Thorax, 1977, 32, 71-79

Lymphomatoid granulomatosis-a condition withaffinities to Wegener's granulomatosis andlymphomaA R. GIBBS

F'rom the Department of Pathology, University Hospital of Wales

Gibbs, A. R. (1977). Thorax, 32, 71-79. Lymphomatoid granulomatosis-a condition withaffinities to Wegener's granulomatosis and lymphoma. A case of lymphomatoid granulomatosisof the lung is described in which the presenting features were a skin eruption and peripheralneuropathy. The onset of the pulmonary symptoms of breathlessness and productive coughwas delayed nine months but, when apparent, the extent of the radiological changes contrastedwith the mildness of the symptoms and the triviality of the physical signs. Biopsy of the affectedlung revealed a mixed lymphocytic, plasma cell, and histiocytic infiltrate following aperivascular distribution. This combination of clinical and pathological findings is in every detailthat of lymphomatoid granulomatosis as recently identified by Liebow et al. (1972).

Additional, previously undescribed, and unexplained findings in this case were persistenthypercalciuria and the presence in three axillary lymph nodes of subcapsular groups of cellsresembling those of a benign naevus. This is the first case described in the British literature, andit is important that more cases be reported in order that the prevalence, prognosis, andaetiology of the condition should be further established.

The combination of pulmonary symptoms andsigns, far less prominent than the lung radio-logical change together with skin rash, peripheralneuropathy, and lymphadenopathy would bringto mind a wide differential diagnosis includingsarcoidosis, Wegener's granulomatosis, lymphoma,occult carcinoma, collagen disease, and histio-cytosis X. To this list should now be addedlymphomatoid granulomatosis identified byLiebow et al. (1972) and Liebow (1973) whileinvestigating the spectrum of pulmonary diseaselying between classical Wegener's granulomatosisand lymphoma. They coined the term 'lymphoma-toid granulomatosis' for a condition whichclinically and radiologically resembles Wegener'sgranulomatosis but has histological affinities withlymphoma; frank lymphoma became evident ter-minally in a number of their cases. In lymphoma-toid granulomatosis an infiltrate involves mainlythe lungs and follows a predominantly perivasculardistribution. It may be associated with vasculitisor vasculonecrosis involving arteries and veins and,where the infiltrate abuts on small bronchi and

bronchioles, it results in the histological featuresof a bronchiolitis obliterans. The infiltrate con-sists of lymphocytes, plasma cells, histiocyticcells, and atypical cells resembling but notidentical with the reticulum cell element seen inHodgkin's disease. An interesting feature of thecondition is the frequent occurrence of cutaneouslesions, nervous system involvement, and renallesions (which, although showing combinations ofcellular infiltration, necrosis, and vascularchanges, do not include glomerulonephritis asseen in classical Wegener's granulomatosis).Lymphomatoid granulomatosis has not been

reported previously in the British literature andit would seem important for it to feature as partof the complete differential diagnosis in a numberof circumstances.

Case report

A 32-year-old white man, a traffic engineer, firstpresented in April 1974 with a rapid onset of askin rash which consisted of red, swollen, papular

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lesions on the face, forearms, and legs. There wasno associated pain or pruritus. A course of topicalprednisone and oral antihistamines was given butwithout any effect.Three months later the patient was admitted to

hospital for investigation and treatment since therash had persisted, and he also complained ofweight loss, numbness of the left heel, and a tight-ness over the lower legs. Positive findings onexamination were: an erythematous, indurated,polycyclic skin eruption which was most markedover the face and upper limbs; an enlarged, non-tender, firm, and mobile lymph node in the leftaxilla; and loss of sensation to light touch overthe lateral aspect of the left calf. Over the nextfew weeks his muscle weakness became moresevere, particularly affecting the hands and toes.Lymphadenopathy of the right axilla was alsonoted.

