—  SPECIALTY CONFERENCE  —

Neuropathology

Case 2 - Radiation-Induced Sarcoma

Bette K. Demasters
University of Colorado School of Medicine
Denver, CO


Click on each slide thumbnail image for an enlarged view
Clinical History
The patient was a 34 year-old male who first presented in 1989, at the age of 23 years, with seizures and migraine headaches. He was treated by his primary care physician with phenytoin; however, no imaging studies were acquired. About one year later, the patient developed a right visual field cut, prompting a visit to an ophthalmologist who ordered a CT scan and discovered a left parietal tumor. The patient was referred to a neurosurgeon. The left parietal tumor was resected on 02/03/90 and diagnosed as glioblastoma multiforme. He received post-operative radiation therapy, but no chemotherapy.

He underwent yearly serial magnetic resonance imaging (MRI) studies for approximately four years, which were negative for recurrence. He was then lost to follow-up, but apparently did well during this time and was employed as a dishwasher.

In 10/2000, 10 years after resection, the patient developed headaches and numbness on the right side of his body. He did not seek medical attention until he started having difficulty with speech, which prompted a visit to a different neurosurgeon in 01/2001. An MRI scan revealed a recurrent enhancing mass in the same region as his original tumor. The patient underwent a second resection on 02/02/2001; it was unclear from the operative report whether this was a gross total or subtotal resection. High grade tumor (with an entirely different appearance than his first tumor) was documented; the patient had no adjuvant therapy.

In 07/2001, the patient experienced recurrent symptoms and MRI showed abnormalities in the site of the resection bed. At the time of surgery he was found to have an abscess in the region of his previous operation; the abscess was drained and the bone flap removed. Blood cultures grew out Staphylococcus aureus and he was treated with six weeks of antibiotics. He had persistent expressive aphasia but did well until a follow-up scan on 10/08/2001 showed regrowth of the tumor.

He was referred to our institution (the fourth hospital and fourth neurosurgeon involved in his care). On admission, MRI scan showed a very large parieto-occipital tumor that had rapidly regrown within the site of the operative bed, extended to the adjacent dura, and into the left lateral ventricle. A separate nodule was seen in choroid plexus. A gross total resection was undertaken on 11/07/01, with placement of a GliaSite balloon into the resection cavity. The balloon was infused with radioactive iodine, delivering 50 Gy to a depth of 1 cm. over 72 hours, after which the balloon was removed.

Several months following resection, he developed a left cerebellopontine angle subarachnoid metastasis for which he received Gamma knife therapy on 3/14/02. A subcutaneous mass along his occipital incision appeared and was removed on 04/24/2002. Over the ensuing months, additional enhancing masses developed along the ependymal surfaces of the ventricle, adjacent to the pons and cerebellar hemispheres, in the left internal auditory canal, and along the spine, all consistent with cerebrospinal fluid dissemination of his tumor. Several cycles of chemotherapy with ifosfamide and mesna proved ineffective and he succumbed on 8/18/2002.


Case 2 - Figure 1 - The original 1990 tumor was composed of pleomorphic cells with enlarged, bizarre, multilobed, hyperchromatic nuclei, but also contained striking numbers of eosinophilic granular bodies.
Case 2 - Figure 2 - The original 1990 tumor also showed denser, more eosinophilic Rosenthal fibers and collections of non-neoplastic lymphocytes.
Case 2 - Figure 3 - A high power photomicrograph of the original 1990 tumor shows the discrete granular or "droplet" appearance of the eosinophilic granular bodies.



Case 2 - Figure 4 - This tumor additionally showed extensive necrosis (lower portion of photograph), as well as mitotic activity.
Case 2 - Figure 5 - When this patient experienced recurrent symptoms 11 years later in 2001, and was found to have a tumor in the same anatomic location, it showed entirely different histological features than the 1990 tumor. Note the fibrosarcomatous appearance of this high grade neoplasm.
Case 2 - Figure 6 - Although the overwhelming majority of the tumor showed a high grade fibrosarcomatous pattern, a small area in the tumor from the first resection in 2001 showed neoplastic bone formation.



Case 2 - Figure 7 - The slide supplied for this USCAP conference was taken from material resected on the second operation in 2001 and clearly illustrates the highly malignant nature of this radiation-induced sarcoma; note the exceedingly high mitotic rate.
Case 2 - Figure 8 - A reticulin stain highlighted the sarcomatous nature of the radiation-induced tumor; GFAP immunoreactivity was not present.



