40 YEAR‐OLD MALE WITH HISTORY OF BRAIN TUMOR 10 YEARS AGO

CLINICAL HISTORY

In 1992, a 30‐year‐old man was diagnosed with a left parietal parafalcine lesion. He had presented with a generalized tonic clonic seizure and had an 8‐year history of carbamazapine‐controlled Jacksonian type seizure of the right arm and leg. MRI showed a well‐defined left parietal parafalcine hypodense lesion with no mass effect or contrast enhancement (Figure 1A).

Figure 1.

A stereotactic biopsy of the left parietal parafalcine lesion was performed. Subsequently, he received a total dose of 54 Gy radiotherapy in 30 fractions over 50 days.

In January 2002, almost 3 years later, he presented again with a 4‐week history of seizures and slowly progressive right hemiparesis. MRI scan of the brain with and without contrast showed a well‐defined enhancing lesion in the left parietal parafalcine region again (Figure 1B), which was debulked surgically.

PATHOLOGY

In 1992, microscopy showed a tumor comprised of protoplasmic astrocytes forming microcysts. Nuclei were moderately pleomorphic. A few large nuclei were seen. Mitoses and necrosis were absent (Figure 2).

Figure 2.

In 2002, the histology showed a malignant neoplasm composed of densely packed, small dark cells with a scanty cytoplasm arranged in sheets. Scattered bizarre larger, multinucleated cells were present. Nuclei were pleomorphic and hyperchromatic. Mitoses, necrosis, thrombosed vessels and clusters of lymphocytes were found (Figure 3).

Figure 3.

Immunostaining was strongly positive for cytoplasmic NCAM and synaptophysin (Figure 4A). GFAP immunopositivity around vessels and between tumor cells was present but only a few actual tumor cells were positive (Figure 4B). CD99 showed perivascular clusters of immunopositive cells. LCA, chromogranin, CAM 5.2 and NFP were immunonegative.

Figure 4.

Virtually all tumor cells nuclei were immunopositive for the proliferation marker MIB‐1 (Figure 4C) and the majority of nuclei expressed p53 (Figure 4D). Electron microscopy showed undifferentiated round cells with pale, featureless cytoplasm showing a few tubules, filaments and calcific bodies.

Cytogenetic analysis in the biopsy from 2002 showed an abnormal hypodiploid clone: 43–46 chromosomes, loss of chromosome 1 and 13q, an unbalanced 4q rearrangement, a balanced translocation t(12;15) and a marker chromosome of unidentified material. Other random abnormalities were detected which could possibly be treatment related. These abnormalities, however, were not suggestive of a primitive neuroectodermal tumor (PNET).

What is the diagnosis of the 1992 lesion?

What is the diagnosis of the current lesion?

How are they related?

FINAL DIAGNOSIS

Diagnosis in 1992: astrocytoma, WHO grade II.

Diagnosis in 2002: primitive neuroectodermal tumor (PNET), WHO grade IV.

DISCUSSION

The original tumor from 1992 was reviewed and immunohistochemically evaluated confirming the original diagnosis, but quite different from the current tumor (tumor cells were synaptophysin, chromogranin, CAM5.2, LCA and neurofilament protein immunonegative; marked cytoplasmic GFAP immunopositivity was present). In 2002, however, the tumor showed sheets of densely packed, small dark cells with a scanty cytoplasm expressing NCAM and synaptophysin with only focal GFAP expression. This dramatic change in morphology was considered a second tumor induced by previous irradiation. However, the possibility of progression of the original tumor (modulated by radiation effect) was not excluded in view of GFAP‐immunopositive cells in the current tumor, albeit in a minority.

Radiation induced cerebral neoplasia is a well‐known phenomenon (9). White matter is more vulnerable to radiation damage than gray matter (10) especially in doses greater than 20 Gy. The evolution of these new tumor entities after irradiation ranges 5–10 years in adolescence and adults (2, 3, 4, 8) and only a few years in children (7).

Radiation induced long‐term side effects for benign brain tumors are well documented (1, 5). Speculation on the biological nature of secondary tumors are fascinating (5). Not well established is the relation between irradiation of low‐grade glioma and consecutive emergence of primitive neuroectodermal tumor (PNET).