Investigations at this time showed: Hb 13 1g/dl, WBC oXX109l1, normal differential, ESR4 mm/hr, normal bone marrow, bilirubin10 mmol/l (06 mg/mmol), SGOT 12 IU/l, SHBD185 IU/1, alkaline phosphatase 27 IU/l, total pro-tein 63 g/l, albumin 39 g/l, normal electro-phoresis, immunoglobulins: IgG 9 6 g/l, IgA4 2 g/l, IgM 1-20 g/l, fasting blood sugar 4 mmol/l(72 mg/100 ml), CPK 10 IU/l. Negative or normalfindings included: rheumatoid factor, antinuclearfactor, smooth muscle antibodies, antimitochon-drial antibodies, LE cells, WR and Kahn, fastinglipids, serum amylase, thyroid function tests, viralagglutinins, Mantoux test, Kveim test, andurinary aminoacids. A chest radiograph wasnormal apart from obliteration of the left costo-phrenic angle. Radiographs of the hands, intra-venous pyelogram, barium meal, and bariumenema showed no abnormality.A positive finding was persistent hyper-

calciuria on numerous occasions (values rangingfrom 9 6-11 7 mmol/24 h (384-468 mg/24 h); thiswas present before the start of steroid therapy.Urinary phosphate excretion and serum calcium,phosphate, and alkaline phosphatase were alwaysnormal, however.Nerve conduction studies supported the diag-

nosis of a peripheral neuropathy.His condition remained reasonably static during

this admission but, in view of the fact that aquestion of malignancy had been raised by thefindings on the axillary lymph node biopsy, itwas decided to perform an exploratory laparo-tomy. This showed no abnormality apart fromsome enlarged, mobile mesenteric lymph nodes.These and the liver were biopsied.

A. R. Gibbs

Oral prednisone (80 mg daily) was started inthe hope that the progression of the neuropathymight be halted. Meanwhile the skin rash hadbegun to improve and continued to do so duringthis period of steroid therapy. It never completelycleared, however, and the peripheral neuropathyand hypercalciuria persisted.

In October 1974, the patient was discharged butcontinued to take oral prednisone. His conditionshowed little change over the next three monthsbut in January 1975 he developed 'flu-like' illnesswith complaints of nausea, productive cough withyellowish sputum, and breathlessness on walking.On examination he was febrile (37 80C), he hada tachycardia (110 beats/min), there were crepita-tions and bronchial breathing at both lung bases,and there was cervical lymphadenopathy. Hisneurological state and skin rash remained un-changed. Investigations showed that he still hadhypercalciuria. This time his chest radiograph(Fig. 1) showed extensive nodular and confluentareas throughout both lower lobes, lingula, andright middle lobes. The changes were present to alesser extent in the mid-zone.The patient was started on antibiotics but, as

little improvement occurred over several weeks,bronchoscopy, which was normal, and an openlung biopsy were performed. The latter showed thepicture of lymphomatoid granulomatosis and thepatient was given oral cyclophosphamide (100 mgdaily) in addition to the prednisone. At about thesame time his chest condition began to improvealthough there was no concomitant improvementin the state of his peripheral neuropathy and skinrash. A chest radiograph taken a few days afterthe beginning of the cyclophosphamide treatmentshowed considerable clearing of the lung fieldsbut with some discrete rounded shadows stillpresent. A further chest radiograph taken a monthlater (Fig. 2) showed further clearing but withsome fibrotic markings present in the left lowerzone.

Since then (12 months) the chest radiologicalappearances and the patient's skin rash, peripheralneuropathy, and hypercalciuria have remainedstatic. His drug therapy now consists only ofprednisone (7 mg on alternate days).Throughout his illness bacteriology of sputum,

pleural fluid, nose, urine, and blood showed nosignificant abnormality.

PATHOLOGYSkin Three separate skin biopsies, the first (Fig.3) taken four months after the onset of the skinrash and the others taken over a further two

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Lymphomatoid granulomatosis

Fig. 1 Postero-anterior radiographshowing diffuse and nodularbilateral infiltrates in the mid andlower zones.

Fig. 2 Postero-anterior radiographtwo months later afteradministration of prednisone andcyclophosphamide.

