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The Community Oncologist

Disseminated Malignancy Misdiagnosed as Thrombotic Thrombocytopenic Purpura: A Report of 10 Patients and a Systematic Review of Published Cases

Hematology-Oncology Section, Department of Medicine, College of Medicine, Department of Biostatistics and Epidemiology, College of Public Health, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

Key Words. Cancer • Thrombotic thrombocytopenic purpura • Hemolytic-uremic syndrome • Microangiopathic hemolytic anemia

Correspondence: James N. George, M.D., The University of Oklahoma Health Sciences Center, Hematology-Oncology Section, Room CHB 358, P.O. Box 26901, Oklahoma City, Oklahoma 73190, USA. Telephone: 405-271-4222; Fax: 405-271-6444; e-mail: james-george{at}ouhsc.edu

Received July 19, 2006; accepted for publication November 2, 2006.

	LEARNING OBJECTIVES

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After completing this course, the reader will be able to:

1. List the diagnostic criteria for thrombotic thrombocytopenic purpura.
   
2. Describe how occult disseminated malignancy can mimic the clinical features of thrombotic thrombocytopenic purpura.
   
3. Identify the clinical clues that indicate additional diagnostic evaluation for possible malignancy in a patient with suspected thrombotic thrombocytopenic purpura.
   

	ABSTRACT

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Background. Patients with disseminated malignancy who present with microangiopathic hemolytic anemia and thrombocytopenia may be misdiagnosed as thrombotic thrombocytopenic purpura (TTP), resulting in inappropriate plasma exchange treatment, a procedure with major risk, and delay of appropriate chemotherapy.

Purpose. To assess clinical features that may distinguish occult disseminated malignancy from TTP.

Patients and methods. We report the 17-year experience of The Oklahoma TTP-Hemolytic-Uremic Syndrome (HUS) Registry (1989–2005) and a systematic review of previously published case reports.

Results. Ten of 351 patients in the Oklahoma Registry who were initially diagnosed with TTP and treated with plasma exchange were subsequently discovered to have disseminated malignancy. Only one patient had a history of cancer. In these 10 patients, neurologic abnormalities, hematocrit, platelet count, and serum creatinine were not different from the 133 concurrent patients with idiopathic TTP. Patients with disseminated malignancy had a longer duration of symptoms, more frequent presence of respiratory symptoms, higher lactate dehydrogenase levels, and more often failed to respond to plasma exchange treatment. Diagnosis of malignancy was made by bone marrow biopsy in six patients but not until autopsy in two patients. A systematic literature review identified 19 additional patients, reported from 1965 to 2005, in whom TTP or HUS was initially suspected and systemic malignancy was subsequently discovered. Fourteen different malignant disorders were diagnosed in these 29 patients.

Conclusions. Occult disseminated malignancy may mimic TTP. A search for systemic malignancy, including a bone marrow biopsy, is appropriate when patients with TTP have atypical clinical features or fail to respond to plasma exchange.

	INTRODUCTION

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The initial diagnosis of thrombotic thrombocytopenic purpura (TTP) may be uncertain because other disorders that can cause microangiopathic hemolytic anemia and thrombocytopenia, the principal diagnostic criteria, may not be initially apparent [1]. Disseminated malignancy is an important consideration in the differential diagnosis of TTP [2] since cancer has been well described for many years as a cause of microangiopathic hemolytic anemia and thrombocytopenia [3–7]. Although in most patients the disseminated malignancy that causes microangiopathic hemolytic anemia and thrombocytopenia is easily recognized, in some patients, the malignancy is not clinically apparent, and therefore TTP is diagnosed and plasma exchange treatment is begun. Failure to diagnose disseminated malignancy exposes the patient to the major risks of plasma exchange [8] and causes delay of appropriate chemotherapy. However, failure to urgently initiate plasma exchange treatment in a patient with TTP may result in death.

To address this diagnostic dilemma, we reviewed the clinical features of patients in The Oklahoma TTP-Hemolytic-Uremic Syndrome (HUS) Registry who were initially diagnosed as TTP and treated with plasma exchange before a disseminated malignancy was discovered. We also performed a systematic literature review to identify all previously published reports of patients with disseminated malignancy who presented with microangiopathic hemolytic anemia and thrombocytopenia and in whom the diagnosis of TTP or HUS was considered. Our goal was to define the clinical features of these patients that may suggest a search for disseminated malignancy.

	PATIENTS AND METHODS

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The Oklahoma TTP-HUS Registry
The Registry, begun on January 1, 1989, includes all consecutive patients for whom the Oklahoma Blood Institute (OBI) is requested to provide plasma exchange treatment for clinically diagnosed TTP or HUS [2, 9] based on the presence of microangiopathic hemolytic anemia and thrombocytopenia without an apparent etiology [1]. Since the OBI is the sole provider of plasma exchange services for all hospitals in central, western, and southeastern Oklahoma, the Registry is an inception cohort of all consecutive patients in a defined geographic region. The standard practice in our region is to treat all adult patients who have clinically diagnosed TTP or HUS, as well as children with TTP or atypical HUS, with plasma exchange. Therefore, the only patients systematically excluded from the Registry are children with typical (diarrhea-associated) HUS who are not treated with plasma exchange. Because the Registry enrolls patients at the time of the initial clinical diagnosis of TTP when plasma exchange treatment is begun, these patients describe the complete community experience and spectrum of disorders that can mimic TTP.

