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Solitary extranodal lymphoma of sciatic nerve
Journal of the Neurological Sciences, 1986, 74:23-34 Elsevier
23
JNS 2662
Solitary Extranodal Lymphoma of Sciatic Nerve Dushyant P. Purohit ~, David J. Dick 2, Robert H. Perry ~, Paul R. Lyons 2, Ian S. Schofield2 and John B. Foster 2 Departments of INeuropathology and 2Neurology, Newcastle General Hospital, Newcastle upon Tyne (U.K.) (Received 16 October, 1985) (Revised, received 10 January, 1986) (Accepted 10 January, 1986)
SUMMARY
A solitary extranodal malignant lymphoma (non-Hodgkin's lymphoma, centrocytic type) of the sciatic nerve is described in a 64-year-old woman. Whereas previous reports of peripheral nervous system lymphoma have described multifocal lesions and generally an association with systemic lymphomas, in this case the lymphoma was confined to a segment of a peripheral nerve and was not associated with systemic lymphoma. The clinical presentation was a progressive weakness and sensory d i s turbance in the right leg. Clinical and electrophysiological examination indicated a lesion in the sciatic nerve, and computerised tomography of the right thigh revealed an enlarged distal segment of the sciatic nerve. On surgical exploration, a fusiform tumour of the sciatic nerve was resected. Pathological examination, including immunohistology and electron microscopy revealed a malignant lymphoma. An unusual histological feature was the presence in the tumour and infiltrated nerve of an extracellular eosinophilic non-amyloid material, similar to that occasionally seen in nodal lymphomas. The patient showed no evidence of lymphoma at other sites at the presentation and this has been confirmed at a 9-month review.
Key words:
Extranodal
lymphoma
- Fibrin - Lymphoma
of peripheral nerve - Sciatic
nerve tumour
Requests for reprints to: Dr. D.P. Purohit, Neuropathology Department, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, U.K. 0022-510X/86/$03.50 © 1986 Elsevier Science Publishers B.V. (Biomedical Division)
24 INTRODUCTION
The occurrence of extranodal lymphomas, that is lymphomas occurring primarily in sites which are not in lymphoreticular system, is well documented. Such lymphomas have been identified in a variety of organs including the central nervous system (CNS) (Russell and Rubinstein 1977a,b; Wright and Isaacson 1983). In the CNS, primary lymphomas are rare and in one large autopsy series (Henry et al. 1974) they accounted for only 0.7-0.85 ~o oflymphomas from all sites. In two further reports concerning CNS tumours, lymphomas accounted for between 0.3 and 1.5~o of all types of intracranial neoplasms (Zimmerman 1975). In the spinal cord and cauda equina lymphomas are even more of a rarity, while there are no reports of solitary extranodal lymphoma in the peripheral nervous system (PNS) (Zimmerman 1971; Bruni et al. 1977; Russell and Rubinstein 1977a,b; Mauney and Sciotto 1983). Of the lymphoma and leukaemic deposits which occur in the PNS (Kohut 1946; Allison and Gordon 1955; Baron et al. 1960; Vital et al. 1975) most have arisen as a consequence of secondary involvement, either due to direct epineurial spread from adjacent tumour, or as distant endoneurial deposits where they may present as a sensorimotor polyneuropathy or polyradiculitis suggesting multiple neural deposits. Primary neoplasms of large or medium-sized nerves are unusual except, of course, in von Recklinghausen's disease, and sciatic nerve tumours are distinctly uncommon. However, neurofibromas, neurilemoma (Dyck et al. 1984), neurofibrosarcoma, haemangiomata (Losli 1952), and some more unusual entities such as endometriosis (Baker et al. 1966), and granular cell tumour (Shimarura et al. 1984) have been reported. The response of secondary peripheral nerve lymphomas to therapy is variable with partial or significant alleviation of nerve deficits in some cases, although the overall prognosis depends on the type, grade and extent of the systemic lymphoma. Solitary extranodal lymphomas, on the other hand, commonly respond favourably to surgery and radiotherapy, and often show long-term remissions (Lee and Spratt 1974; Wright and Issacson 1983). This tumour also exhibits an unusual histological feature in the form of large amounts of extracellular eosinophilic non-amyloid proteinaceous material. It is known that certain types of lymphomas, particularly those with plasmacytic differentiation, may contain amyloid or, occasionally, a similar but non-Congophilic extracellular material (Wright and Isaacson 1983). The amyloid deposited in such lymphomas and in myeloma is usually of immunological origin (AIO); the non-amyloid variety of extracellular material is less well characterised and its identity and origin are not known. In this study, the non-amyloid material deposited in the lymphoma has been characterised. CASE REPORT
A 64-year-old woman presented with an 18-month history of progressive weakness and numbness in the right foot. She eventually developed a flail foot and a disturbance of sensation which extended proximally over the lateral aspect of the leg.
25 There was no disturbance of sphincter function. Except for a past history of pulmonary tuberculosis she had previously been in good health. On physical examination the right foot showed a marked weakness of dorsiflexion, inversion, eversion and plantarflexion, and weakness of intrinsic foot muscles. The pattern of sensory loss suggested a sciatic nerve lesion. There was no abnormality detected elsewhere on neurological examination. Systemic examination showed no evidence of hepatosplenomagaly or lymphadenopathy. Standard laboratory investigations showed ESR 40 mm/h (Westergren), haemoglobin 12.2 g/dl, WBC 3.2 x 109/1 with a normal differential count, and a platelet count of 270 x 109/1. The biochemical profile was normal. Tests for Rheumatoid factor and antinuclear factor were positive with titres of 1 : 40 and 1 : 80, respectively, and DNA binding was 22 units/ml (normal < 20 units/ml). No abnormal protein bands were detected on electrophoresis of serum or concentrated urine and estimation of serum immunoglobulin was normal. VDRL was negative. Bone marrow smear and trephine biopsy were normal and there was no evidence of bone marrow neoplasm.