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S4~~~~~~~~~~~~

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Fig. 3 Skin showing the periadnexal and perivascular dermal cellular infiltrate. Haematoxylin and eosin X32

months, were examined histologically. They weretaken from the left forearm and right wrist.Each showed, to a varying degree, a mixed

cellular infiltrate affecting the mid and lowerdermis predominantly but also sometimes extend-ing into the subcutaneous tissue. The infiltrate wassituated predominantly around appendages, butin some areas infiltration of veins and smallarteries could be seen. The infiltrate consistedmostly of mature and immature lymphocytes andalso larger pale histiocytic cells and plasmacytoidcells. A few scattered foreign body type giantcells were also present in the infiltrate (Fig. 4).

Direct immunofluorescence was negative forIgG and complement; indirect immunofluores-cence on the patient's blood was also negative.Liver There was a mild focal lymphocytic in-filtration of the parenchyma and of portal tractsbut there was no associated cell necrosis ordisturbance in the architecture.Lymph nodes Three lymph nodes from the rightaxilla, three out of six lymph nodes from the leftaxilla, and the mesenteric lymph nodes showed

varying degrees of follicular and sinus hyperplasiaranging from mild to marked; none showedfeatures suggestive of malignant lymphoma.Three lymph nodes from the left axilla, how-

ever, showed focal collections of rounded, pale,basophilic cells with poorly defined cytoplasmwhich were present in the capsule and extendedslightly into the peripheral and medullary sinuses.The cells were uniform, lacked mitoses, and sug-gested the appearance of benign naevus cells(Fig. 5). They contained no pigment, and notissue was available for testing by the DOPAreaction.Rectal biopsy Normal.Lung biopsy Grossly the lung tissue, measuring4X2XO05 cm, was rectangular in shape, firmand consolidated and had a greyish-yellow appear-ance. Histologically, no unaffected lung tissue waspresent and the predominant feature was an inter-stitial, perivascular, and peribronchial cellularinfiltrate (Fig. 6) composed of plasma cells, plas-macytoid cells, lymphocytes, and larger histiocyticcells (Fig. 7). Some of the latter possessed

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Fig. 4 Skin showing the predominantly lymphocytic and histiocytic nature of the cellularinfiltrate. H and E X 365

acidophilic cytoplasm and contained large, pale,vesicular nuclei with prominent acidophilicnucleoli not unlike the atypical reticulum cells ofHodgkin's disease. There was little mitotic activityand eosinophils were almost completely absent.Many of the small muscular arteries and veinsshowed involvement of their media and adventitiaby this infiltrate and some showed intimal fibrosis.There was minimal vasculonecrosis. Fibrosis wasdeveloping in association with the infiltrativeprocess.A secondary obstructive effect upon the airways

was apparent (Fig. 8) as bronchiolar obliterationby granulation tissue (bronchiolitis obliterans). Aspart of the obstruction there was marked alveolaraccumulation of lipid-laden macrophages (endo-genous lipid pneumonia). Cuboidal metaplasia ofthe alveolar lining cells occurred.

Discussion

Of these cases of lymphomatoid granulomatosisso far described (Liebow et al., 1972; Liebow, 1973;Allen, 1974; Kay et al., 1974) most cases presentedin early middle age with cough, fever or dyspnoea.In a small proportion of cases, however, thepatients presented with a skin rash, lymphadeno-

pathy or nervous system involvement and did notshow the pulmonary involvement until later. Allshowed pulmonary involvement at some time.Cutaneous involvement occurred in approxi-

mately 50%, renal involvement in 45%, centralnervous system involvement in 23%, and peri-pheral neuropathy in 15% of cases. The renallesions were usually discovered only at necropsyand consisted of wedge-shaped infarcts or roundedtumour-like masses which often bulged thecapsular surfaces. The histology of the renal lesionswas that of a mixed lymphoreticular infiltratefollowing for the most part a perivascular distri-bution in combination with varying degrees ofnecrosis and vascular occlusion, a similar histo-logical picture to that seen in the lungs. In theother organs involved by the disease process thehistological pattern of cellular infiltration,necrosis, and vascular changes was similar.

