Management of immune thrombocytopoenia in a patient with newly-diagnosed smouldering myeloma and colorectal cancer

Abstract

Immune thrombocytopoenia (ITP) is one of the most common autoimmune manifestations of B cell lymphoproliferative diseases. The association with multiple myeloma (MM) and solid tumours is rare. Here, a case of ITP associated with asymptomatic multiple myeloma and colon carcinoma, refractory to standard therapy and responsive to rituximab, is described. ITP should be considered in the differential diagnosis of thrombocytopoenia in MM and colon cancer. Understanding of the potential risk and reversibility of ITP should aid in the management of these patients.

BACKGROUND

Immune thrombocytopoenia (ITP) is classified as a primary disorder, previously referred to as idiopathic thrombocytopenic purpura, or as secondary to a variety of malignant and non-malignant disorders.¹ ITP is one of the most common autoimmune manifestations of B cell lymphoproliferative diseases.² However, its association with multiple myeloma is rare,³ as is its occurrence with solid tumours.⁴ We describe a case of a patient with ITP associated with asymptomatic multiple myeloma (MM) and colon carcinoma.

CASE PRESENTATION

In June 2008, a 67-year-old man with a history of gastrointestinal bleeding was admitted to our institution for severe thrombocytopoenia. Initial investigations showed thrombocytopoenia (3000 platelets/μl), hypochromic and microcytic anaemia (10 g/dl), hypoferritinaemia, a serum monoclonal paraprotein characterised as IgG κ (2.6 g/dl) and Bence–Jones proteinuria (κ light chain =950 mg/24 h). Renal function and serum calcium levels were normal as well as white blood cells and coagulation parameters including normal D-dimers. Schystocytes and platelet aggregates were absent on peripheral blood smear. Anti-platelet IgG antibodies were not detectable. A bone marrow biopsy revealed clusters of abnormal clonal plasma cells, including about 30% nucleated cells (fig 1A–D). There were also an increased number of megakaryocytes in all stages of maturation (fig 1F), as seen in thrombocytopoenias as a result of increased platelet destruction.⁵ Further work-up included an x ray skeletal survey revealing no osteolytic lesions. A diagnosis of asymptomatic multiple myeloma and secondary ITP was made. The patient was given steroid therapy (prednisolone 1 mg/kg) with a partial and transient incremental platelet count (38 000 platelets/μl) and underwent a colorectalendoscopy for his gastrointestinal bleeding that revealed a severe stricture due to an irregular circular tumour with ulceration of the sigmoid colon. Afterwards, the patient received intravenous Ig (0.4 mg/kg body weight daily for 5 days) with an increment of platelet counts in excess of 100 000 platelets/μl and underwent a low-level emergency operation. At laparotomy no neoplastic dissemination was observed. A surgical resection of the involved bowel was made and a microscopic examination revealed the presence of colon adenocarcinoma. The surgical margins were free from tumour cells; all lymph nodes found in the specimen were not metastatic. The pathological TNM staging was: T2, N0, Mx.

Figure 1.

Bone marrow biopsy showed a nodular cluster of a monomorphous population of mature plasma cells (A,B) that expressed CD138 antibody (C) and was monoclonal for κ light chain (D); λ light chain was not expressed (E). These immunomorphological findings were indicative of a neoplastic bone marrow infiltration by a multiple myeloma. Other areas of biopsy showed haematopoietic cells lines with marked hyperplasia of the megakaryocytes, which have dismorphic cytological features such as small and monolobated forms (F). These latter morphological findings were compatible with an immune thrombocytopoenia, such as that revealed by clinical history, probably related and secondary to plasma cell discrasia. (A) E/E stain at ×10 magnification, (B–F) E/E stain at ×40 magnification, (C) immunohistochemical stain for CD138 antibody at ×40 magnification, (D,E) immunohistochemical stain for κ and λ light chain antibody at ×40 magnification.