Registry patients are assigned in a hierarchical order to one of six clinical categories based on their initial presentation: (a) patients who have had a hematopoietic stem cell transplantation; (b) patients who are pregnant or postpartum; (c) patients with drug-associated TTP or HUS; (d) patients who have a prodrome of bloody diarrhea; (e) patients who have a concurrent additional disorder known to be associated with TTP or HUS or who have the diagnosis of an alternative etiology made after plasma exchange is begun; and (f) patients whose presentation is idiopathic [2, 9]. Data are recorded in Microsoft Access for all patients. Lactate dehydrogenase (LDH) levels are normalized to an upper limit of normal of 200 U/l to compare results among different hospitals. All hospital and follow-up data are complete to the present time for 349 of 351 patients enrolled through December 2005. Since November 13, 1995, serum samples have been obtained immediately before beginning the first plasma exchange treatment [2, 9]. ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity was measured by Drs. Bernhard Lämmle and Johanna Kremer Hovinga (University Hospital Inselspital, Berne, Switzerland) using their previously published immunoblotting method [10, 11]. The Registry is approved by the institutional review board of each participating hospital.

Systematic Review of Published Reports
Ovid software was used to search the Medline database through January 2006. The keywords and medical subject heading (MeSH) terms searched for TTP were "thrombotic thrombocytopenic purpura," "hemolytic uremic syndrome," "microangiopathic hemolytic anemia," and "thrombotic microangiopathy." The key words and MeSH terms searched for malignancy were "cancer," "carcinoma," "sarcoma," "neoplasm," and "malignancy." The search was limited to the English language. All articles identified by both one of the TTP terms and one of the malignancy terms were reviewed, and their bibliographies were searched for additional relevant articles. Articles were excluded after review if they had no primary patient data or focused on complications of chemotherapy for malignancy. Patients reported in the selected articles were included in our analysis if they fulfilled the following criteria: (a) TTP or HUS was initially suspected; (b) malignancy was not considered as an initial diagnosis and the patient had not received chemotherapy or had evidence for malignancy within the past year; and (c) there was no evidence for disseminated intravascular coagulation (DIC). Patient selection was performed independently by three of the authors (N.K., K.K.F., and J.N.G.).

	RESULTS

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Oklahoma Registry Patients

Patient Characteristics
The Oklahoma TTP-HUS Registry has enrolled and prospectively followed 351 consecutive patients who were treated with plasma exchange for a diagnosis of TTP or HUS for 17 years, from January 1, 1989 to December 31, 2005. Ten (3%) patients were initially diagnosed with TTP and began treatment with plasma exchange, and systemic malignancy was subsequently discovered. Their presenting features and clinical courses are described in Table 1. Each of these patients fulfilled the diagnostic criteria for TTP: microangiopathic hemolytic anemia and thrombocytopenia without an apparent alternative etiology [1]. These 10 patients presented in seven different years from 1995 to 2005 and in nine different hospitals; the diagnosis of TTP was made by 10 different hematologists. Initially, 9 of the 10 patients were considered to have idiopathic TTP; one had human immunodeficiency virus (HIV) infection and therefore was in the clinical category described as having a concurrent additional disorder [9].

Presenting Clinical and Laboratory Features
Weakness, dyspnea and cough, fever, and abdominal pain were the most common presenting symptoms. Among the seven patients with symptoms of dyspnea and cough, the chest x-ray was normal in patient 6; patient 3 had only a right pleural effusion; the other five patients had bilateral pulmonary infiltrates or congestion. Patients 2, 4, and 9 also had normal bronchoscopies. The median duration of symptoms prior to the diagnosis of TTP in all 10 patients was 21 days (range, 1–85 days); however, in some patients, the illness seemed to become acute on the day of hospitalization. Two patients had severe neurologic abnormalities; six others had confusion. Six patients had increased creatinine levels; patients 4, 9, and 10 had acute renal failure that required dialysis. All patients had increased LDH levels; four had values exceeding 5,000 U/l. Prothrombin time, activated partial thromboplastin time, and fibrinogen levels were normal in seven patients; in patient 4, abnormal coagulation tests were attributed to acute liver failure; in patient 5, DIC was suspected; no coagulation tests were done in patient 1. ADAMTS13 activity was measured in eight patients; the median value was 50% (range, 13%–100%). Patient 9, who had HIV infection, had the lowest value.

Clinical Course
The median number of plasma exchange treatments was five (range, 1–9). Patient 2 fulfilled criteria for response to plasma exchange treatment with an increased platelet count to >150,000/µl; in retrospect, it was assumed that effective treatment for pneumonia and hypotension was responsible for the platelet count recovery.