Although the pathological features of lympho-matoid granulomatosis resemble lymphoma, in sofar as the nature of the cellular infiltrate and thenodular gross appearance of the lesions are con-cerned, the condition shows several differences.It tends to affect the lungs early while the lymphnodes, spleen, and bone marrow are spared and itshows a much higher incidence of central nervous

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a wt #A*4^ tw-.,a <+ b, > s s , Sg - >as-~~~~~~~~~~~~~~~~~4

AAA. 04 v ...................................;g

Fig. 5 Lymph node containing the subcapsular groups of naevus cells. H and E X 143

system involvement than occurs in lymphoma.rhe tendency to a perivascular distribution of thecellular infiltrate in lymphomatoid granuloma-tosis with concomitant vascular occlusion andvasculonecrosis also differs from that seen inlymphoma. In the minority of patients who haveexhibited lymphadenopathy in lymphomatoidgranulomatosis the lymph nodes have shownatypical hyperplasia, but in five out of the original40 cases described by Liebow et al. (1972) therewas progression to an atypical lymphoma whichcould not be assigned to one of the usual histo-logical classes.Lymphomatoid granulomatosis has similarities

to Wegener's granulomatosis in the distributionof lesions and the combination of a focal granulo-

matous disease with destructive vascular changes.The age distribution is approximately the same andthe radiographic appearances are similar. How-ever, lymphomatoid granulomatosis rarely involvesthe upper respiratory tract and there is absence ofglomerulonephritis. In addition, lymphomatoidgranulomatosis shows a much higher frequency ofcentral nervous system and skin involvement thandoes Wegener's granulomatosis. Histologically,lymphomatoid granulomatosis shows a much moremarked lymphoid character to the cellular in-filtrate and the cells are more atypical andmitotically active than those usually seen inWegener's granulomatosis. Also the tuberculoidlesions showing necrosis and giant cell formation.often present in Wegener's granulomatosis

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Lymphomaloid granulomatosis

Fig. 6 Lung showing the interstitial and perivascular cellular infiltrate. H and E X35

(Wegener, 1936; Wegener, 1939; Godman andChurg, 1954), are rarely seen in lymphomatoidgranulomatosis.The pulmonary radiological picture of lympho-

matoid granulomatosis usually shows bilateral,nodular densities predominantly in the mid andlower lung fields. They tend to wax and wane andoften became confluent, cavitation occurring inapproximately one-third of cases. Enlargement ofhilar lymph nodes occurs in very few patients. Theradiological changes of lymphomatoid granulo-matosis, although overlapping with those ofWegener's granulomatosis, show slight differ-ences, for example, the lesions are more numer-ous and peripherally situated, less well-defined,and often more confluent in lymphomatoidgranulomatosis.

I found in our case, as in the other casesdescribed, that the diagnosis depended on theclinical features taken together with the pul-monary histological changes rather than on thelaboratory investigations.

I report this case of lymphomatoid granulo-matosis because it illustrates many of the featuresof a condition which is, as yet, not widely known,viz, the onset of skin and nervous system mani-festations, which may precede the onset of pul-monary involvement by a considerable period oftime, and the histological features, which althoughnot pathognomonic, when taken together with theclinical features combine to form a distinct clinico-pathological entity. Secondly, this case showsfeatures not previously mentioned in associationwith the condition-unexplained persistent hyper-calciuria and the presence in three lymph nodesof subcapsular groups of benign appearing naevus-like cells. The latter feature has been describedpreviously (Stewart and Copeland, 1931; Stewart,1960; Johnson and Helwig, 1969) and it is interest-ing that in most of the cases the abnormalityoccurred in axillary lymph nodes. It was suggestedthat this could represent a variation of normalanatomy, although this is unlikely, or be theresult of aberrant migration of naevus cells from

