neurofibrosarcoma recklinghausen's angiosarcomafrom the departmentof pathology...

Journal ofNeurology, Neurosuirgery, and Psychiatry, 1978, 41, 474-478

Neurofibrosarcoma of the radial nerve invon Recklinghausen's disease with metastaticangiosarcoma

R. A. A. MACAULAY

From the Department of Pathology (Neuropathology), Stanford University School of Medicine,Stanford, California, USA

S U M M A R Y A case of von Recklinghausen's disease with multiple neurofibromatosis isdescribed in which death was caused by intracerebral haemorrhage due to metastatic angio-sarcoma. The primary site was a peripheral nerve tumour which, on microscopic examination,showed both angiosarcoma and neurofibrosarcoma with transitional zones between the two.This is interpreted as another example of divergent differentiation in malignant nerve sheathtumours, and the case is compared with the two similar examples found in the literature.

The development of malignancy in a peripheralnerve tumour of von Recklinghausen's disease iswell-known (Harkin and Reed, 1969; Krucke,1974; Russell and Rubinstein, 1977). Distinctionbetween typical forms of malignant Schwannoma,malignant neurofibroma or, alternatively, neuro-fibrosarcoma is sometimes possible on morpho-logical grounds but is often difficult to establishin their most undifferentiated forms (Krucke,1974).A rare but well-established feature in the malig-

nant tumours is the presence of focal metaplasticchange into other mesenchymal elements such ascartilage, osteoid, bone, and skeletal muscle(Russell and Rubinstein, 1977).

This paper presents in detail the development ofyet another example of divergent differentation inmalignant neurofibrosarcoma originating in vonRecklinghausen's disease, namely that of angio-sarcomatous features.

Case report

The patient was an 18 year old white male withvon Recklinghausen's disease diagnosed on thebasis of numerous cafe-au-lait spots over his trunkand limbs, and multiple neurofibromas. He first

Address for correspondence and reprint requests: R. A. A. Macaulay,Department of Forensic Medicine, Edinburgh University MedicalSchool, Teviot Place, Edinburgh, Scotland.Accepted 14 December 1977

presented with a right axillary mass which hadbeen enlarging for six months, right wrist drop,haemoptysis, and a 9 kg weight loss. Chest radiog-raphy showed diffuse right upper lobe infiltration.Biopsy of the axillary mass demonstrated a neuro-fibrosarcoma. He was presumed to have pul-monary metastases, and received radiotherapy tothe right lung, mediastinum, and the axillary mass.Two months later he was readmitted complainingof headaches, nausea, and vomiting. He was dis-orientated and had papilloedema. Brain scan(99n'Tc) and electroencephalography demonstratedbilateral frontal lobe lesions. He died soon afteradmission.

NECROPSY FINDINGS (oG-160)The right radial nerve 10 mm distal to its origin inthe brachial plexus, expanded into a firm palefusiform mass approximately 150X50X50 mm,which compressed and was firmly attached to theulnar nerve (Fig. 1). The mass was easily separatedfrom the surrounding musculature and from thesheath of the axillary artery and vein. On sectionit was firm, white, and whorled with a haematomain the region of a wedge shaped excisional biopsy,and with several other areas of haemorrhage dis-tant from the biopsy site.

Both lungs contained round, grey-white haemor-rhagic parenchymatous and subpleural nodules.None was associated with any of the majorbronchi. The nodules measured up to 15 mm indiameter.

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Neurofibrosarcoma of the radial nerve in von Recklinghausen's disease

Fig. 1 Diagrammaticrepresentation of the dissectednecropsy specimen of the rightbrachial plexus showin1gfusiform expansioni of the radialnerve by neurofibrosarcoma.Note the diffuse thickeningof other nerves due to vonRecklinghausen 's disease.

Immediately next to the left adrenal gland therewas a retroperitoneal haematoma containing anestimated 750 ml of clotted blood which appearedto have originated from a ruptured haemorrhagicadrenal neoplasm. Numerous grey nodules measur-ing up to 3 mm were seen both in the compressedremnant of this adrenal gland and in the adrenalgland on the other side.The brain showed two haematomas measuring

50X30X40 mm in the centra ovalia of bothfrontal lobes. The surrounding parenchyma wasoedematous and contained numerous punctatehiaemorrhages. Smaller haemorrhages measuring10 mm were present in the frontal cortex, thecorpus callosum, and the tuber cinereum.Numerous somatic, sympathetic, and para-

sympathetic nerves and ganglia were grosslythickened, rubbery, and firm (Fig. 2), and cystsup to 3 mm in diameter containing gelatinousmaterial were seen on section.

MICROSCOPYSections of biopsy and necropsy tissues from theright radial nerve mass showed an encapsulatedtumour almost completely obliterating the archi-tecture of the nerve. The tumour showed twodistinct patterns of growth, one merging into theother. The first pattern, seen in the white whorledareas, consisted of spindle shaped cells arrangedin a "herring-bone" pattern with numerousmitoses, many of them bizarre (Fig. 3). Thinwalled vascular channels were present but theendothelial cells lining them did not have amalignant appearance. The intervening delicate

fibrillary ground substance was alcian blue posi-tive. These are the typical appearances of aneurofibrosarcoma (Harkin and Reed, 1969).The second histological pattern, seen in thehaemorrhagic areas distant from the biopsy site,was that of an angiosarcoma. Malignant cellsappeared to line a network of anastomosingvascular channels (Fig. 4). Reticulin stains of theseareas emphasised the vascular architecture and

Fig. 2 Somatic and autonomic nerves at necropsyshowing diffuse and focal thickening by vonRecklinghausen's disease. From left to right: (1)left femoral nerve; (2) and (3) left and right superiorcervical ganglia and sympathetic chains; (4) rightvagus nerve.