Neurophysiology Nerve conduction studies were performed on the right peroneal, posterior tibial, superficial peroneal and sural nerves. Using a recording electrode over extensor digitorum brevis and stimulation at the ankle and the head of the fibula, no identifiable response was found from the common peroneal nerve. On stimulating the posterior tibial nerve at the ankle and popliteal fossa no reponse was seen in abductor hallucis. No sensory nerve action potentials were recorded from the sural and superficial peroneal nerves. A concentric needle electrode was used to study a number of muscles. Profuse insertional activity of fibrillation potentials and positive sharp waves were noted in extensor digitorum brevis, abductor hallucis, tibialis anterior, soleus and gastrocnemius. No volitional activity was found at any of the sites studied. A response was evoked in tibialis anterior following stimulation of the common peroneal nerve at the fibular head and several other sites as far as the apex of the popliteal fossa. No definite evidence of a discrete conduction disturbance was seen in this region. An examination of the medial hamstrings, biceps femoris, tensor fascia lata, glutei and vastus lateralis did not reveal any insertional activity and the volitionally recruited motor units were within normal limits for the patient's age. The pattern of involvement indicated a lesion of the sciatic nerve between the origin of the muscular branches to biceps femoris and medial hamstrings and the apex of the popliteal fossa.
Radiology Routine radiology of the chest and right femur was normal. An isotope bone scan was also normal. A computerized tomography scan of the thighs during an infusion of intravenous urografin revealed an enhancing fusiform expansion of a 10-cm segment of the distal right sciatic nerve (Fig. I). A femoral arteriogram was normal. In view of these f'mdings it was decided to explore the right sciatic nerve.
26
Fig. 1. Computerised tomography scan at mid-thigh level demonstrating an enhancing mass (arrow) involving the right sciatic nerve. This was the only enhancing mass in the CT scan of the right thigh and no evidence of neoplasm was observed in the femur, soft tissue around the sciatic nerve or in the inguinal and popliteal regions.
Operative findings Exploration o f the right leg through a mid-line posterior thigh incision revealed a large fusiform t u m o u r o f the sciatic nerve at the mid-thigh level. It was entirely confined to the nerve, without any evidence of tumour in the surrounding soft tissue or in the popliteal fossa (Fig. 2). Histological a p p e a r a n c e s of a frozen section suggested that the t u m o u r was a diffuse metastatic infiltrate. The nerve tumour was resected with proximal and distal clearance.
Pathological findings Gross pathology The resected segment o f the sciatic nerve was 21 cm in length containing a large fusiform t u m o u r o f the middle 9.0 c m o f the nerve with a m a x i m u m diameter o f 4 c m (Fig. 3). Multiple cross-sections of the t u m o u r showed a smooth cut surface with off-white, pale grey a n d brownish areas, some o f which a p p e a r e d to be enlarged and thickened nerve fascicles. The t u m o u r also showed on its surface a well defined longitudinal linear and firm ridge at one place which, on cut surface was a circumscribed
27
Fig. 2. Sciatic nerve tumour exposed through a mid-thigh surgical incision. The rectangular defect in the expanded nerve represents the frozen-section biopsy site.
I
Fig. 3. Excised sciatic nerve segment with a fusiform tumour reconstructed after histological sampling. Bar = 1 cm. Inset shows a transverse section of the turnout illustrating diffuse involvement of the nerve by the tumour. An arrow marks a compactly cellular area forming a ridge on the surface of the tumour. This nodular area contained cells with prominent plasma cell differentiation. Haematoxylin and eosin, x 2.
28 pale brown nodule measuring 1.0 cm in diameter (Fig. 3). The proximal and distal excision ends were 1.1 cm and 0.6 cm in diameter, respectively. Methods
The specimen was fixed in 10~o buffered formalin for 24 h, and multiple sections from the tumour and excision ends were paraffin-processed. Histological sections (5 and 10/~m) were stained by the following methods: H&E (haematoxylin and eosin), Foot's method for reticulin, PAS (periodic acid-Schif0 with and without diastase, MSB (Martius, Scarlet, Blue), UP (Unna Pappenheim's methyl green pyronin) method, Loyez iron haematoxylin method for myelin, and Congo-red, Sirius red, and Thioflavin-T methods for amyloid. Immunohistological investigation of formalin fixed paraffin-embedded sections was performed by the PAP method using commercially available polyclonal antisera (Dako Corp.) for heavy and light chain immunoglobutins (dilutions 1 : 1000 and 1 : 2000, respectively), muramidase and alpha-1 anti-trypsin (dilutions 1 : 200 and 1 : 500, respectively), fibrinogen (dilution 1 : 100), and S-100 protein (dilution 1:500). Positive controls used for immunoglobulins and macrophage markers were obtained from the standard cases of multiple myeloma and histiocytic lymphoma; and for fibrinogen from a histological section of an organising arterial thrombus. In all these immunohistological procedures, the incubation was carried out for 18 h at room temperature. A small piece of tumour was postfixed in glutaraldehyde for electron microscopy. Further pieces of tissue were taken for semi-thin sections using the celloidin embedding technique. RESULTS The histological features are summarised as follows: In the frozen section, groups of small round tumour cells, separated by eosinophilic, fibrous type material and nerve bundles suggested a diagnosis of a metastasis from a carcinoma or lymphoma. In the paraffin sections the majority of the regions examined showed infiltration and destruction of nerve by a tumour composed of round, slightly pleomorphic cells with large nuclei containing condensed chromatin and small nucleoli (Fig. 4A). In semi-thin sections many of the tumour cells showed features ofcentrocytes (Fig. 5). Mixed with these cells were small lymphocytes and a small number of centroblasts. In addition, cells with variable plasmacytic differentiation (pyroninophilic in UP stain) were present in focal aggregates and as compact sheets in the nodular area (Fig. 3, inset). A moderate number of mitoses were present. An unusual histological feature was the presence of abundant extracellular eosinophilic material (Figs. 6 and 7) which was deposited as amorphous material or as fibrous and band like structures; this was present both in the tumour and in the adjacent interfascicular connective tissue. There was frequently a marked foreign body granulomatous reaction in relation to this material. On special stains, this material showed a negative staining reaction for amyloid, but a positive reaction for fibrin by the MSB stain, the amorphous material staining bright red, and the fibrous material a pale blue, suggesting old fibrin. Immunohistological investigation showed a positive reaction
29
Fig. 4. Photomicrographfrom a typical area of the tumour which consisted predomenantlyof compactly cellularsheets ofplasmacytoidand lymphoidcells. Scatteredpale cellsare macrophages.Haematoxylinand eosin, x 400.
