THYMOMA WITH AGRANULOCYTOSIS
AND HYPOGAMMAGLOBULINAEMIA
R, H. Young School of Pathology, Trinity College, Dublin 2. fntrod~[Ion A 68 year old femare and a thymoma, agranuIoeytosis and hypogammaglobulinaemia is described. The patient presented with symptoms of infection, was treated with a variety of drugs but d~ed alter 10 days. The association between thymoma and haemopoiefic insufficiency is well recognised (Rogers, 1968). The mosl common histological type of thymoma associated with haematorogical abnormalities is the spJndle cell type similar to 1hat seen in this ease (Burrows, 1971). The comrnonest haematological disorder associated wkh Ih ymo ma rs " red celt aplasia. There have also been some reports of disorders of the myelcid series {Jacobsen, 1971). HypogammaglobuJmaem~a has been found in 6 per cent of cases of thymoma (Souadjian, 1974), The occurrence of agranulocytosis and mar}{ed hypegammaglobul~naemia wkh thymoma has prompted tMs case report. Case Report A 69 year ord femare attended her doctor complaining of cough, diarrhoea, and oral ulcers. She was treated with antibiotics but was admitted to hospital for investigation when her condition d~d not improve. On admission she had a temperature of 101 F , cervicar lymphadenopathy and was noted to be pale. Laboratory )nvestigations showed a haemoglobin of &7 gm/dl with a hypochromic peripheral blood gicture and white cell count of 200/dh Platerets were 29O x 10~/l. A bone marrow aspirate showed absence of mye[old elements. The erythroid series was normal and megakaryocytes were present in normal numbers. ;mmunorogical studies showed positive anti nuclear factor, and electrophoresis revealed subnormal [mmunogrobuHn levels, IgG, 38 ]U/ml (N=84201 /U/mJ) IgA 34 IU/ml (N=45-211 IU/ml) IgM 39 IU/ml (N=82-313 [g/ml). Chest x-ray showed a large clearly defined mediastJnal mass projecting outwards into the left lung from the Mlar region. There was persistent pyrexia in spite of intensive antibiotic therapy, Blood cultures grew KlebsieHa aerogenes and Pseudomenas aeruginesa. The patient became progressively more drowsy and died 11 days after admission.
At autopsy there was a mass weighing 165 gms in the anterior superior mediastinum and adherent to the pericardium. Histology of the mass showed an encapsutated tumour composed of haphazardly arranged small spindle shaped cells, divided into Iobules by thick fibrous trabeouJae (Fig. 1 }. The turnout tissue was traversed by numerous capillary channels around which the spindle cells were arranged cJrcumferentially. Apparently n o ~ a l small mature lymphocytes were sprinkled throughout the tumour tissue. The spindle celrs demonstrated moderate variability in size and shape but no mitotic figures were identdied. Sections of bone marrow showed hypm prasia (Fig. 2 ) The myetoid series was completely absent. The maierity of cells were erythroid precursors, the remainder being megakaryocytes with ~ small proportion of stem cells. Discussion The most interesting feature of thymic turnouts is their frequent association with other diseases some of which, such as myasthenia gravis, are thought to have an autoimmune basis. ApproxJm ately 7O per cent of patients with a thymoma have an additional disease p r o c e ~ the most common being myastheni~ gravis, haemocytopaeni~, cancer and hypogammaglobuiinaemia (Souadjian, 1974). In most cases the thymic turnouts are noninvas~ve ~ d asymptornatic, being discovered incidentally by chest x ray or, as in this case, at autopsy (Rogers, 1968). Since first being recorded (Kaznelson, 1922) there have been over 50 reports of pure red cell aprasia associated with thymoma. The effects of removal of the thymoma on the course of the red cell aplasia are variable and unpredictable (Rubin, 1964). Animal experiments to demonstrate that the thymoma cells have a direct role in depressFng erythropoietic activgY have so far failed {CJarkson, 1958). In some series (Hirst, 1967) antinuclear antibodies have been found in alp cases in which they were sought, reading some to pesturate that the pure red cod aplasia is an autoimmune disorder (Souadjian, 1974), Cases ~n which thymcmas have been associated with disorders of the myeloid series are much less frequent, but isolated case reports have appeared in the literature over the past few years
Fig. 1--High power view of representative field of thymic tumour demonstrating haphazardly arranged spin01e cells scattered lymphccyles (arrow L) and numerous capillary charmers (arrow C) (H and E. x 400).
tosis, hypegammagiobulinaemia and KlebsJe[la septicaemia. The possibJe relationship between thymoma and the disorders of the myeloid series is obscure.