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A. R. Gibbs

Fig. 7 The pulmonary infiltrate showing lymphocytes, plasma cells and histiocytic cells, some

with pale nuclei and prominent nucleoli. H and E X370

the neural crest. A third unlikely possibility is thatthe cells migrate from a naevus in the skin.Of the 40 original cases of lymphomatoid

granulomatosis described by Liebow et al., 28 haddied and pulmonary involvement was the majorcause of death in 14, central nervous systeminvolvement accounting for four. In four casesthe chest films cleared and there was no furtherevidence of disease. The longest survivor, whowas apparently well, had lived for 17 years afterthe onset of disease. In eight patients evidence ofhealing of the lung lesions was found at necropsybut it must be stated that the disease process maystill continue in other organs.The precise role of steroids and immuno-

suppressives in the treatment of this condition hasyet to be established. Certainly in our case thepulmonary manifestations appeared to improvewith cyclophosphamide. Also there was initialimprovement in the skin condition followingprednisone administration but since then it hasremained static. The nervous system involvementhas shown no change with either steroids orcyclophosphamide. Most of the cases described

by Liebow et al. received steroids and/or im-munosuppressives but the results were variableand, in one case, there was a seven-year remissionfrom the disease without any treatment whatso-ever. At present no clinical or histologicalfeatures have been found to help in assessingprognosis in this condition.The only large series of cases has been described

by Liebow et al. (1972) in the USA. This, however,is the first reported case in Britain. This mayreflect a genuine difference in frequency ofoccurrence, or it may be that until now thedisease has been overlooked. It is important,therefore, that more people should be aware of thecondition and that more cases should be reported.Only from a larger world series of cases can linesof division within the spectrum of disease,described by Liebow and his colleagues, beevaluated.

I thank Dr. R. Marks for permission to publishdetails of the case, Dr. J. G. Leopold for helpfuladvice, and the staff of the Department of Path-ology of the University Hospital of Wales.

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Fig. 8 Bronchiole showing obliteration by a rounded mass of cellular fibrous tissue; the adjacent vessel(left centre) shows surrounding lymphoid infiltrate. The obstructive pneumonitis can also be seen.A Idehyde-fuchsin X215

References

Allen, P. W., ed. (1974). A case of chronic lymphaden-opathy and bilateral pulmonary nodules (Confer-ence). Medical Journal of Australia, 1, 231-237.

Godman, G. and Churg, J. ((1954). Wegener's granu-lomatosis. Pathology and review of the literature.Archives of Pathology, 58, 533-553.

Johnson, W. T. and Helwig, E. B. (1969). Benignnevus cells in the capsule of lymph nodes. Cancer,23, 747-756.

Kay, S., Fu, Y., Minars, N., and Brady, J. W. (1974).Lymphomatoid granulomatosis of the skin: lightmicroscopic and ultrastructural studies. Cancer, 34,1675-1682.

Liebow, A. A. (1973). Pulmonary angitis and granulo-matosis. A merican Review of Respiratory Diseases,108, 1-18.

Liebow, A. A., Carrington, C. B., and Friedman, P. J.(1972). Lymphomatoid granulomatosis. HumanPathology, 3, 457-558.

Stewart, F. W. (1960). Early cancer (Tayer lecture,Johns Hopkins University) as quoted by Wood, S.,Jr (1961), Canadian Cancer Conference, 4, 172.Academic Press, New York.

Stewart, F. W. and Copeland, M. M. (1931). Neuro-genic sarcoma. American Journal of Cancer, 15,1235-1320.

Wegener, F. (1936). Uber generalisierte septischeGefasserkrankungen. Verhandlungen der DeutschenGesellschaft fur Pathologie, 29, 202.

Wegener, F. (1939). Uber eine eigenartige rhinogeneGranulomatose mit besonderer Beteiligung desArteriensystems und der Nieren. Beitrage zurpathologischen Anatomie und zur allgemeinenPathologie, 102, 36-68.

Requests for reprints to: Dr. A. R. Gibbs., Depart-ment of Pathology, University Hospital of Wales,Cardiff.

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