Association of breast cancer and immune thrombocytopenic purpura.

ABSTRACT: Immune thrombocytopenic purpura (ITP) and breast cancer are common disorders. Only six cases in which patients have had both diseases have been reported. We describe a 40-year-old woman who had ITP while responding to therapy for metastatic breast cancer. Given the few reported cases, the diverse presentations of thrombocytopenia during the course of each patient's breast cancer and the variable therapeutic responses of ITP, the association of breast cancer and ITP is probably coincidental.

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IMMUNE THROMBOCYTOPENIC PURPURA (ITP), the most common autoimmune disorder, results from accelerated platelet destruction after the binding of autoreactive antibodies to platelets. It is estimated that this entity affects approximately 1 in 10,000 people among the general population. (1) Most patients with ITP have detectable immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies against platelet glycoprotein complexes on their platelets or in their plasma. (2)

Although ITP is often associated with lymphoproliferative disorders, the medical literature has only occasionally linked ITP with solid tumors. (3-9) To date, only 6 cases of ITP have been reported in patients with breast cancer. (4-8) Carcinoma of the breast is the most common malignancy in women; a woman has a 1 in 8 (12.2%) chance of having breast cancer in her lifetime. (10) We present a patient who had ITP while responding to chemotherapy for metastatic breast cancer.

CASE REPORT

A 40-year-old African American woman was seen on May 18, 2000, because of an enlarging right breast mass. A needle core biopsy of the lesion revealed moderately differentiated invasive ductal carcinoma. Estrogen-progesterone receptors were positive. She had no history of any autoimmune disorders. Her only medication was a fentanyl patch. Positive physical findings included a large mass in the right breast and palpable right supraclavicular and right axillary lymph nodes. A nuclear bone scan showed widespread bone metastases. Computed tomography (CT) of the chest and abdomen showed enlarged pretracheal lymph nodes and several small (approximately 1 cm), round hypodensities suggestive of metastases in the anterior and posterior segments of the right lobe of the liver. Complete blood count revealed a hemoglobin level of 10 g/dL, platelet count of 129,000/[mm.sup.3], and white blood cell count (WBC) of 5,200/[mm.sup.3].

A combination of cyclophosphamide (600 mg/[m.sup.2]) and doxorubicin (60 mg/[m.sup.2]) was initiated for treatment of metastatic invasive ductal breast cancer on May 25, 2000. Three more courses were given at attenuated doses because of severe mucositis. Follow-up was erratic because she had problems with transportation and social support.

The patient was seen on October 19, 2000, for her fifth cycle of chemotherapy, 6 weeks after her previous treatment. She had no specific complaints. Physical examination showed a reduction in the right breast mass. No residual lymphadenopathy, hepatosplenomegaly, ecchymoses, or petechiae were found. Repeated CT revealed resolution of mediastinal lymphadenopathy and liver hypodensities. Pertinent laboratory values included hemoglobin, 10.1 g/dL; platelet count, 8,000/[mm.sup.3]; WBC, 4,600/[mm.sup.3] (59% neutrophils, 32% lymphocytes, 8% monocytes, and 1% eosinophils); reticulocyte count, 2.2%; and mean cell volume (MCV), 80.1/[micro][m.sup.3]. The peripheral smear showed no granulocytic precursors, nucleated red cells, or schistocytes. Urinalysis revealed numerous red blood cells, but results of renal function tests and electrolyte levels were normal. The activated partial thromboplastin time and prothrombin time were normal. Tests for antinuclear antibody (ANA) and platelet antibodies were negative. The pati ent did not consent to human immunodeficiency virus (HIV) testing, but HIV serology had been negative 2 years before. On September 1, 2000, the day of her fourth chemotherapy treatment, her platelet count had been 103,000/[mm.sup.3]. Bone marrow aspirate and biopsy specimens showed maturing hematopolesis and an increase in megakaryocytes but no evidence of metastatic carcinoma. The diagnosis of ITP was established, and prednisone therapy (1 mg/kg per day) was initiated. The platelet count increased to 51,000/[mm.sup.3] over 2 days. By the following week, it had increased to 165,000/[mm.sup.3]. Chemotherapy was resumed. Her initial response to therapy was followed by progression of breast cancer. Docetaxel therapy was initiated in December 2000. Prednisone therapy was tapered while the platelet count was 198,000/[mm.sup.3] in February 2001. The platelet count decreased to 4,000/[mm.sup.3] 1 week after prednisone therapy had been discontinued. By that time, a second response of the breast cancer had been achiev ed with docetaxel. One week after reinitiation of prednisone therapy, the platelet count increased to 435,000/[mm.sup.3]. The patient maintained an adequate platelet count and continued to receive both chemotherapy and prednisone at a maintenance dose of 40 mg daily.