The postoperative course was unremarkable and a subsequent total body CT scan did not reveal any metastatic disease. No additional treatment, such as chemotherapy or radiotherapy, was given. A week after hemicolectomy, the platelet count decreased to 2000 platelets/μl. A new bone marrow biopsy was taken, which showed a significant reduction of plasma cells (5%) but still an increased number of megakaryocytes. The paraprotein level in the serum was stable at 2.6 g/dl. The patient was treated again with prednisone 1 mg/kg, with no further response. A second course of intravenous Ig was subsequently administered, which resulted in a transient benefit. Splenectomy was not taken into consideration because of the high risk of perioperative complications, and treatment with rituximab (4 weekly infusions at 375 mg/m²) was given. The platelet count increased to 50 000 platelets/μl and 120 000 platelets/μl after one dose of rituximab and at the end of the treatment schedule, respectively. A restaging of haematological disease showed a small monoclonal protein (1 g/dl) and a bone marrow plasmocytosis <5%. The platelet count has been normal ever since.

DISCUSSION

In our case, the diagnosis of secondary ITP was made on clinicopathological grounds of thrombocytopoenia, the presence of an underlying lymphoproliferative disorder, an increased number of megakaryocytes in the bone marrow and the exclusion of microangiopathic haemolytic anaemia, disseminated intravascular coagulation and other possible causes of non-immune thrombocytopoenia. We were no able to detect anti-platelet IgG antibodies. In primary ITP the pathogenetic role of polyclonal anti-platelet IgG antibodies and removal of antibody-labelled platelets by the spleen has been well documented, although autoantibodies are not detectable in up to 50% of the patients.^6,7 Platelet antibodies have not been systematically investigated in ITP associated with lymphoproliferative disorders, and it is uncertain whether these patients differ from ITP with IgG antibodies in the pathophysiology of their thrombocytopoenia. ITP is often seen in patients with chronic lymphocytic leukaemia,⁸ less commonly observed in non-Hodgkin’s lymphoma and Hodgkin’s disease and rarely described in multiple myeloma.³ The reasons for the rare incidence of ITP in MM remain speculative, and include the impaired antibody production in response to antigenic challenge⁹ and/or the elevated myeloma Ig that inhibits platelets immune destruction.³ By contrast, the paraprotein in monoclonal gammopathy of unknown significance (MGUS)-associated ITP can occasionally act as a platelet-reactive autoantibody.¹⁰

ITP has also been rarely reported in association with carcinoma of the gastrointestinal tract and other solid malignancies.^4,11 Colorectal cancer tissue is characterised by a specific pattern of cytokine gene expression including interleukin (IL)1, IL6, IL10 and acute phase proteins. IL6 is implicated in survival pathways of B cell malignancies, especially MM, in growth pathways for solid tumours and as a possible cofactor for tumour promotion.^12,13 Given the few reported cases, the diverse presentations of thrombocytopoenia during the course of each patient’s cancer and the variable therapeutic responses of ITP, the association of colorectal cancer, myeloma and ITP is probably coincidental in this case. Corticosteroids, intravenous immunoglobulin and splenectomy remain mainstays of treatment of primary ITP and in many cases of secondary ITP.¹⁴ However, newer therapies are remodelling conventional treatment algorithms.¹⁵ Several options exist or may be proposed as third-line treatment, including rituximab and the new thrombopoietin receptor agonists.¹⁶ As compared to splenectomy, however, rituximab therapy is a non-surgical and reversible measure with a favourable safety profile and reasonably high response rates. Furthermore, rituximab therapy may achieve long-lasting remission in nearly one-third of patients with relapsed or refractory primary ITP, with a good safety profile.¹⁷

In conclusion, we report a rare case of ITP associated with asymptomatic MM and colon carcinoma refractory to standard therapy and responsive to rituximab. ITP should be considered in the differential diagnosis of thrombocytopoenia in MM and colon cancer, and requires exclusion of all possible causes of non-immune thrombocytopoenia. Understanding of the potential danger and reversibility of ITP may aid in the management of these patients.

LEARNING POINTS

• Interleukin (IL)6 plays a role in survival pathways of B cell malignancies and solid tumours.

• Immune thrombocytopoenia (ITP) should be considered in the differential diagnosis of thrombocytopoenia in multiple myeloma (MM) and colon cancer.

• Rituximab can play a role in the management of ITP.