for fibrinogen. S I00 protein was not identified in this material, thus excluding the presence of myelin. Immunohistology of the lymphoma cells showed a monotypical reaction to IgA and Kappa light chain in the differentiated plasma cells and in some centrocytes. Overall the features of the tumour were of a non-Hodgkin lymphoma of B-cell (follicle centre cell) origin, classified as malignant lymphoma, centrocytic type (Lennert's modification of the Kiel classification: Lennert 1978; Wright 1982), with an added feature of a prominent plasma cell differentiation. The excision ends of the specimen showed no evidence of tumour infiltration. There was severe axonal degeneration of the nerve fibres of the distal excision end. The nerve fibres of the proximal excision end showed a slight loss of myelinated nerve fibres and interfascicular oedema. Electron microscopy confirmed the centrocytic and plasmacytic differentiation of the tumour cells. On low power electron microscopy, the extracellular deposit was densely osmophilic and coarsely granular; and on high magnification it showed very fine fibrillary and granular structures, lacking the characteristic ultrastructural features of amyloid (e.g. filaments or thread-like structures with diameters of 8-40 nm).
30
Fig. 5. Semi-thin section of celloidin-embedded tissue showing cellular detail of the tumour cells: centrocytes with a cleaved nucleus showing a delicate nuclear membrane and clumped chromatin (small arrow-heads • ); centroblasts identified as larger cells with a large round or oval vesicular nucleus containing condensed chromatin arranged peripherally at the distinct nuclear membrane, and one or more prominent nucleoli (large arrow-heads •); plasmacytes with prominent cytoplasm and round, accentrically placed nucleus containing characteristic peripherally clumped ('clock-face') chromatin (open arrow ~ ); differenciating plasma cells (plasmablasts); and lymphoid cells (filled arrow~l~). Toluidine blue, × 800.
DISCUSSION The clinical and pathological findings suggest that this tumour is a solitary primary lymphoma of sciatic nerve. It is k n o w n that malignant lymphomas may present, and even remain, at sites other than in the lymphoreticular system, and such nondisseminated (solitary) lymphomas of extranodal origin have been identified in a variety of organs. These include stomach and intestine, lung, tonsil, skin, connective tissue, bone, testis, salivary gland, breast, thyroid and the C N S (Freeman et al. 1972; Lee and Spratt 1974; Wright and Isaacson 1983), but they have not been previously reported in peripheral nerve. These extranodal lymphomas are not rare: in a study (Freeman et al. 1972) based on the findings of the End Result Study G r o u p of the National Cancer Institute covering the period between 1950-64, about 16~o of 12497 cases of lymphomas were said to have arisen at sites other than in the lymph nodes. Most of
31
Fig. 6. Amorphousand fibrousband-likeeosinophilicnon-amyloidmaterialdepositedin the tumour. In this photomicrographit shows a positivestaining reactionfor fibrinby the Martius, Scarlet,Bluemethod, x 344.
these extranodal lymphomas were of the type now classified as non-Hodgkin's lymphoma, and less than 5 ~o were Hodgkin's disease. In attempting to explain the sites of predilection of extranodal lymphomas, it has been suggested (Wright and Isaacson 1983) that such sites are not randomly selected, but are connected with the physiological distribution and 'homing pattern' of lymphocytes. Lymphoma arising in the gastrointestinal tract, thyroid, salivary gland, and Burkitt's lymphoma and T-cell lymphoma of skin may be explained by this phenomenon. There is no immediate evidence, however, of such a physiological connection in peripheral nerves and there are no reports of lymphomas arising in primary inflammatory conditions such as polyneuritis. It has also been observed (Wright 1982) that lymphomas occurring at sites other than those with a natural or physiological population of lymphocytes are more likely to be metastases from nodal lymphomas. But it should also be noted that cases of solitary, extranodal lymphoma in organs such as breast, testis and brain are well documented, and in many of these reported cases nodal lymphoma has not been identified either at the clinical presentation or at autopsy (see references above). The present case of solitary extranodal lymphoma also falls into this category, and suggests that different mechanisms for the origin of such tumours may operate in some cases.
32
Fig. 7. Foreign-body giant cell reaction prow)ked by the eosinophilic non-amyloid material. In this photomicrograph, the multinucleated giant cells are arranged at the edge of the deposit of the extracellular material. Haematoxylin and eosin, x 412.
