Aust. N.Z. J. Med. (1975). 5, pp. 469471

CASE REPORT

Successful Use of Combination Chemotherapy in Pure Red Cell Aplasia Associated with Malignant Lymphoma, Histiocytic Type F. A. Hunt' and C. M. Lander? From the Departments of Medicine and Pathology, Royal Brisbane Hospital

Summary:

Successful use of combination chemotherapy in pure red cell aplasia associated with malignant lymphoma, histiocytic type. F. A. Hunt and C. M. Lander, Aust. N.Z.J. Med., 1975, 5,

pp. 469-471.

A case of pure red cell aplasia developing in a woman aged 78 is reported. Biopsy of an enlarged axillary lymph node disclosed a malignant lymphoma, histiocytic type. Therapy with intermittent cyclophosphamide and prednisone was instituted. There was rapid remission of the red cell aplasia. Clinical recurrence of the histiocytic lymphoma has not occurred. Anaemia due to red cell aplasia is a relatively rare disorder in adults. Recognizable red cell precursors, but not other marrow elements, are absent, and severe reticulopenia is present in the peripheral blood. Approximately half of the patients with red cell aplasia have a thymoma', and a few cases have been reported associated with other neoplasms.', 3 * Administration of medications4, and exposure to organic agents4 have also been causally related. Recently it has been recognized that this disorder, which is often refractory to other forms of treatment, may respond to immunosuppressive therapy.'' * , The occurrence of red cell aplasia with malignant lymphoma of histiocytic type, and its subsequent remission following combination chemotherapy, as described in this case report, has not been previously described. ' 9

* Haematologist. tMedical Registrar. Correspondence: Dr. F. A. Hunt, Department of Pathology, Royal Brisbane Hospital, Herston Road, Brisbane, Queensland 4029 Accepted for publication: 19 May, 1975

Case Report

A 78-year-old lady was referred on 11.6.74 to Medical Outpatients following the development of a purpuric rash on the limbs and abdomen. This had occurred two weeks after the commencement of phenylbutazone for osteoarthritis. She gave a history of 6 kg weight loss over the preceding twelve months. The haemoglobin was 9.8 g/dl, ESR 71 mm/hr (Westergren) and platelet count I75,000/$ (normal range 150,000-400,000/pl). The blood smear showed a normochromic normocytic anaemia. Anti nuclear factor was weakly positive (homogeneous pattern). On 9.7.74, she was admitted to hospital with pallor, dyspnoea and lethargy. Examination revealed a large mobile lymph node with maximum diameter of 4 cm in the right axilla. The haemoglobin was 5 9 g/dl, and reticulocytes constituted 0.2% of red cells, the absolute reticulocyte count being 4,4OO/pl (normal range 25,000-125,000/pLI). The white cell count was 4,800/$ and a differential count was normal apart from lymphopenia of 672 lymphocytes/pl (normal range 1,500-4,500/p0. The serum folate and vitamin B,,, direct Coombs test, haptoglobins, plasma haemoglobin and G6PD screening test were normal. Quantitation of IgG, IgA and IgM was within the normal range. No paraprotein band was detected on the serum electrophoretic pattern. The antinuclear factor was weakly positive (speckled pattern). Striated muscle antibodies were absent. Chest X-ray was normal; there was no evidence of a mediastinal tumour. Bone Marrow aspiration disclosed pure red cell aplasia (Figure 1). Marrow cellularity was normal. There was absence of recognizable red cell precursors. Elements of the myeloid and megakaryocyte series were morphologically and quantitatively normal. Lymphocytes constituted 5% and plasma cells 1% of all nucleated marrow cells. There was no evidence of marrow infiltration by neoplastic or other abnormal cells. A marrow trephine biopsy was not performed. On 13.7.74, excision biopsy of the right axillary lymph nodes disclosed a malignant lymphoma of histiocytic type. Further staging of the lymphoma was not undertaken because of the patient's age. On 18.7.74, therapy was commenced with oral prednisone (60 mg/day for four days then decreasing over three days) and intravenous cyclophosphamide (beginning with 400 mg/mz with first course and increasing to 800 mg/mz with 3rd course) given at second weekly intervals. The response of haemoglobin, reticulocytes and lymphocytes is illustrated in Figure 3. Following the first course, the patient has attended as an outpatient. She remains very well. There is no clinical recurrence of lymphoma. Bone marrow aspiration was repeated on 23.9.74 and all marrow elements were mor-