Activation of K‐ras gene has been implicated in the emergence of a PNET after radiation therapy for acute lymphocytic leukemia (3). There is also growing evidence for emergence of PNET after radiation therapy in gliomas (5, 7).

To the five cases reported so far we add a sixth case. The present case shows the emergence of a supratentorial PNET after irradiation for an astrocytoma, WHO grade II. Table 1 shows a synopsis of all reported PNET cases after irradiation for a primary glial neoplasm. In all cases total removal of the primary neoplasm was achieved (Patient 4 is reported to had a subtotal resection).

Table 1.

Synopsis of six PNETs following irradiation of glial neoplasms. M = male; F = female; PNET = primitive neuroectodermal tumor.

Nr	Sex/age	Location	Primary tumor	Therapy (Gy/fractions)	Latency to PNET	Survival
1	M 4	R occipital	Oligodendroglioma Grade II	44/20	29 months	36 months
2	F 6	Cerebella	Pilocytic astrocytoma Grade I	5000 c/25	11 years	11 months
3	M 9	Cerebellar	Malignant ependymoma	3500 c/18 2000 c/10 boost	16 years	18 months
4	M 37	Temporal	Astrocytoma Grade II	5000 c/25	5 years	6 months
5	M 17	IV ventricle	Astrocytoma Grade II	3400 c/17 1600 c/8 boost 2500 c/45	18 years	12 months
6	M 30	L parietal	Astrocytoma Grade II	54/30	10 years	9 months

In patients 1, 5 and 6 the PNET appeared at the site of the irradiated primary lesion. The first patient had a recurrence of the primary tumor after 9 months. He developed a PNET after 29 months from the first operation. It appears the survival period roughly equals the number of years of latency to PNET expressed in months, although this needs further cytogenetic and clinical examination.

Occurrence of a PNET after irradiation of a primary brain tumor appears to be more common than previously thought. Evolution into these “secondary PNETs” needs to be considered in patients receiving radiotherapy for a glial neoplasm. It also adds to the differential diagnosis in patients with a long‐term sequela of irradiation. Table 1 shows the aggressive nature of these “secondary PNETs”. In the majority of cases, the survival time appears shorter than known for supratentorial PNETs (6).

CASE OF THE MONTH: ABSTRACTS

January 2007, Case 1. A 27‐year‐old woman presented with a 5‐month history of headache, hoarseness and swallowing dysfunction, which begun during the last trimester of her second pregnancy. Neurological examination demonstrated right‐sided deafness and dysfunction of the right VII, IX, X and XI cranial nerves. Computed tomography (CT) and magnetic resonance imaging (MRI) disclosed a right temporal bone mass with invasion of the jugular foramen. A massive calcified portion of the tumor significantly compressed the brain stem. The patient underwent surgical resection of the tumor. Microscopic examination disclosed two well‐demarcated components within the tumor. The predominating components were highly cellular areas consisting of ovoid‐to‐spindled cells and numerous osteoclast‐like multinucleated giant cells that frequently contained cytoplasmic vacuoles. Minor lobulated areas consisted of round or polygonal‐shaped cells with grooved, ovoid, hyperchromatic nuclei, surrounded by an eosinophilic chondroid matrix. Calcifications were mainly found in the minor lobulated components of the tumor. The diagnosis was a chondroblastoma of the petrous portion of the temporal bone. Cranial chondroblastomas are extremely rare. Misinterpretation of the histology of chondroblastomas may occur because the multinucleated giant cell containing stroma may be much more predominating than tumor components revealing the typical chondroid differentiation with chondroblasts and a chondroid matrix, making the giant cell tumors the principal differential diagnosis in such cases.

January 2007, Case 2. A 76‐year‐old woman with prior history of bladder cancer 2 months ago presented with dysarthria and brachiofacial hypesthesia of the left side. MRI revealed a mass in the right frontal lobe with inhomogeneous Gadolinium enhancement. The patient underwent stereotatic biopsy. Cytologically, the lesion showed moderate cellularity with conspicuous astrocyte‐like cells with radiating or plump processes, marked endothelial proliferation and amounts of variable Creutzfeldt astrocytes with multiple micronuclei or chromatin clumps as well as granular mitoses. The differential diagnoses included acute demyelinating disease and diffuse glioma. The lesion was histologically and immunohistochemically consistent with a high‐grade glioma. The presented case indicates that care should be taken regarding the diagnostic importance of Creutzfeldt cells in a small biopsy.