F~g. 2--High power view of marrow showing several megakaryocytes and many red cell procurers. Myeloid cells not identifiable. H and E X 400. (Jacobsen, 1971 ). J acobson's case bears a striking resemblance to the current report, a spindle cell thymon}a being associated with agranulocy-
Approximately 6 per cent of oases of lhymoma have associated hypogammaglobulinaemia (Souadjian, 1974) commonly coexisting with e;ther myasthenia grav[s or red cell hypoplasia (Rub[n et al., 1964). The possible mechanism by which these haematoleg[ca] and immunological disorders may be related to thymomas is still a matter for speculation. It has been postulated that an abnormal thymus may permit the development of reactive or 'forbidden" clones of cells that produce antibodies to host antigens to which the host is normally tolerant (•urnet, 1962). In the case under discussion it is possible that antibodies have been produced to red and white cell precursors. The present case is presented to emphasise the range of disorders which may be associated with thymoma. A knowledge of this range is important if a clinical diagnosis Js to be made, and if the possibility of thymectomy is to be considered in therapy
Relerences
Burner, M. 1962. Role of the thymus and related organs in immunity. Brir reed. J. ii, 807. Burrows, S., Carroll, R. 1971 Thymoma assoeiated with pancytopenia. Arch. Path 92, 465. Clarkson, B. and Prockop, S. J. 1958. Aregenera Five anaemia associated with benign thymoma. New England J. Med. 259, 253. Hir~t, E., Robertson, T. L 1967 The syndrome of thymoma and erythroblastic anaemia : a rm view of 56 cases including three case reports Medicine, 46, 225. dacobson, B. M. 1971 C~se records of the
Massachussetts General HospitaJ. New England J. Med. Z34, 39. Kazne~son, P. ~922, Zur Ensten~ung der 31utzplat(chert, Verh, Deutsch. Gas Inn. Med, 34, 557. Rogers, B. H. G., Manaligod, J S, and Blazek, W . V . 1968. Thymoma with pancytopaenia and hypogammagtobulinaemia, Am J. Med, 44, 154. Rubln, M., Strauss, B., Allen, L 1964. Clinical disorders associated with thymic tumou~. A r c h Int. Med. 11, 389. Souadjian, J. V, Enriquez, P 3ilwrstein, M. N. and Pepin, d. M. 1974. The spectrum of di~ eases associated with ~hymoma. Arch. ~nt. Med. 134, 374
AND HYPOGAMMAGLOBULINAEMIA
R, H. Young School of Pathology, Trinity College, Dublin 2. fntrod~[Ion A 68 year old femare and a thymoma, agranuIoeytosis and hypogammaglobulinaemia is described. The patient presented with symptoms of infection, was treated with a variety of drugs but d~ed alter 10 days. The association between thymoma and haemopoiefic insufficiency is well recognised (Rogers, 1968). The mosl common histological type of thymoma associated with haematorogical abnormalities is the spJndle cell type similar to 1hat seen in this ease (Burrows, 1971). The comrnonest haematological disorder associated wkh Ih ymo ma rs " red celt aplasia. There have also been some reports of disorders of the myelcid series {Jacobsen, 1971). HypogammaglobuJmaem~a has been found in 6 per cent of cases of thymoma (Souadjian, 1974), The occurrence of agranulocytosis and mar}{ed hypegammaglobul~naemia wkh thymoma has prompted tMs case report. Case Report A 69 year ord femare attended her doctor complaining of cough, diarrhoea, and oral ulcers. She was treated with antibiotics but was admitted to hospital for investigation when her condition d~d not improve. On admission she had a temperature of 101 F , cervicar lymphadenopathy and was noted to be pale. Laboratory )nvestigations showed a haemoglobin of &7 gm/dl with a hypochromic peripheral blood gicture and white cell count of 200/dh Platerets were 29O x 10~/l. A bone marrow aspirate showed absence of mye[old elements. The erythroid series was normal and megakaryocytes were present in normal numbers. ;mmunorogical studies showed positive anti nuclear factor, and electrophoresis revealed subnormal [mmunogrobuHn levels, IgG, 38 ]U/ml (N=84201 /U/mJ) IgA 34 IU/ml (N=45-211 IU/ml) IgM 39 IU/ml (N=82-313 [g/ml). Chest x-ray showed a large clearly defined mediastJnal mass projecting outwards into the left lung from the Mlar region. There was persistent pyrexia in spite of intensive antibiotic therapy, Blood cultures grew KlebsieHa aerogenes and Pseudomenas aeruginesa. The patient became progressively more drowsy and died 11 days after admission.