Lymphoma may affect peripheral nerves by tumour infiltration or as a paraneoplastic manifestation of malignancy (Currie et al. 1970; Currie and Henson 1971). Paraneoplastic neuropathies are of 3 main types: an acute demyelinating polyneuropathy associated with segmental demyelination and mononuclear cell infiltrate (Cameron et al. 1958; Lisak et al. 1977), a sensorimotor polyneuropathy which may be due to segmental demyelination or primary axonal degeneration (Currie and Henson 1971; Walsh 1971) and rarely a pure sensory neuropathy in which neuronal degeneration in the dorsal root ganglia may occur (Van Gehuchten 1952). Peripheral nerve involvement by actual invasion by lymphoma may occur either as a local spread from the adjacent lymph node or bone lymphoma or as a remote metastasis from nodal lymphoma (and leukemia) which may manifest as polyneuritis and sensorimotor polyneuropathy obviously attributable to multiple peripheral nerve involvement (Kohut 1946; Allison and Gordon 1955; Baron et al. 1960; Vital et al. 1975). The treatment of these multifocal lymphomas of peripheral nerves is often chemotherapy, which if successful, may eliminate or suppress undetected or occult nodal lymphomas. The present case of sciatic nerve lymphoma, being a case of solitary lymphoma, was treated by surgical excision followed by local radiotherapy. At clinical review 9 months after this treatment there was no evidence of recurrence of the neoplasm, or of a lymphoma developing elsewhere. The patient's general health is good. Freeman et al. (1972) in their
33 study of extranodal tymphoma, reported that 57~o of extranodal lymphomas did not spread to adjacent organs or to the regional lymph nodes. The adjusted 5-year survival rate amongst these cases was as high as 59~o. The 5-year survival rate for extranodal lymphoma arising in stomach, lung and tonsil was particularly good when compared with other malignancies arising in these sites. From these reports, and the known relatively low grade biological behaviour of centrocytic lymphomas (Lennert 1978), it is hoped that this case of sciatic nerve lymphoma will have a favourable outcome. An interesting histological feature of this lymphoma was the presence of amorphous fibrous or band like non-amyloid material. Similar material has previously been described in nodal lymphomas (Wright and Isaacson 1983), although its nature and origin have not been identified. We have attempted to characterise the deposit of non-amyloid material in our case of lymphoma, and have found that the material has histological, immunohistologicat and ultrastructural features of fibrin or a fibrinoid product. Although it is possible that the origin and nature of 'amyloid-like' material in lymphomas may differ from case to case, in the present instance it is related to fibrin or a fibrinoid product. Note added in proof
Three years after presentation, the patient developed enlarged axillary lymph nodes. Biopsy and histological examination revealed a high grade non-Hodgkin's lymphoma - centroblastic type, indicating the development of a systemic disease. ACKNOWLEDGEMENTS We thank Mr. M . J . M . Black for contributing the section on operative findings in this paper. We also thank Dr. D. Patrick for his help in the section on radiological diagnosis. We are indebted to Mr. J. Stanger and Mr. R. B. Jewitt for the technical work and for photographic assistance. We thank Mrs. Ira Purohit for preparing the manuscript, and we gratefully acknowledge the help and suggestions of Mrs. Hether Russell during the preparation of the manuscript. REFERENCES Allison, R.S. and D.S. Gordon (1955) Reticulosis of the nervous system simulating acute infective polyneuritis, Lancet, ii: 120. Baker, G.S., W.R. Parson and J.S. Welch (1966) Endometriosis within the sheath of the sciatic nerve, J. Neurosurg., 25: 652-655. Baron, K. D., L. P. Rowland and H. M. Zimmermann(1960) Neuropathywith malignanttumour metastases, J. Nerv. Ment. Dis., 131: 10. Bruni, J., J.M. Bilbao and T. Gray (1977) Primary intramedullarymalignant lymphomaof the spinal cord, Neurology, 27: 896-898. Cameron, D.J., D. A. Howell and J. L. Hutchison (1958) Acute peripheral neuropathyin Hodgkin'sdisease, Neurology (Minneap.), 8: 575. Currie S. and R.A. Henson (1971) Neurological syndromes in reticulosis, Brain, 94: 307-320. Currie, S., R. A. Henson and A.J. Poolie (1970) The incidence of the non-metastatic neurological syndromes of obscure origin in the reticuloses, Brain, 93: 629-640. Dyck, P.C., P.K. Thomas, E.H. Lambert and R. Bunge (1984) Peripheral Neuropathy, W.B. Saunders, Philadelphia.
34 Freeman, C., J. W. Burg and S.J. Cutler (1972) Occurrence and prognosis of extranodal lymphoma, Cancer, 29: 1594-1601. Henry, J. M., R. R. Heffner, S. H. DiUard, K. M. Earle and R. L. Davis (1974) Primary malignant lymphomas of the central nervous system, Cancer, 34: 1293-1302. Kohut, H. (1946) Unusual involvement of the nervous system in generalised lymphoblastoma, J. Nerv. Ment. Dis., 103: 9. Lee, Y.-Tn. and J. S. Spratt (1974) Malignant Lymphoma - - Nodal and Extranodal Diseases (Modern Surgical Monograph), Grune and Stratton, New York. Lennert, K. (1978) Malignant lymphoma other than Hodgkin's disease. In: H. Mohri, H. Stein, E. Kaiserling and H.K. Mullerhermelink (Eds.), Handbuch der Speziellen Pathologischen Anatomie und Histologie, Vol. 1, Part 3, Sect. B, Springer-Verlag, Berlin. Lisak, R. P., R. Mitchell, B. Zwieman, E. Orrechio and A. K. Asbury (1977) Guillain-Barr6 syndrome and Hodgkin's disease - - Three cases with immunological studies, Ann. Neurol., 1: 27. Losli, E.V. (1952) Intrinsic haemangiomas of the peripheral nerves, Amer. Arch. Path., 53: 226-232. Mauney, M. and C.G. Sciotto (1983) Primary malignant lymphoma of the cauda equina, Amer. J. Surg. Path., 7: 185-190. Russell, D. S. and L.J. Rubinstein (1977a) Tumours of the reticular tissue, reticuloses and allied conditions. In: D.S. Russell and L.J. Rubinstein, Pathology of Tumours of the Nervous System, Edward Arnold, London, pp. 101-115. Russell, D. S. and L.J. Rubinstein (1977b) Secondary neoplasms - - Nerve roots, ganglia and peripheral nerves. In: D.S. Russell and L.J. Rubinstein, Pathology of Tumours of the Nervous System, Edward Arnold, London, p. 358. Shimarura, K., Y. R. Osamura, Y. Ueyama, J. Hata, N. Tamaoki, N. Machida, H. Fakuda and K. Uemura (1984) Malignant granular cell tumour of the right sciatic nerve, Cancer, 53: 524-529. Van Gehuchten, P. (1952) Polyganglionite subaiguE ~t symptomatologie de polyn6vrite, Rev. Neurol. (Paris), 87: 410. Vital, C., E. Bonnard, L. Arne, M. Barrat and M. Leblane (1975) Unusual involvement of the nervous system in generalised lymphoblastoma, J. Nerv. Ment. Dis., 103: 9. Walsh, J.C. (1971) Neuropathy associated with lymphoma, J. Neurol. Neurosurg. Psychiat., 34: 42-50. Wright, D. H. (1982) The identification and classification of non-Hodgkin's lymphoma - - A review, Diagn. Histopath., 2: 73-112. Wright, D.H. and P.G. Isaacson (1983) Lymphocytic-plasmacytic lymphomas. In: D. H. Wright and P.G. Isaacsou, Biopsy Pathology of the Lymphoreticular System, Chapman and Hall, London, pp. 142-145. Zimmerman H.M. (1971) Malignant lymphomas. In: J. Minckler (Ed.), Pathology of the Nervous System, Vol. 2, McGraw-Hill, New York, p. 2175. Zimmerman, H.M. (1975) Malignant lymphoma of the nervous system, Acta Neuropath. (Berl.), Suppl. 6, pp. 69-74.
23
JNS 2662
Solitary Extranodal Lymphoma of Sciatic Nerve Dushyant P. Purohit ~, David J. Dick 2, Robert H. Perry ~, Paul R. Lyons 2, Ian S. Schofield2 and John B. Foster 2 Departments of INeuropathology and 2Neurology, Newcastle General Hospital, Newcastle upon Tyne (U.K.) (Received 16 October, 1985) (Revised, received 10 January, 1986) (Accepted 10 January, 1986)
SUMMARY
A solitary extranodal malignant lymphoma (non-Hodgkin's lymphoma, centrocytic type) of the sciatic nerve is described in a 64-year-old woman. Whereas previous reports of peripheral nervous system lymphoma have described multifocal lesions and generally an association with systemic lymphomas, in this case the lymphoma was confined to a segment of a peripheral nerve and was not associated with systemic lymphoma. The clinical presentation was a progressive weakness and sensory d i s turbance in the right leg. Clinical and electrophysiological examination indicated a lesion in the sciatic nerve, and computerised tomography of the right thigh revealed an enlarged distal segment of the sciatic nerve. On surgical exploration, a fusiform tumour of the sciatic nerve was resected. Pathological examination, including immunohistology and electron microscopy revealed a malignant lymphoma. An unusual histological feature was the presence in the tumour and infiltrated nerve of an extracellular eosinophilic non-amyloid material, similar to that occasionally seen in nodal lymphomas. The patient showed no evidence of lymphoma at other sites at the presentation and this has been confirmed at a 9-month review.
Key words:
Extranodal
lymphoma
- Fibrin - Lymphoma
of peripheral nerve - Sciatic
nerve tumour
Requests for reprints to: Dr. D.P. Purohit, Neuropathology Department, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, U.K. 0022-510X/86/$03.50 © 1986 Elsevier Science Publishers B.V. (Biomedical Division)
24 INTRODUCTION
The occurrence of extranodal lymphomas, that is lymphomas occurring primarily in sites which are not in lymphoreticular system, is well documented. Such lymphomas have been identified in a variety of organs including the central nervous system (CNS) (Russell and Rubinstein 1977a,b; Wright and Isaacson 1983). In the CNS, primary lymphomas are rare and in one large autopsy series (Henry et al. 1974) they accounted for only 0.7-0.85 ~o oflymphomas from all sites. In two further reports concerning CNS tumours, lymphomas accounted for between 0.3 and 1.5~o of all types of intracranial neoplasms (Zimmerman 1975). In the spinal cord and cauda equina lymphomas are even more of a rarity, while there are no reports of solitary extranodal lymphoma in the peripheral nervous system (PNS) (Zimmerman 1971; Bruni et al. 1977; Russell and Rubinstein 1977a,b; Mauney and Sciotto 1983). Of the lymphoma and leukaemic deposits which occur in the PNS (Kohut 1946; Allison and Gordon 1955; Baron et al. 1960; Vital et al. 1975) most have arisen as a consequence of secondary involvement, either due to direct epineurial spread from adjacent tumour, or as distant endoneurial deposits where they may present as a sensorimotor polyneuropathy or polyradiculitis suggesting multiple neural deposits. Primary neoplasms of large or medium-sized nerves are unusual except, of course, in von Recklinghausen's disease, and sciatic nerve tumours are distinctly uncommon. However, neurofibromas, neurilemoma (Dyck et al. 1984), neurofibrosarcoma, haemangiomata (Losli 1952), and some more unusual entities such as endometriosis (Baker et al. 1966), and granular cell tumour (Shimarura et al. 1984) have been reported. The response of secondary peripheral nerve lymphomas to therapy is variable with partial or significant alleviation of nerve deficits in some cases, although the overall prognosis depends on the type, grade and extent of the systemic lymphoma. Solitary extranodal lymphomas, on the other hand, commonly respond favourably to surgery and radiotherapy, and often show long-term remissions (Lee and Spratt 1974; Wright and Issacson 1983). This tumour also exhibits an unusual histological feature in the form of large amounts of extracellular eosinophilic non-amyloid proteinaceous material. It is known that certain types of lymphomas, particularly those with plasmacytic differentiation, may contain amyloid or, occasionally, a similar but non-Congophilic extracellular material (Wright and Isaacson 1983). The amyloid deposited in such lymphomas and in myeloma is usually of immunological origin (AIO); the non-amyloid variety of extracellular material is less well characterised and its identity and origin are not known. In this study, the non-amyloid material deposited in the lymphoma has been characterised. CASE REPORT
A 64-year-old woman presented with an 18-month history of progressive weakness and numbness in the right foot. She eventually developed a flail foot and a disturbance of sensation which extended proximally over the lateral aspect of the leg.