Case 2 - Figure 9A - The second most frequent pattern in the radiation-induced sarcoma was seen in the slide submitted for this USCAP conference; note clusters of cells with abundant, strap-like eosinophilic cytoplasm (insert). These cells showed strong immunoreactivity for desmin, but not GFAP.
Case 2 - Figure 9B - The second most frequent pattern in the radiation-induced sarcoma was seen in the slide submitted for this USCAP conference; note clusters of cells with abundant, strap-like eosinophilic cytoplasm (insert). These cells showed strong immunoreactivity for desmin, but not GFAP.

Diagnosis: Radiation-induced sarcoma (complex, with rhabdomyosarcomatous and osteogenic sarcoma differentiation), arising in the site of his original tumor, 11 years after receiving cranial irradiation for a pleomorphic xanthoastrocytoma with anaplastic features

Discussion
There are several interesting features in this case, each of which are topics unto themselves (criteria for, and behavior of, PXA with anaplastic features; the use of GliaSite; cerebrospinal fluid dissemination of sarcomas; implantation tumors caused by surgery; primary versus radiation-induced sarcomas of the CNS; sarcoma nomenclature). The focus of the discussion will be on radiation-induced brain tumors, tumors that appear to be an increasingly frequent problem.

This patient experienced a long survival after what was originally diagnosed as a glioblastoma multiforme (GBM) of the left occipital lobe at the age of 23 years. "Spontaneous" GBMs do occur occasionally in young individuals who lack identifiable genetic or historical risk factors for brain tumors (such as Li-Fraumeni syndrome, neurofibromatosis, and previous cranial radiation therapy). Nevertheless, the diagnosis of GBM is sufficiently uncommon in persons under 35 years that slides should probably be obtained and reviewed to determine if an alternate diagnosis could be rendered. More unusual than the young age at diagnosis is his extended survival with a diagnosis of GBM. A 10 year survival is rare for true GBMs, and alternate diagnoses should also be considered to explain the long survival. Tumor types that can be mistaken for GBMs include anaplastic oligodendrogliomas and mixed oligo-astrocytomas, pleomorphic xanthoastrocytomas (with or without anaplastic features), and gangliogliomas. Once these confounding types of glial tumors are excluded, it is clear that rare patients with true GBMs do enjoy long survival. Long term survivors number no more than 1-5% of all GBM patients and are predominantly under the age of 35 years. Re-examination of these tumors usually discloses no unusual, "signature" histological or genetic features that might predict long term survival in a given patient. Several studies have noted, however, that some of these tumors show positive immunoreactivity for TP53, despite the absence of p53 mutations.

We felt that this patient's original 1990 tumor was a PXA with anaplastic features. Although criteria for "pleomorphic xanthoastrocytoma with anaplastic features" have been published, the full range of morphological features for these uncommon tumors has not yet been established. This patient's 1990 slides (illustrated on the USCAP website) showed pleomorphic tumor cells and copious numbers of eosinophilic granular bodies, with more focal lymphocytic collections, xanthic cells, Rosenthal fibers, and elongate spindle tumor cells, all features of PXA, but with superimposed necrosis, microvascular proliferation and mitoses. PXA with anaplastic features is a tumor with behavior most similar to a grade 3 anaplastic astrocytoma, not a grade 4 GBM.

This patient received only cranial radiation therapy (XRT), but no adjuvant chemotherapy, after his first tumor resection in 1990. When symptoms reappeared 11 years later in 2001, and he was found to have a tumor with a very different histological appearance in the same, radiated site, he was diagnosed with a radiation-induced brain tumor. Hence the XRT alone can be implicated as the oncogenic agent in this patient, as it is for patients who receive XRT alone for benign tumors such as pituitary adenomas or craniopharyngiomas and then develop post-treatment brain tumors years later within the radiation portals.

Cahan et al. in 1948 established criteria for tumors deemed to be "radiation-induced". First, the new tumor had to arise within the field of irradiation. Second, there had to be a histological difference between the initial and the second tumor. Third, a sufficient latency period had to exist between irradiation and the development of the second tumor. Fourth, the patient had to have an absence of predisposing condition for tumor development. Our NP-Case 2 patient fulfilled all 4 of these criteria for a radiation-induced brain tumor.