At autopsy there was a mass weighing 165 gms in the anterior superior mediastinum and adherent to the pericardium. Histology of the mass showed an encapsutated tumour composed of haphazardly arranged small spindle shaped cells, divided into Iobules by thick fibrous trabeouJae (Fig. 1 }. The turnout tissue was traversed by numerous capillary channels around which the spindle cells were arranged cJrcumferentially. Apparently n o ~ a l small mature lymphocytes were sprinkled throughout the tumour tissue. The spindle celrs demonstrated moderate variability in size and shape but no mitotic figures were identdied. Sections of bone marrow showed hypm prasia (Fig. 2 ) The myetoid series was completely absent. The maierity of cells were erythroid precursors, the remainder being megakaryocytes with ~ small proportion of stem cells. Discussion The most interesting feature of thymic turnouts is their frequent association with other diseases some of which, such as myasthenia gravis, are thought to have an autoimmune basis. ApproxJm ately 7O per cent of patients with a thymoma have an additional disease p r o c e ~ the most common being myastheni~ gravis, haemocytopaeni~, cancer and hypogammaglobuiinaemia (Souadjian, 1974). In most cases the thymic turnouts are noninvas~ve ~ d asymptornatic, being discovered incidentally by chest x ray or, as in this case, at autopsy (Rogers, 1968). Since first being recorded (Kaznelson, 1922) there have been over 50 reports of pure red cell aprasia associated with thymoma. The effects of removal of the thymoma on the course of the red cell aplasia are variable and unpredictable (Rubin, 1964). Animal experiments to demonstrate that the thymoma cells have a direct role in depressFng erythropoietic activgY have so far failed {CJarkson, 1958). In some series (Hirst, 1967) antinuclear antibodies have been found in alp cases in which they were sought, reading some to pesturate that the pure red cod aplasia is an autoimmune disorder (Souadjian, 1974), Cases ~n which thymcmas have been associated with disorders of the myeloid series are much less frequent, but isolated case reports have appeared in the literature over the past few years
Fig. 1--High power view of representative field of thymic tumour demonstrating haphazardly arranged spin01e cells scattered lymphccyles (arrow L) and numerous capillary charmers (arrow C) (H and E. x 400).
tosis, hypegammagiobulinaemia and KlebsJe[la septicaemia. The possibJe relationship between thymoma and the disorders of the myeloid series is obscure.
F~g. 2--High power view of marrow showing several megakaryocytes and many red cell procurers. Myeloid cells not identifiable. H and E X 400. (Jacobsen, 1971 ). J acobson's case bears a striking resemblance to the current report, a spindle cell thymon}a being associated with agranulocy-
Approximately 6 per cent of oases of lhymoma have associated hypogammaglobulinaemia (Souadjian, 1974) commonly coexisting with e;ther myasthenia grav[s or red cell hypoplasia (Rub[n et al., 1964). The possible mechanism by which these haematoleg[ca] and immunological disorders may be related to thymomas is still a matter for speculation. It has been postulated that an abnormal thymus may permit the development of reactive or 'forbidden" clones of cells that produce antibodies to host antigens to which the host is normally tolerant (•urnet, 1962). In the case under discussion it is possible that antibodies have been produced to red and white cell precursors. The present case is presented to emphasise the range of disorders which may be associated with thymoma. A knowledge of this range is important if a clinical diagnosis Js to be made, and if the possibility of thymectomy is to be considered in therapy
Relerences
Burner, M. 1962. Role of the thymus and related organs in immunity. Brir reed. J. ii, 807. Burrows, S., Carroll, R. 1971 Thymoma assoeiated with pancytopenia. Arch. Path 92, 465. Clarkson, B. and Prockop, S. J. 1958. Aregenera Five anaemia associated with benign thymoma. New England J. Med. 259, 253. Hir~t, E., Robertson, T. L 1967 The syndrome of thymoma and erythroblastic anaemia : a rm view of 56 cases including three case reports Medicine, 46, 225. dacobson, B. M. 1971 C~se records of the
Massachussetts General HospitaJ. New England J. Med. Z34, 39. Kazne~son, P. ~922, Zur Ensten~ung der 31utzplat(chert, Verh, Deutsch. Gas Inn. Med, 34, 557. Rogers, B. H. G., Manaligod, J S, and Blazek, W . V . 1968. Thymoma with pancytopaenia and hypogammagtobulinaemia, Am J. Med, 44, 154. Rubln, M., Strauss, B., Allen, L 1964. Clinical disorders associated with thymic tumou~. A r c h Int. Med. 11, 389. Souadjian, J. V, Enriquez, P 3ilwrstein, M. N. and Pepin, d. M. 1974. The spectrum of di~ eases associated with ~hymoma. Arch. ~nt. Med. 134, 374