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Fig. 3 Neurofibrosarcoma of right radial nerve showing hyperchromatic spindleshaped nuclei compactly arranged in herring-bone pattern. Inset: tumour cell withquadripolar mitotic figure. Both H and E X400.

showed that the cells were inside the reticulinsheath of the vessels. In the transitional zonesbetween these two patterns the cells became moreanaplastic and lost their herring-bone arrangementwith the formation of a few small blood vesselslined by malignant cells (Fig. 5).

Sections from the lung (Fig. 6) and brain meta-stases showed angiosarcoma in a pattern moredistinct than that in the radial nerve. The adrenalcortex and medulla adjacent to the retroperi-toneal haematoma, as well as on the other side,showed both nodular and diffuse infiltration bytumour showing both neurofibrosarcoma andangiosarcoma, the latter demonstrating a morecompact pattern than in the primary lesion.

Sections of all the other peripheral nervetumours showed typical benign neurofibromas.

Discussion

Vascular lesions are known to occur in vonRecklinghausen's disease. They mostly consist ofbenign capillary haemangiomas, although Krucke(1974) has reported a case of generalised neuro-fibromatosis in the newborn in which haeman-gioblastoma and neurofibroma were closelyintermingled in the cerebral pia mater, peripheralnerves and ganglia, skin, soft tissues, vertebralbodies, and several viscera.

In the case reported in this paper, the angio-matous tissue was obviously malignant, and itsprimary derivation in the radial nerve by meta-plasia from the adjacent neurofibrosarcoma wasestablished by the presence of transitional zonesbetween the two.Examples comparable with this case appear to

be extremely rare, and have not so far beendescribed in detail. Woodruff et al. (1973) quotedunpublished data on a case of angiosarcoma in aperipheral nerve tumour without giving details orillustrations. Another case is mentioned briefly, butnot illustrated, by Russell and Rubinstein (1977).This was the case of a 35 year old male withclassical von Recklinghausen's disease who had aneurofibrosarcoma with areas of chondroblasticmetaplasia in the left femoral nerve. This hadmetastasised to the omentum and peritoneumwhere areas comprised of vascular spaces lined bymalignant endothelium were closely associatedwith malignant neurofibrosarcoma. This case isdescribed in more detail by Rubinstein (1963,case 2).Divergent mesenchymal elements in peripheral

nerve sheath tumours such as bone, cartilage,adipose tissue, and skeletal muscle may occursingly or in combination (Woodruff et al.,1973). This case illustrates another form of dif-ferentiation, and the presence of transitional

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Fig. 5 Transitional zone between neurofibrosarcoma and angiosarcoma in rightradial nerve. The cells are less compactly arranged than in Fig. 3 and are

beginning to line ill-defined branching channels at centre and right (arrows).H and E X140.

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Fig. 6 Angiosarcomatous metastasis in right lung. Note the polypoid tuft ofmalignant cells growing into the lumen of the vessel at lower left (arrow).H and E X400.

zones provides further evidence that all thesevariants represent metaplastic potential ofmalignant nerve sheath cells. Of special interestin this context is the simultaneous presence ofdivergent chondroblastic metaplasia in the onlyother example of angiosarcomatous differentia-tion with which the present case can becompared.

In two series (White, 1971; Woodruff et al.,1973), metaplastic elements made no significantdifference to the prognosis. However, in this case,the haemorrhagic nature of the angiosarcomatousmetastases in the brain rather than the actualextent of tumour growth undoubtedly caused thepatient's death.

I would like to acknowledge the encouragementand criticism of Professor L. J. Rubinstein duringthe preparation of this paper. The work was sup-ported in part by Graduate Neuropathology Train-ing Grant 5 TOI NS-05500-10 of the US PublicHealth Service (Dr L. J. Rubinstein).

References

Harkin, J. C., and Reed, R. J. (1969). Tumors ofthe peripheral nervous system. In Atlas of TumorPathology, Fasc. 3 (2nd series). Armed ForcesInstitute of Pathology: Washington DC.

Krucke, W. (1974). Pathologie der Peripheren Nerven.In Handbuch der Neurochirurgie. Edited by H.Olivecrona, W. Tonnis and W. Krenkel. Volume 7,part 3. Springer-Verlag: Berlin.

Rubinstein, L. J. (1963). Tumeurs et hamartomesdans la neurofibromatose centrale. In PhacomatosesCerebrales. Edited by L. Michaux and M. Feld,pp. 427-452. SPEI: Paris.

Russell, D. S., and Rubinstein, L. J. (1977). Pathologyof Tumours of the Central Nervous System. Fourthedition. Edward Arnold: London.

White, H. R. (1971). Survival in malignant Schwan-noma. Cancer, 27, 720-729.

Woodruff, J. M., Chernik, N. L., Smith, M. C.,Millet, W. B., and Foote, F. W. (1973). Peripheralnerve tumours with rhabdomyosarcomatousdifferentiation (Malignant "Triton tumours").Cancer, 321, 426-439.

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