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HUNT AND LANDER

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FIGURE 1. Bone marrow aspirate. Recognizable erythroid precursors are not present. Jenner-Giemsa. ( x 1075)

FIGURE 2. Lymph node biopsy. The normal architecture is replaced by an infiltrate of malignant histiocytic cells. Haematoxylin and Eosin. (~870)

phologically normal. Erythropoesis was mildly hypercellular, with a myeloiderythroid ratio of 1.1:l. The antinuclear factor reverted to negative six weeks after commencement of therapy.

Discussion

Pathology of Lymph Node The lymph node was ovoid in shape, measuring 4 x 3 x 2.5 cm, and was of firm consistency. The cut surface was homogeneous and pale grey. Histologically, the normal lymph node architecture was replaced by an infiltrate of cells with abundant pale cytoplasm and large polymorphic nuclei containing one or more prominent often angular nucleoli. Mitoses were infrequent. The appearances were those of a diffuse malignant lymphoma, histiocytic type (Figure 2).

cyclophosphamidc pndnisone

and

I

I

Pure red cell aplasia is an uncommon cause of anaemia in adults, and is associated with reticulocytopenia and an almost complete absence of marrow red cell p re ~ u r s o r s .~ Other marrow elements are almost always normal, and this differentiates the disorder from aplastic anaemia.' It may occur as a congenital disorder'' which often remits later in childhood." Approximately

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transfusions

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FIGURE 3.

7.0 AUGUST

SEPT EM BE R

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Therapy and haematological progress

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RED CELL APLASIA AND MALIGNANT LYMPHOMA

half of the cases occurring in adults are associated with a thymoma', which is usually benign.'' Although thymomas may invade adjacent tissues, they rarely give rise to metastases; in one case in which a thymoma metastasis was present in an axillary lymph node, extensive spread of neoplasm extending from the mediastinum to the axilla was dem~nstrated.'~ It seems highly improbable that the neoplasm present in this patient's axillary node was a metastasis from a thymoma, since there was no evidence of a thoracic neoplasm radiologically. Pure red cell aplasia has also been reported with other neoplasms, including carcinoma of the bronchus3 and Hodgkins disease', but not malignant lymphoma of histiocytic type. Temporary erythroblastopenia may occur in childhood especially in the first few years of life.I4 On occasions transient episodes of red cell aplasia complicate haemolytic disorders, and are often preceded by upper respiratory or gastrointestinal symptoms, possibly of viral aeti010gy.'~ There was no evidence of haemolysis demonstrable in this patient. Pure red cell aplasia has been associated with the ingestion of a number of drugs, notably diphenylhydant~in~, chloramphenico16, and s~lphonamides.~The role of phenylbutazone in this regard is not clearly defined. Exposure to benzene derivatives and benzol has been incriminated as an aetiological factor in the development of pure red cell aplasia4; no history of such exposure could be elicited from the patient who is the subject of this report. In adults with chronic pure red cell aplasia, IgG antibodies which inhibit in vitro erythropoiesis are present in the majority of cases.I6 Antibodies to erythroblast nuclei may also be demonstrable in some cases." Patients possessing antibody usually respond well to treatment with immunosuppressive agents, notably cyclophosphamide and prednisone.' * Evidence of qualitative immunological abnormalities, such as monoclonal serum com-

47 1

ponents" and autoimmune phenomena, including autoimmune haemolytic anaemialg, and idiopathic thrombocytopenic purpura2O, may occur in malignant lymphoma of non-Hodgkin type. The concurrence of red cell aplasia and malignant lymphoma of histiocytic type reported in this patient may be of similar pathogenesis. Acknowledgement We wish to thank Dr. John Nye for his assistance.

