of preradiation chemotherapy should be considered. 6 A regimen with a platinum and etoposide would be a reasonable approach. Craniospinal irradiation with a boost to the primary tumor or postoperative bed should be done on every patient without a pineocytoma component to the tumor; 5400 to 5580 cgy in 180 cgy fractions should be delivered to the primary tumor with 3600 cgy in 180 cgy fractions delivered to the entire neuraxis. If the patient is not treated with CSI initially, then CSI should be performed at the first sign of recurrent disease (such as spinal seeding). Follow-up scans should be performed within 2 months of completing radiation to assess response to chemotherapy and radiation. References 1. Louis D, Ohgaki H, Wiestler O, Cavenee W, eds. WHO classification of tumours of the central nervous system. Geneva, Switzerland: IARC; Jouvet A, Saint-Pierre G, Fauchon F, et al. Pineal parenchymal tumors: a correlation of histological features with prognosis in 66 cases. Brain Pathol. 2000;10: Fauchon F, Jouvet A, Paquis P, et al. Parenchymal pineal tumors: a clinicopathologic study of 76 cases. Int J Radiat Oncol Biol Phys. 2000;46: Stoiber EM, Schaible B, Herfarth K, et al. Long term outcome of adolescent and adult patients with pineal parenchymal tumors treated

6 e34 M. Kathpal et al Practical Radiation Oncology: January-March 2013 with fractionated radiotherapy between 1982 and 2003 a single institution's experience. Radiat Oncol. 2010;5: Schild SE, Scheithauer BW, Schomberg PJ, et al. Pineal parenchymal tumors: clinical, pathologic, and therapeutic aspects. Cancer. 1993;72: Lutterbach J, Fauchon F, Schild SE, et al. Malignant pineal parenchymal tumors in adult patients:. patterns of care and prognostic factors. Neurosurgery. 2002;51: Chang SM, Lillis-Hearne PK, Larson DA, Wara WM, Bollen AW, Prados MD. Pineoblastoma in adults. Neurosurgery. 1995;37: