Journal of Clinical Pathology, 1978, 31, 757-760

Giant lymph node hyperplasia of the mediastinumand refractory anaemiaC. G. GEARY AND H. FOX

From the Department ofHaematology, Manchester Royal Infirmary and the Department ofPathology,University of Manchester, UK

SUMMARY An example is described of the syndrome of refractory anaemia in association with theplasma cell variant of giant lymph node hyperplasia of the mediastinum; the anaemia responded toremoval of the lymphoid mass. The entity of giant lymph node hyperplasia is discussed and itsrelationship to the haematological syndrome is considered.

We report an example of the rare syndrome of severeanaemia in association with the plasma cell variant ofgiant lymph node hyperplasia of the mediastinum,this being, as far as we are aware, the first such caseto be recorded in this country.

Case report

A female student aged 21 gave a history of lassitudefor several months; she had also noted menorrhagiabut there were no systemic symptoms such as fever,weight loss, or anorexia. Physical examinationshowed mucosal pallor but there were no otherabnormal signs.A chest radiograph demonstrated a large upper

mediastinal shadow, and other investigationsshowed a haemoglobin of 7-2 g/dl; MCV 62 fl;MCHC 32Y%; white blood count 6-4 x 109/1(neutrophils 72Y%, lymphocytes 20Y%, monocytes8%); platelets 327 x 109/l; serum albumin 37 g/l;serum globulin 52 g/l; serum electrophoresisshowed a polyclonal increase in globulins; serumiron 2-148 tumol/l (12 ,ug/100 ml); TIBC 62-3 ,umol/l(348 ,ig/100 ml); serum ferritin 201 pg/l (201 ng/ml).Bone marrow aspiration yielded a cellular sampleshowing granulocytic hyperplasia and an increasedcontent (8%) of mature plasma cells; erythropoiesisand thrombopoiesis were orderly, but there was astriking increase in RE cell iron. The liver appearednormal on biopsy, and a gallium scan showed noevidence of generalised lymphadenopathy.A presumptive diagnosis of malignant lymphoma

was made but at this stage the patient mentioned

Received for publication 16 January 1978

that a routine chest x-ray six years previously hadalso been abnormal; these films were obtained, and itwas apparent that there had been no significantchange in the size of the mediastinal mass over thisperiod. It therefore appeared that the mass wasunlikely to be neoplastic but as blood transfusion wasrequired to maintain the patient's haemoglobin levela thoracotomy was undertaken (Mr H. F. M. Bassett).A mass was found in the superior mediastinum inclose apposition to the trachea and was removed.

PATHOLOGICAL FINDINGSThe specimen received was a rounded mass with abosselated surface; it measured 6-2 x 4-4 x 3-6 cm.On section there was a slightly lobulated appearance,and the mass was formed ofhomogenous, moderatelyfirm, pinkish-grey tissue.On histological examination the mass was seen to

consist oflymphoid tissue, in which the normal nodalarchitecture had been largely obliterated by a pro-fusion of follicles; in some areas, however, a peri-pheral subcapsular sinus was still discernible (Fig.1). A majority of the follicles were moderately large,contained well-formed germinal centres, and had aclearly defined, dense peripheral mantle of lympho-cytes (Fig. 2). Many of the follicles were penetratedby vessels, seen either in transverse section runningthrough the centre of the follicle or in longitudinalsection coursing into the follicle radially; only a fewof these vessels were noticeably thick-walled, andhyalinisation was rare. There was a conspicuousproliferation of small vessels in the interfollicularspaces (Fig. 3) which also contained, in many areas,sheets of mature plasma cells (Fig. 4).A diagnosis of plasma cell variant of giant lymph

node hyperplasia was made.757

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C. G. Geary and H. Fox

Fig. 1 Low-power view of the edge of the lymphoidmass. The remnants ofa subcapsular sinus can bediscerned. (Haematoxylin and eosin x 40)

Fig. 2 High-power view ofa follicle. This consists ofagerminal centre with a mantle of lymphocytes, and avessel can be seen running into the centre of the follicle.(H and E x 380)

Fig. 3 An interfollicular space stainedfor reticulin.There is a profusion ofsmall vessels. (Gomori x 255)

Fig. 4 An interfollicular space which contains largenumbers ofmature plasma cells. (H and E x 340)

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Giant lymph node hyperplasia of the mediastinum and refractory anaemia

PROGRESSAfter removal of the mass the patient's clinicalcondition improved, and six months later herhaemoglobin was 12-4 g/dl and the serum globulinlevel had fallen to normal.

Discussion

Giant lymph node hyperplasia was first defined byCastleman et al. (1956) as an asymptomatic, massivehyperplasia of the mediastinal lymph nodes, pro-ducing a mass that often mimics, both radiologicallyand on gross pathological examination, a thymoma.Since then a wide variety of synonyms have beenapplied to this form of nodal hyperplasia; theseinclude angiofollicular lymph node hyperplasia,lymphonodal hamartoma, angiomatous lymph nodehamartoma, benign giant lymphoma, and follicularlymphoreticuloma, this plethora of names beingengendered by different concepts of its pathogenesis.

Giant lymph node hyperplasia is uncommon butnot excessively rare for Keller et al. (1972) were ableto review 81 cases, of which 61 were from their ownpractice and 20 were culled from the literature. Asexperience has widened, it has become clear thatlesions of this typearenotconfinedtothemediastinumbut can occur elsewhere, such as in the neck, axilla,retroperitoneum, and mesentery. The characteristichistological features of giant lymph node hyperplasia,as described originally by Castleman et al. (1956) andconfirmed subsequently in many other reports, arethe presence-often in what can still be recognised asa lymph node-of numerous small lymphoid fol-licles. These contain thick-walled, frequently hyali-nised, vessels, around which the central follicularcells tend to be arranged in a tight concentric'onion-skin' pattern; the interfollicular spaces alsocontain numerous vessels of the same type, with avariable number of immunoblasts, eosinophils, andplasma cells. The majority of cases of giant lymphnode hyperplasia conform to this 'hyaline-vascular'pattern, but a plasma cell variant has also beendescribed in which, as in the case reported here, thelymphoid follicles are large and reactive, the vascularcomponent is less marked or even absent, and theinterfollicular spaces are obiliterated by sheets ofplasma cells (Keller et al., 1972). This 'plasma cellvariant' accounts for about 10% of cases of giantlymph node hyperplasia, though occasional examplesof a form intermediate between the two mainvarieties have been noted; rarely, there may be a

hyaline-vascular pattern in one area of a mass and aplasma cell pattern elsewhere.The nature of this lesion remains obscure; Keller

et al. (1972) reviewed critically the claims that it iseither a hamartoma (Abell, 1957; Lattes and

Pachter, 1962) or a malignant lymphoma (Zettergren,1961; Fisher et al., 1970), concluded that littleevidence existed for either assertion, and suggestedthat it represents an exaggerated hyperplasticreaction of lymph nodes to an antigenic stimulus.Dorfman and Warnke (1974), while agreeing that, inmost instances, the lesion develops in a node, notedexamples in sites such as the broad ligament and softtissues of the shoulder, in which microscopicexamination of the mass did not reveal any evidenceof a pre-existing nodal structure.

Giant lymph node hyperplasia is usually eitherasymptomatic and revealed only by routine chest x-ray or produces mechanical symptoms due to thepresence of a tumour-like mass. Lee et al. (1965),however, described a patient in whom giant lymphnode hyperplasia was associated with a refractoryanaemia, which remitted completely after removal ofthe lymphoid mass. Seven years later Keller et al.(1972) were able to collect from their own experienceand from the literature 12 cases of this syndrome, andadditional examples have been recorded by Sethi andKepes (1971), Boxer et al. (1972), Kahn et al. (1973),Namba et al. (1973), Dorfman and Warnke (1974),Ende et al. (1975), Burgert et al. (1975), and Notomiet al. (1976). The anaemia, which is always refractoryto any form of treatment apart from removal of thenodal mass, may be normocytic and normochromicor microcytic and hypochromic: it commonly has thefeatures of 'the anaemia of chronic disorders', which,as described by Cartwright and Lee (1971), ischaracterised by an abnormal avidity of the RE cellsfor transferrin-bound iron. Additional features of thissyndrome vary but have included fever, an elevatedESR, hypergammaglobulinaemia, hypoalbuminae-mia, thrombocytosis, leucocytosis, and, in children,retardation of growth; in some patients there hasbeen an elevated plasma alkaline phosphatase and anincreased bromsulphalein retention but in only onehas jaundice occurred, this being, rather surprisingly,of the obstructive type (Notomi et al., 1976).The association between a haematological syn-

drome and giant lymph node hyperplasia is confinedto the plasma cell variant of this condition and doesnot occur with the hyaline-vascular form. The onlyclue as to the nature of this association has comefrom Burgert et al. (1975), who used an exhypoxicpolycythaemic mouse assay system to demonstratethat preoperative serum from their patient containeda factor which inhibited erythropoietin activity anddecreased the uptake of 59Fe; this serum factor haddisappeared by the sixth day after removal of themass, but unfortunately the anti-erythropoietinactivity of the abnormal lymphoid tissue was notestimated.The natural history of this disorder is probably

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760 C. G. Geary and H. Fox

always benign but, because of its rarity, it is usuallydiagnosed before operation as being either amalignant lymphoma or a thymoma with anassociated haematological abnormality. The patho-logical distinction between these conditions and giantlymph node hyperplasia does not, however, presentany great difficulty.

References

Abell, M. R. (1957). Lymphnodal hamartoma versusthymic choristoma of pulmonary hilum. Archives ofPathology, 64, 584-588.

Boxer, L. A., Boxer, G. J., Flair, R. C., Engstrom, P. F.,and Brown, G. S. (1972). Angiomatous lymphoidhamartoma associated with chronic anemia, hypo-ferremia, and hypergammaglobulinemia. Journal ofPediatrics, 81,,66-70.

Burgert, E. 0. Jr., Gilchrist, G. S., Fairbanks, V. F.,Lynn, H. B., Dukes, P. P., and Harrison, E. G., Jr.(1975). Intra-abdominal, angiofollicular lymph nodehyperplasia (plasma-cell variant) with an antierythro-poietic factor. Mayo Clinic Proceedings, 50, 542-546.

Cartwright, G. E., and Lee, G. R. (1971). The anaemia ofchronic disorders. British Journal of Haematology, 21,147-152.

Castleman, B., Iverson, L., and Pardo Menendez, V.(1956). Localized mediastinal lymph-node hyperplasiaresembling thymoma. Cancer, 9, 822-830.

Dorfman, R. F., and Warnke, R. (1974). Lymphadeno-pathy simulating the malignant lymphomas. HumanPathology, 5, 519-550.

Ende, J. van den, Kahn, L. B., and Jacobs, P. (1975).-Giant lymph node hyperplasia with haematologicalabnormality. South African Medical Journal, 49, 170.

Fisher, E. R., Sieracki, J. C., and Goldenberg, D. M.(1970). Identity and nature of isolated lymphoidtumors (so-called nodal hyperplasia, hamartoma, andangiomatous hamartoma), as revealed by histologic,

electron microscopic, and heterotransplantation stud-ies. Cancer, 25, 1286-1300.

Kahn, L. B., Ranchod, M., Stables, D. P., King, H., andYudelman, I. (1973). Giant lymph node hyperplasiawith haematological abnormalities. South AfricanMedicalJournal, 47, 811-816.

Keller, A. R., Hochholzer, L., and Castleman, B. (1972).Hyaline-vascular and plasma-cell types of giant lymphnode hyperplasia of the mediastinum and otherlocations. Cancer, 29, 670-683.

Lattes, R., and Pachter, M. R. (1962). Benign lymphoidmasses of probable hamartomatous nature. Cancer, 15,197-214.

Lee, S. L., Rosner, F., Rivero, I., Feldman, F., andHurwitz, A. (1965). Refractory anemia with abnormaliron metabolism: its remission after resection of hyper-plastic mediastinal lymph nodes. New England JournalofMedicine, 272, 761-766.

Namba, M., Ogura, T., Hirao, F., Yamamura, Y., andMoA, T. (1973). Mediastinal lymph node hyperplasia:a report oftwo cases, hyaline-vascular type and plasma-cell type. Medical Journal ofOsaka University, 23, 239-247.

Notomi, A., Iwamoto, Y., and Kikuchi, M. (1976). Giantlymph node hyperplasia with fever, anemia, hyper-gammaglobulinemia and jaundice. Acta HaematologicaJaponica, 39,11-19.

Sethi, G., and Kepes, J. J. (1971). Intrathoracic angio-matous lymphoid hamartomas; a report of three cases,one of iron refractory anemia and retarded growth.Journal ofThoracic and Cardiovascular Surgery, 61, 657-664.

Zettergren, L. (1961). Probably neoplastic proliferation oflymphoid tissue (follicular lympho-reticuloma). ActaPathologlcaetMicrobiologica Scandinavica, 51, 113-126.

Requests for reprints to: Dr H. Fox, Department ofPathology, University of Manchester, Stopford Building,Oxford Road, Manchester M13 9PT.

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