References M. and HARRISON,E. G. (1965): Thymoma associated with pure red cell agenesis: review of literature and report of 4 cases, Cancer 18, 216. 2. FIELD,E. O., CAUGHI, M. N., BLACKETF,N. M. and SUITHERS. D . W. (1968): Marrow-suppressing factors in the blood in pure red-cell aplasia, thymoma and Hodgkin's disease, Brif. J . Haemof. 15, 101. 3. ENWHISTLEC. C., FENTEM, P. H . and JACOBS, A. (1964): Red cell aplasia with carcinoma of the bronchus, Brif. med. J . 2, 1504. 4. SCHMID, J. R., KEY, J. M., PUSE, G L. and HARGRAVES, M. H. (1963): Acquired pun red cell agenesis, Acro hoemof, 30,255. 5 . B R I m N G H A M . T. E.. LUTHER.C. L and MURPHY. D.L. (1964): Reversible erythroid aplasia Induced by diphenylhydantoin. Arch. infern. Med. 113,764. 6 . OGORMANHUGHES.D. W. (1973): Studies of chloramphenicol. Possible determinants and progress of haemopoiebc toxicity during chloramphenicol therapy, Med. J. Awf. 2, 1142. 7. KRANTZ,S. 9. and KAO,V. (1969): Studies on red cell aplasia. Report of a second patient with an antibody to erythroblast nuclei and a remission after immunosuppressive therapy, Blood 34, I . 8. KRANTZ,S. B. (1973): Pure red cell aplasia, &if. J . Hoemaf. 25, 1. 9. KRANTZ,S. B. (1974): Pure red cell aplasia, New Engl. J . Med. 291, 345. 10. DIAMOND, L. K., ALLEN,D. M. and MCGILL,F. B. (1961): Congenital (erythroid) hypoplastic anemia. A 25 year study. Amer. J . Dzs. Child. 102, 403. 1 1 . O'GORMANHUOHES, D . W. (1973): Bone marrow depression in childhood, Med. J . A w l . I, 357. 12. HAVARD,C. W. H. and PARRISH,J. A. (1962): Thymic tumour and erythroblastic aplasia, J. Amer. med. Ass. 179, 228. 13. CASTLE MAN,^. (1955):Tumoursofthethymusgland,ArmedForcesInstitute of Pathology. Washington, p. 53. 14. LOURC, V. A. (1970): Anaemia and temporary erythrohlastopenia in children: a syndrome, A w l . Ann. Med. 19, 34. 15. BAUMAN, A. W. and SWISHER, S. N. (1967): Hyporegenerative processes in haemolytic anaemia, Semmors Haemal. 4, 265. 16. KRANTZ.S. B.,MOORE,W. H. and ZAENTL,S. D. (1973): Studies on red cell aplasia. V. Presence of erythroblast cytotoxicity in G-globin fraction of plasma, J . din. Invest. St, 324. 17. KRANTZ,S. B. and KAO,V. (1969): Studies on red cell aplasia. 11. Report of a second patient with an antibody to erythroblast nuclei and a remission after immunosuppressive therapy, Blood 34, 1. 18 MOORE,D.F., MIOLIORE, P. J., SHULLMBERGER, C. C. and ALEXANIAN. R. (1970): Monoclonal macroglobulinemia in malignant lymphoma, Ann. inrern. Med. 72, 43. 19. DACE,J. V. (1967): The haemolytic anaemias, Part 111. Secondary or Symptomatic haemolytic anaemias. Grune and Stratton. New York, p. 719. 20. J O N ~ SS. , E.( I 973): Autoimmune disorders and malignant lymphoma, Cancer 31, 1092. 1. SCHMID,J . R., KIELY,J.

Addendum

The patient recently presented with clinical evidence of widespread malignant lymphoma, and died shortly thereafter. Pure red cell aplasia was not a feature of the terminal phase of her illness.

Successful use of combination chemotherapy in pure red cell aplasia associated with malignant lymphoma, histiocytic type.

A case of pure red cell aplasia developing in a woman aged 78 is reported. Biopsy of an enlarged axillary lymph node disclosed a malignant lymphoma, h...
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