DISCUSSION

Thrombocytopenia frequently occurs during the course of treatment in patients with solid tumors. Chemotherapy-induced myelosuppression, chemotherapy-induced myelodysplasia, and bone marrow involvement by cancer cells are the most common causes for low platelet counts in these patients. Thrombotic microangiopathies associated with cancer and chemotherapy have also been described in a small number of patients. Our patient's clinical presentation and the course of her disease suggested an autoimmune etiology.

The relationship between ITP and carcinoma has rarely been reported in the literature (3-9) Investigators have shown the presence of circulating immune complexes that may interact with platelets; however, the clinical significance of this observation remains unproven. (11)

Uncommon before the age of 30, breast cancer incidence increases with age. From an incidence of 117 per 100,000 women aged 40 to 44 years, breast cancer strikes 296 per 100,000 aged 55 to 59 years. (10) Chronic ITP most commonly affects women between 30 and 50 years of age, (12) but the association of both diseases has been reported in only six patients. Five of them were 40 to 60 years of age, and the remaining two were 69 and 72 years of age, respectively, when ITP was detected (Table).

Of the 6 previously described patients who had ITP during the course of breast cancer, 5 had metastatic or recurrent breast cancer when ITP was diagnosed (Table). (4-8) All but 1 of them were successfully managed with commonly used therapies for ITP, including steroids, intravenous immunoglobulin (IVIG), and/or splenectomy. The remaining patient was treated solely for breast cancer with radiotherapy and tamoxifen, and her platelet count returned to normal. (6) On the basis of available information, there remains no demonstrable relationship between ITP and breast cancer. Immune thrombocytopenic purpura has apparently responded to therapy directed against breast cancer in only 1 of these 6 cases. (6) The appearance of ITP in the course of breast cancer has been variable. Among some individuals, ITP became manifested simultaneously with the initial presentation of breast cancer. For others, it appeared at the time of a late recurrence or during the course of treatment for advanced disease, as in our case (Tabl e) (4-7). In another case report from our center, Jillella et a1 (8) described ITP manifested after high-dose chemotherapy and autologous stem-cell rescue in a patient with high-risk breast cancer. (8) Four of the 6 previously reported patients had bone marrow metastases, and 2 had diffuse splenic involvement (Table).

Our patient became thrombocytopenic after the fourth cycle of chemotherapy; however, her leukocyte count was normal, and her hemoglobin level had remained stable over four treatment cycles. The evaluation of her bone marrow biopsy confirmed the absence of myelosuppression and myelodysplasia. Results of a bone marrow biopsy showed no evidence of metastatic breast cancer. The number of megakaryocytes was increased. There was no history of blood transfusion or use of drugs that can cause thrombocytopenia and no evidence of a thrombotic microangiopathy or consumptive coagulopathy. Thrombocytopenia recurred immediately after prednisone therapy was discontinued. Solid tumors may cause low-grade disseminated intravascular coagulation (DIG) that can lead to thrombocytopenia. (13) Our patient did not have superficial venous thrombosis or migratory venous thrombosis, however, and her thrombocytopenia responded twice to prednisone, which is not effective in the treatment of chronic DIG. We ruled out other disorders ass ociated with thrombocytopenia and established a diagnosis of ITP in our patient using the guidelines of the American Society of Hematology. (14) We did not test for antibodies against platelets in her serum; however, the antiplatelet antibody assay has a predictive value of only 46% and a negative predictive value of 82%. (1 The diagnosis and relapse of ITP were not associated with progression of breast cancer.

CONCLUSION

At present, seven cases of ITP in breast cancer patients have been reported. Most have responded to treatment directed toward the autoimmune process rather than to the primary cancer treatment. The presentations of thrombocytopenia during the course of each patient's breast cancer were varied. The diagnosis of ITP in our patient was established while her breast cancer was responding to treatment; treatment with prednisone increased the platelet count. Because both are common disorders in the general population, and considering the low number of reported cases of concurrence, the diverse presentations of thrombocytopenia during the course of each patient's breast cancer, and the variable therapeutic responses of ITP, we suggest that the association of breast cancer and ITP may be only a coincidence.

After an initial partial response to docetaxel, the patient's breast cancer has remained stable, and she continues to receive chemotherapy. In January 2002, candidal esophagitis developed, and the patient consented to a repeat HIV test that was positive. With the known association of corticosteroid responsive thrombocytopenia and HIV infection, our patient's clinical course supports the premise that breast cancer and ITP may be only a coincidence and that other causes of ITP should be considered.