The patient in this case developed a radiation-induced brain sarcoma, a well-known radiation-induced tumor type, but less well-studied that radiation-induced meningiomas or radiation-induced high grade gliomas. Meningiomas are the most commonly reported radiation-induced cranial tumor type and have been categorized based on the amount of radiation therapy the patient received. Meningiomas secondary to low dose radiation to the scalp for tinea capitis (800 rads-1.5 Gy) constitute the majority of the cases, although recently more examples of meningiomas arising after high dose therapeutic radiation (greater than 2000 rads) have been reported. Generally, the lower the dosage of radiation the patient receives, the longer the interval to development of the meningioma. Patients with meningiomas occurring after therapeutic cranial XRT usually received their therapy at a young age, often in childhood, and develop their tumors after a shorter latency period (5-20 years) than those who received low-dose scalp irradiation for tinea capitis. Children with acute lymphoblastic leukemia (ALL) are particularly prone to the development of secondary brain tumors, both due to the prophylactic cranial irradiation they received and, in some cases, to the therapy related to marrow transplantation.

Adults receiving high dose (therapeutic) cranial radiation also are at risk for radiation-induced meningiomas. The link between radiation and meningiomas is also evidenced by the fact that meningiomas were also the most frequent cranial tumor type to develop in atomic bomb survivors of Hiroshima and Nagasaki. Compared with sporadic meningiomas, radiation-induced meningiomas are more likely to be aggressive, multiple, and have a higher recurrence rate following treatment. They also are more likely to show loss of 1p and less frequently deletion of chromosome 22q.

Like radiation-induced meningiomas, radiation-induced gliomas may occur after low dose irradiation for tinea capitis or after high dose (therapeutic) cranial radiation therapy for pituitary adenomas, ALL (cranial prophylactic radiation), or various types of brain tumors (such as ependymoma, medulloblastoma, astrocytomas). Radiation-induced gliomas are usually glioblastomas or anaplastic astrocytomas, although radiation-induced gliosarcomas, primitive neuroectodermal tumors, and (rarely) oligodendroglioma have been reported. Tumors develop 5-25 years post-radiation, with an average of 9.6 years. Most disturbing is the fact that at least 5 cases of radiation-induced neoplasms have been reported following stereotactic radiosurgery.

Less frequently, the radiation-induced tumor may be a sarcoma or other tumor type (such as schwannoma or malignant peripheral nerve sheath tumor). As noted above, a sarcomatous component is fairly common in post-radiation GBMs, but patients may also develop pure sarcomas. Most sarcomas are fibrosarcomas, but malignant fibrous histiocytomas, osteogenic sarcomas, chondrosarcomas, mesenchymal chondrosarcomas, "fibrochrondrosarcoma", and other unusual "mixed" forms have been reported. Whether radiation-induced sarcomas are more likely to contain mixed mesenchymal elements than spontaneous primary CNS sarcomas is uncertain, due to the case-report nature and relative rarity of all non-metastatic CNS sarcomas.

This case showed a predominantly fibrosarcomatous pattern, with the most second frequent element being skeletal muscle differentiation; infrequent foci of osteogenic sarcoma were also noted on the first resection (illustrated on the USCAP website for this case). The differential diagnoses for this case include fibrosarcoma, gliosarcoma, malignant peripheral nerve sheath tumor, and rhabdomyosarcoma. The suggested battery of immunohistochemical stains for CNS sarcomas includes vimentin, desmin, GFAP, cytokeratin, neurofilament, epithelial membrane antigen, S100, factor 8/CD31/CD34 , and muscle specific actin. These were all negative or very focal, with the exception of the desmin immunoreactivity which was strikingly positive, but irregular, in distribution. The desmin IHC in this NP-2 case is illustrated as Figure 9b on the USCAP website. No definite residual PXA and no well-developed high grade glioma component were found on the surgical material from either of his resections in 2001. The histology was that of a fibrosarcoma with mixed mesenchymal differentiation. Malignant peripheral nerve sheath tumors may also show skeletal muscle differentiation, ie., a malignant Triton tumor, and Triton tumors may additionally have pluridirectional differentiation with osteosarcomatous elements. Our NP-2 case did not show immunoreactivity for S100 protein and we had no proof that this was of nerve sheath origin. Hence we felt the best diagnosis was a radiation-induced sarcoma and the addition of the "mixed mesenchymal" sarcomatous components probably did not further worsen the already poor prognosis. The patient developed CSF dissemination of his tumor and succumbed 9 months after his second 2001 cranial resection; no autopsy was performed.

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