February 2007, Case 1. Pleomorphic xanthoastrocytomas (PXA) typically present as superficial tumors, not infrequently associated with a cystic component. While tumoral involvement of the leptomeninges is common, infiltration of the dura is rare. We report the case of a 35‐year‐old woman with recent onset seizure activity and an enhancing 2.5 × 2 × 2.7 cm left temporal mass with a dural tail. Intraoperatively, the mass was noted to be grossly dural based with no attachment to the cortical surface. An intraoperative pathology consultation rendered the diagnosis of meningioma based upon a cytologic preparation. The permanent sections demonstrated diagnostic histologic and immunophenotypical features of PXA. This case represents an uncommon presentation of PXA. The clinical (patient’s age and gender) and radiographic features (enhancing, homogeneous neoplasm with a dural tail) were typical for a meningioma. Intraoperative non‐representative sampling of the neoplasm at the time of intraoperative consultation resulted in an erroneous diagnosis, albeit concordant with the clinical and radiographic findings. In consideration of this atypical presentation, several other pathologic entities were considered before arriving at the correct final diagnosis.

February 2007, Case 2. A 30‐year‐old man suffered severe headaches over six months but without any neurological deficit. On physical examination he presented the clinical picture of Tuberous Sclerosis Complex (TSC). Neuroradiological studies showed a calcifying isointense mass of the right lateral ventricle, measuring 3.5 cm in diameter. The tumor was entirely removed, and histology revealed a subependymal giant cell astrocytoma (SEGA) with elevated mitotic activity. The patient relapsed five months after surgery, and was treated postoperatively by external irradiation. Six months thereafter he complained of imbalance and gait difficulties, and MRI of the spinal axis showed a tumor of the cervical spinal cord that was also biopsied. This uncommonly aggressive tumor showed histopathological features of atypia already in the primary tumor with a further progression to frank malignancy in the recurrence and additional axial spread. This case demonstrates that SEGAs, on rare occasions, may carry a malignant potential.

March 2007, Case 1. Seven months after diagnosis of esophageal adenocarcinoma, this 65‐year‐old man presented with a transcalvarial frontal mass. He expired eleven months later. An autopsy revealed widespread metastatic adenocarcinoma to the lungs, liver and calvarium with extension into the frontal lobes. In addition, a tan, firm, fusiform intradural mass, measuring 5 cm in length and 0.7 cm in diameter was found attached to the lumbosacral cord. The lesion was moderately cellular, consisting of spindle cells with scant cytoplasm and elongated oval nuclei arranged in interlacing bundles and fascicles with negligible fibrous stroma. Bielschowsky silver and Luxol fast blue stained sections revealed an abundance of dense interlacing axons that were surrounded by thin myelin sheaths. His past medical history includes hemipelvectomy following a motor vehicle accident in 1970. Based on the histology, location and the history of hemipelvectomy the diagnosis is traumatic neuroma. Traumatic neuroma is a non‐neoplastic, disorganized proliferation of axons with accompanying Schwann and perineurial cells set in a collagenous stroma, occurring at the site of partial or complete nerve transection.

March 2007, Case 2. A 30‐year‐old male presented in 1992 with headaches and seizures. Imaging showed a left parietal parafalcine mass. A stereotactic biopsy revealed an astrocytoma (WHO grade II) and he was treated with radiotherapy. Ten years later he again presented with seizures and a progressive right hemiparesis. A tumor was debulked from the same location as the previous lesion. This lesion showed densely packed, small round cells with a scant cytoplasm forming sheets. Multinucleation, mitoses, necrosis and thrombosed vessels were present. The tumor cells were strongly positive for NCAM and synaptophysin, but only a few actual tumor cells were GFAP‐positive. Electron microscopy and cytogenetic analysis were performed. The original tumor biopsy from 10 years ago was reviewed and stained and proved to be strongly positive for GFAP and was negative for synaptophysin. The phenotypic change in the second tumor is discussed and it is concluded that the present case shows the emergence of a supratentorial PNET after irradiation for an astrocytoma, WHO grade II. Five previously reported similar cases are reviewed in comparison considering possible underlying genotypic implications.