25 There was no disturbance of sphincter function. Except for a past history of pulmonary tuberculosis she had previously been in good health. On physical examination the right foot showed a marked weakness of dorsiflexion, inversion, eversion and plantarflexion, and weakness of intrinsic foot muscles. The pattern of sensory loss suggested a sciatic nerve lesion. There was no abnormality detected elsewhere on neurological examination. Systemic examination showed no evidence of hepatosplenomagaly or lymphadenopathy. Standard laboratory investigations showed ESR 40 mm/h (Westergren), haemoglobin 12.2 g/dl, WBC 3.2 x 109/1 with a normal differential count, and a platelet count of 270 x 109/1. The biochemical profile was normal. Tests for Rheumatoid factor and antinuclear factor were positive with titres of 1 : 40 and 1 : 80, respectively, and DNA binding was 22 units/ml (normal < 20 units/ml). No abnormal protein bands were detected on electrophoresis of serum or concentrated urine and estimation of serum immunoglobulin was normal. VDRL was negative. Bone marrow smear and trephine biopsy were normal and there was no evidence of bone marrow neoplasm.
Neurophysiology Nerve conduction studies were performed on the right peroneal, posterior tibial, superficial peroneal and sural nerves. Using a recording electrode over extensor digitorum brevis and stimulation at the ankle and the head of the fibula, no identifiable response was found from the common peroneal nerve. On stimulating the posterior tibial nerve at the ankle and popliteal fossa no reponse was seen in abductor hallucis. No sensory nerve action potentials were recorded from the sural and superficial peroneal nerves. A concentric needle electrode was used to study a number of muscles. Profuse insertional activity of fibrillation potentials and positive sharp waves were noted in extensor digitorum brevis, abductor hallucis, tibialis anterior, soleus and gastrocnemius. No volitional activity was found at any of the sites studied. A response was evoked in tibialis anterior following stimulation of the common peroneal nerve at the fibular head and several other sites as far as the apex of the popliteal fossa. No definite evidence of a discrete conduction disturbance was seen in this region. An examination of the medial hamstrings, biceps femoris, tensor fascia lata, glutei and vastus lateralis did not reveal any insertional activity and the volitionally recruited motor units were within normal limits for the patient's age. The pattern of involvement indicated a lesion of the sciatic nerve between the origin of the muscular branches to biceps femoris and medial hamstrings and the apex of the popliteal fossa.
Radiology Routine radiology of the chest and right femur was normal. An isotope bone scan was also normal. A computerized tomography scan of the thighs during an infusion of intravenous urografin revealed an enhancing fusiform expansion of a 10-cm segment of the distal right sciatic nerve (Fig. I). A femoral arteriogram was normal. In view of these f'mdings it was decided to explore the right sciatic nerve.
26
Fig. 1. Computerised tomography scan at mid-thigh level demonstrating an enhancing mass (arrow) involving the right sciatic nerve. This was the only enhancing mass in the CT scan of the right thigh and no evidence of neoplasm was observed in the femur, soft tissue around the sciatic nerve or in the inguinal and popliteal regions.
Operative findings Exploration o f the right leg through a mid-line posterior thigh incision revealed a large fusiform t u m o u r o f the sciatic nerve at the mid-thigh level. It was entirely confined to the nerve, without any evidence of tumour in the surrounding soft tissue or in the popliteal fossa (Fig. 2). Histological a p p e a r a n c e s of a frozen section suggested that the t u m o u r was a diffuse metastatic infiltrate. The nerve tumour was resected with proximal and distal clearance.
Pathological findings Gross pathology The resected segment o f the sciatic nerve was 21 cm in length containing a large fusiform t u m o u r o f the middle 9.0 c m o f the nerve with a m a x i m u m diameter o f 4 c m (Fig. 3). Multiple cross-sections of the t u m o u r showed a smooth cut surface with off-white, pale grey a n d brownish areas, some o f which a p p e a r e d to be enlarged and thickened nerve fascicles. The t u m o u r also showed on its surface a well defined longitudinal linear and firm ridge at one place which, on cut surface was a circumscribed
27
Fig. 2. Sciatic nerve tumour exposed through a mid-thigh surgical incision. The rectangular defect in the expanded nerve represents the frozen-section biopsy site.
I
Fig. 3. Excised sciatic nerve segment with a fusiform tumour reconstructed after histological sampling. Bar = 1 cm. Inset shows a transverse section of the turnout illustrating diffuse involvement of the nerve by the tumour. An arrow marks a compactly cellular area forming a ridge on the surface of the tumour. This nodular area contained cells with prominent plasma cell differentiation. Haematoxylin and eosin, x 2.