TABLE

Summary of Reported Cases of Breast Cancer and Immune Thrombocytopenic
Purpura (ITP)

                                       Interval Between
                                       Breast Cancer     Stage of Breast
Reference, Year               Age/Sex  and ITP           Cancer

Schwartz et al, (4) 1982      44, F    -                 IV

Cummings and Mazur; (5) 1992  46, F    6 years           IV, recurrent

                              59, F    6 months          IV

Igarashi et al, (6) 1998      72, F    At time of        III, recurrent
                                       relapse
Poratta et al, (7) 1999       69, M    13 months         IV

Jillella et al, (8) 2000      58, F    7 months          III
Present case                  40, F    5 months          IV recurrent



                              Site of
Reference, Year               Metastases           Therapy for ITP

Schwartz et al, (4) 1982      Cortical bone,       Prednisone
                              bone marrow
Cummings and Mazur; (5) 1992  Cortical bone, bone  Splenectomy
                              marrow, spleen
                              Spleen, bone         Splenectomy
                              marrow
Igarashi et al, (6) 1998      -                    None

Poratta et al, (7) 1999       Cortical bone, bone  Prednisone
                              marrow, lung
Jillella et al, (8) 2000      -                    Prednisone
Present case                  Cortical bone,       Prednisone
                              lung, liver

IVIG = Intravenous immunoglobulin.

References

(1.) Berchtold P, McMillan R: Therapy of chronic idiopathic thrombocytopenic purpura in adults. Blood 1989; 74:2309-2317

(2.) Berchtold P, Wenger M: Autoantibodies against platelet glycoproteins in autoimmune thrombocytopenic purpura: their clinical significance and response to treatment. Blood 1993; 81:12464250

(3.) Bellone JD, Kunicki TJ, Aster RH: Immune thrombocytopenia associated with carcinoma. Ann Intern Med 1983; 99:470-472

(4.) Schwartz KA, Slichter SJ, Harker LA: Immune-mediated platelet destruction and thrombocytopenia in patients with solid tumors. Br] Haematol 1982; 51:17-24

(5.) Cummings OW, Mazur MT: Breast carcinoma diffusely metastatic to the spleen. a report of two cases as idiopathic thrombocytopenic purpura. Am J Clin Pathol 1992; 97:484489

(6.) Igarashi T, Itoh K, Fujii H, et al: Successful treatment by radiation and hormone therapy of isolated local recurrence of breast cancer 24 years after mastectomy accompanied by immune thrombocytopenia: a case report. Jpn J Clin Oncol 1998; 28:270-275

(7.) Porrata LF, Alberts 5, Hook C, et al: Idiopathic thrombocytopenic purpura associated with breast cancer: a case report and review of the literature. Am J Clin Oncol 1999; 22:411-413

(8.) Jillella AP, Kallab AM, Kutlar A: Autoimmune thrombocytopenia following autologous hematopoietic cell transplantation: review of literature and treatment options. Bone Marrow Transplant 2000; 26:925-927

(9.) Demirer T, Celebi H, Arat M, et al: Autoimmune thrombocytopenia in a patient with small cell lung cancer developing after chemotherapy and resolving following autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 1999; 24:335-337

(10.) Ries LAG, Kosary CL, Hankey BF, et al (eds): SEER Cancer Statistics Review, 1973-1996. Bethesda, Md, National Cancer Institute, 1999

(11.) Horvath M, Fekete B, Rahoty F: Investigation of circulating complexes in patients with breast cancer. Oncology 1982; 39:20-22

(12.) Stasi R, Stipa E, Masi M, et al: Long-therm observation of 208 adults with chronic idiopathic thrombocytopenic purpura. Am J Med 1995; 98:436-442

(13.) Sack OH, Levin J, Bell WR: Trousseau's syndrome and other maifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features. Medicine 1977; 56:1-37

(14.) George JN, Woolf SH, Raskob GE, et al: Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996; 88:3-40

(15.) Kelton JG, Powers PJ, Carter CJ: A prospective study of the usefulness of the measurement of platelet-associated IgG for the diagnosis of idiopathic thrombocytopenic purpura Blood 1982; 60:1050-1053

RELATED ARTICLE: KEY POINTS

* Despite the fact that immune thrombocytopenic purpura (ITP) and breast cancer are common among women, the association of both diseases has rarely been reported.

* Among the published cases, no common findings suggest a causal relationship between these 2 disorders.

* The response of ITP to treatment appears unrelated to the clinical course of breast cancer; conventional approaches are often successful.

From the Department of Internal Medicine, Section of Hematology/Oncology, Medical College of Georgia, Augusta.

Reprint requests to Paul Dainer, MD, Medical College of Georgia, Department of Medicine, Section of Hematology/Oncology, 1120 15th St, BAA 5407, Augusta, GA 30912-3125.