28 pale brown nodule measuring 1.0 cm in diameter (Fig. 3). The proximal and distal excision ends were 1.1 cm and 0.6 cm in diameter, respectively. Methods
The specimen was fixed in 10~o buffered formalin for 24 h, and multiple sections from the tumour and excision ends were paraffin-processed. Histological sections (5 and 10/~m) were stained by the following methods: H&E (haematoxylin and eosin), Foot's method for reticulin, PAS (periodic acid-Schif0 with and without diastase, MSB (Martius, Scarlet, Blue), UP (Unna Pappenheim's methyl green pyronin) method, Loyez iron haematoxylin method for myelin, and Congo-red, Sirius red, and Thioflavin-T methods for amyloid. Immunohistological investigation of formalin fixed paraffin-embedded sections was performed by the PAP method using commercially available polyclonal antisera (Dako Corp.) for heavy and light chain immunoglobutins (dilutions 1 : 1000 and 1 : 2000, respectively), muramidase and alpha-1 anti-trypsin (dilutions 1 : 200 and 1 : 500, respectively), fibrinogen (dilution 1 : 100), and S-100 protein (dilution 1:500). Positive controls used for immunoglobulins and macrophage markers were obtained from the standard cases of multiple myeloma and histiocytic lymphoma; and for fibrinogen from a histological section of an organising arterial thrombus. In all these immunohistological procedures, the incubation was carried out for 18 h at room temperature. A small piece of tumour was postfixed in glutaraldehyde for electron microscopy. Further pieces of tissue were taken for semi-thin sections using the celloidin embedding technique. RESULTS The histological features are summarised as follows: In the frozen section, groups of small round tumour cells, separated by eosinophilic, fibrous type material and nerve bundles suggested a diagnosis of a metastasis from a carcinoma or lymphoma. In the paraffin sections the majority of the regions examined showed infiltration and destruction of nerve by a tumour composed of round, slightly pleomorphic cells with large nuclei containing condensed chromatin and small nucleoli (Fig. 4A). In semi-thin sections many of the tumour cells showed features ofcentrocytes (Fig. 5). Mixed with these cells were small lymphocytes and a small number of centroblasts. In addition, cells with variable plasmacytic differentiation (pyroninophilic in UP stain) were present in focal aggregates and as compact sheets in the nodular area (Fig. 3, inset). A moderate number of mitoses were present. An unusual histological feature was the presence of abundant extracellular eosinophilic material (Figs. 6 and 7) which was deposited as amorphous material or as fibrous and band like structures; this was present both in the tumour and in the adjacent interfascicular connective tissue. There was frequently a marked foreign body granulomatous reaction in relation to this material. On special stains, this material showed a negative staining reaction for amyloid, but a positive reaction for fibrin by the MSB stain, the amorphous material staining bright red, and the fibrous material a pale blue, suggesting old fibrin. Immunohistological investigation showed a positive reaction
29
Fig. 4. Photomicrographfrom a typical area of the tumour which consisted predomenantlyof compactly cellularsheets ofplasmacytoidand lymphoidcells. Scatteredpale cellsare macrophages.Haematoxylinand eosin, x 400.
for fibrinogen. S I00 protein was not identified in this material, thus excluding the presence of myelin. Immunohistology of the lymphoma cells showed a monotypical reaction to IgA and Kappa light chain in the differentiated plasma cells and in some centrocytes. Overall the features of the tumour were of a non-Hodgkin lymphoma of B-cell (follicle centre cell) origin, classified as malignant lymphoma, centrocytic type (Lennert's modification of the Kiel classification: Lennert 1978; Wright 1982), with an added feature of a prominent plasma cell differentiation. The excision ends of the specimen showed no evidence of tumour infiltration. There was severe axonal degeneration of the nerve fibres of the distal excision end. The nerve fibres of the proximal excision end showed a slight loss of myelinated nerve fibres and interfascicular oedema. Electron microscopy confirmed the centrocytic and plasmacytic differentiation of the tumour cells. On low power electron microscopy, the extracellular deposit was densely osmophilic and coarsely granular; and on high magnification it showed very fine fibrillary and granular structures, lacking the characteristic ultrastructural features of amyloid (e.g. filaments or thread-like structures with diameters of 8-40 nm).
30
Fig. 5. Semi-thin section of celloidin-embedded tissue showing cellular detail of the tumour cells: centrocytes with a cleaved nucleus showing a delicate nuclear membrane and clumped chromatin (small arrow-heads • ); centroblasts identified as larger cells with a large round or oval vesicular nucleus containing condensed chromatin arranged peripherally at the distinct nuclear membrane, and one or more prominent nucleoli (large arrow-heads •); plasmacytes with prominent cytoplasm and round, accentrically placed nucleus containing characteristic peripherally clumped ('clock-face') chromatin (open arrow ~ ); differenciating plasma cells (plasmablasts); and lymphoid cells (filled arrow~l~). Toluidine blue, × 800.
DISCUSSION The clinical and pathological findings suggest that this tumour is a solitary primary lymphoma of sciatic nerve. It is k n o w n that malignant lymphomas may present, and even remain, at sites other than in the lymphoreticular system, and such nondisseminated (solitary) lymphomas of extranodal origin have been identified in a variety of organs. These include stomach and intestine, lung, tonsil, skin, connective tissue, bone, testis, salivary gland, breast, thyroid and the C N S (Freeman et al. 1972; Lee and Spratt 1974; Wright and Isaacson 1983), but they have not been previously reported in peripheral nerve. These extranodal lymphomas are not rare: in a study (Freeman et al. 1972) based on the findings of the End Result Study G r o u p of the National Cancer Institute covering the period between 1950-64, about 16~o of 12497 cases of lymphomas were said to have arisen at sites other than in the lymph nodes. Most of
31
Fig. 6. Amorphousand fibrousband-likeeosinophilicnon-amyloidmaterialdepositedin the tumour. In this photomicrographit shows a positivestaining reactionfor fibrinby the Martius, Scarlet,Bluemethod, x 344.
these extranodal lymphomas were of the type now classified as non-Hodgkin's lymphoma, and less than 5 ~o were Hodgkin's disease. In attempting to explain the sites of predilection of extranodal lymphomas, it has been suggested (Wright and Isaacson 1983) that such sites are not randomly selected, but are connected with the physiological distribution and 'homing pattern' of lymphocytes. Lymphoma arising in the gastrointestinal tract, thyroid, salivary gland, and Burkitt's lymphoma and T-cell lymphoma of skin may be explained by this phenomenon. There is no immediate evidence, however, of such a physiological connection in peripheral nerves and there are no reports of lymphomas arising in primary inflammatory conditions such as polyneuritis. It has also been observed (Wright 1982) that lymphomas occurring at sites other than those with a natural or physiological population of lymphocytes are more likely to be metastases from nodal lymphomas. But it should also be noted that cases of solitary, extranodal lymphoma in organs such as breast, testis and brain are well documented, and in many of these reported cases nodal lymphoma has not been identified either at the clinical presentation or at autopsy (see references above). The present case of solitary extranodal lymphoma also falls into this category, and suggests that different mechanisms for the origin of such tumours may operate in some cases.
32
Fig. 7. Foreign-body giant cell reaction prow)ked by the eosinophilic non-amyloid material. In this photomicrograph, the multinucleated giant cells are arranged at the edge of the deposit of the extracellular material. Haematoxylin and eosin, x 412.
Lymphoma may affect peripheral nerves by tumour infiltration or as a paraneoplastic manifestation of malignancy (Currie et al. 1970; Currie and Henson 1971). Paraneoplastic neuropathies are of 3 main types: an acute demyelinating polyneuropathy associated with segmental demyelination and mononuclear cell infiltrate (Cameron et al. 1958; Lisak et al. 1977), a sensorimotor polyneuropathy which may be due to segmental demyelination or primary axonal degeneration (Currie and Henson 1971; Walsh 1971) and rarely a pure sensory neuropathy in which neuronal degeneration in the dorsal root ganglia may occur (Van Gehuchten 1952). Peripheral nerve involvement by actual invasion by lymphoma may occur either as a local spread from the adjacent lymph node or bone lymphoma or as a remote metastasis from nodal lymphoma (and leukemia) which may manifest as polyneuritis and sensorimotor polyneuropathy obviously attributable to multiple peripheral nerve involvement (Kohut 1946; Allison and Gordon 1955; Baron et al. 1960; Vital et al. 1975). The treatment of these multifocal lymphomas of peripheral nerves is often chemotherapy, which if successful, may eliminate or suppress undetected or occult nodal lymphomas. The present case of sciatic nerve lymphoma, being a case of solitary lymphoma, was treated by surgical excision followed by local radiotherapy. At clinical review 9 months after this treatment there was no evidence of recurrence of the neoplasm, or of a lymphoma developing elsewhere. The patient's general health is good. Freeman et al. (1972) in their
33 study of extranodal tymphoma, reported that 57~o of extranodal lymphomas did not spread to adjacent organs or to the regional lymph nodes. The adjusted 5-year survival rate amongst these cases was as high as 59~o. The 5-year survival rate for extranodal lymphoma arising in stomach, lung and tonsil was particularly good when compared with other malignancies arising in these sites. From these reports, and the known relatively low grade biological behaviour of centrocytic lymphomas (Lennert 1978), it is hoped that this case of sciatic nerve lymphoma will have a favourable outcome. An interesting histological feature of this lymphoma was the presence of amorphous fibrous or band like non-amyloid material. Similar material has previously been described in nodal lymphomas (Wright and Isaacson 1983), although its nature and origin have not been identified. We have attempted to characterise the deposit of non-amyloid material in our case of lymphoma, and have found that the material has histological, immunohistologicat and ultrastructural features of fibrin or a fibrinoid product. Although it is possible that the origin and nature of 'amyloid-like' material in lymphomas may differ from case to case, in the present instance it is related to fibrin or a fibrinoid product. Note added in proof
Three years after presentation, the patient developed enlarged axillary lymph nodes. Biopsy and histological examination revealed a high grade non-Hodgkin's lymphoma - centroblastic type, indicating the development of a systemic disease. ACKNOWLEDGEMENTS We thank Mr. M . J . M . Black for contributing the section on operative findings in this paper. We also thank Dr. D. Patrick for his help in the section on radiological diagnosis. We are indebted to Mr. J. Stanger and Mr. R. B. Jewitt for the technical work and for photographic assistance. We thank Mrs. Ira Purohit for preparing the manuscript, and we gratefully acknowledge the help and suggestions of Mrs. Hether Russell during the preparation of the manuscript. REFERENCES Allison, R.S. and D.S. Gordon (1955) Reticulosis of the nervous system simulating acute infective polyneuritis, Lancet, ii: 120. Baker, G.S., W.R. Parson and J.S. Welch (1966) Endometriosis within the sheath of the sciatic nerve, J. Neurosurg., 25: 652-655. Baron, K. D., L. P. Rowland and H. M. Zimmermann(1960) Neuropathywith malignanttumour metastases, J. Nerv. Ment. Dis., 131: 10. Bruni, J., J.M. Bilbao and T. Gray (1977) Primary intramedullarymalignant lymphomaof the spinal cord, Neurology, 27: 896-898. Cameron, D.J., D. A. Howell and J. L. Hutchison (1958) Acute peripheral neuropathyin Hodgkin'sdisease, Neurology (Minneap.), 8: 575. Currie S. and R.A. Henson (1971) Neurological syndromes in reticulosis, Brain, 94: 307-320. Currie, S., R. A. Henson and A.J. Poolie (1970) The incidence of the non-metastatic neurological syndromes of obscure origin in the reticuloses, Brain, 93: 629-640. Dyck, P.C., P.K. Thomas, E.H. Lambert and R. Bunge (1984) Peripheral Neuropathy, W.B. Saunders, Philadelphia.
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