Disseminated malignancy was diagnosed 2–14 days (median, 6 days) after the initial diagnosis of TTP. In six patients, disseminated malignancy was diagnosed by bone marrow biopsy. In patient 3, the serum alkaline phosphatase was 1,003 IU/l, suggesting obstructive liver disease. Although CT scans were normal, a subsequent bone scan indicated metastatic cancer that was then documented by bone marrow biopsy. Pancreatic carcinoma was suggested by a serum cancer antigen 19–9 level of 14,541. In patient 10, the extremely elevated LDH level of 10,126 U/l and a serum uric acid level of >24 mg/dl suggested tumor lysis; therefore, bone marrow biopsy was done on the day after initiation of plasma exchange that diagnosed diffuse large B-cell lymphoma. In four other patients, the diagnosis was also made by bone marrow biopsy. A bone marrow biopsy was done in patient 4 because of neutropenia (absolute neutrophil count, 684/µl) in addition to the anemia and thrombocytopenia. Bone marrow biopsy was done after the discovery of a breast mass in patient 7 and because of no response to plasma exchange in patients 1 and 5. An additional indication for the bone marrow biopsy in patients 5 and 7 was the presence of many nucleated red cells on the peripheral blood smear.

In patients 2, 8, and 9, bone marrow biopsies were normal. Patient 2 was the only patient who did not have evidence for multiorgan dissemination. In this patient, diffuse, extensive squamous cell carcinoma was diagnosed by an open-lung biopsy after bronchoscopy had been normal. It was then assumed that cancer was the etiology of his bilateral pulmonary infiltrates and that he did not have concomitant TTP. Patient 8 presented with an ST-elevation myocardial infarction; sepsis was initially suspected to be the etiology of her anemia and thrombocytopenia; TTP was diagnosed and plasma exchange begun on her second hospital day. When there was no response to plasma exchange, CT scans were done that demonstrated metastatic renal cancer. Patient 9 was initially assumed to have a systemic infection because of his HIV infection and interstitial pulmonary infiltrates. TTP was diagnosed and plasma exchange begun on his sixth hospital day when no infection or malignancy was found by CT scans or bronchoscopy. Disseminated Kaposi’s sarcoma was discovered at autopsy. Patient 6 did not have a bone marrow biopsy; she died suddenly on her third hospital day, and systemic microvascular metastatic breast cancer was identified at autopsy, but only by microscopic examination. Marrow involvement at autopsy suggested that a bone marrow biopsy would have demonstrated the metastatic cancer [12].

All 10 patients died soon after the initial diagnosis of TTP (median, 12 days; range, 3–75 days). Of the eight patients who were diagnosed before death, only patient 10 received chemotherapy, but he died 6 days after beginning cyclophosphamide/doxorubicin/vincristine/prednisone/rituximab treatment. Patients 2 through 5 died before chemotherapy could be administered; patients 1, 7, and 8 were considered to be too ill to receive chemotherapy.

The final diagnoses included eight different malignancies: breast carcinoma (two patients), non-small cell lung cancer (two patients), pancreatic carcinoma, renal carcinoma, myelodysplasia (refractory anemia with excess blasts), acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and Kaposi’s sarcoma (one patient each).

Comparison of Patients with Disseminated Malignancy to Patients with Idiopathic TTP
Table 2 compares the 10 patients in whom disseminated malignancy was diagnosed to the 133 patients enrolled during the same period of time (1989–2005) whose final clinical category assignment was idiopathic TTP. Patients with idiopathic TTP were selected for this comparison because this was the initially assigned clinical category for 9 of our 10 patients and would have been their definitive clinical category assignment if malignancy had not been diagnosed. Patients with malignancies were more often men, had a longer duration of symptoms before the diagnosis of TTP, more frequently presented with respiratory symptoms of dyspnea and cough, and had greater elevations of serum LDH. Only 3 (2%) of the 133 patients with idiopathic TTP had LDH values over 5,000 U/l (5,955–12,587 U/l). However, there was no significant difference in age, race, frequency of neurologic abnormalities, severity of anemia and thrombocytopenia, serum creatinine, or ADAMTS13 activity. Although no patients with disseminated malignancy had severely deficient ADAMTS13 activity (<5%), this was not different from patients with idiopathic TTP, 70% of whom also did not have severely deficient ADAMTS13 activity. Patients with disseminated malignancy responded less often to plasma exchange and had a higher mortality rate.

	DISCUSSION

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Microangiopathic hemolytic anemia and thrombocytopenia caused by systemic malignancies have been well described [3–7], but it is uncommon for microangiopathic hemolytic anemia and thrombocytopenia to be the predominant presenting clinical features in patients whose systemic malignancy is not initially apparent. Although occult malignancy causing microangiopathic hemolytic anemia and thrombocytopenia may be uncommon, it is an important consideration in the evaluation of patients for TTP. In the Oklahoma TTP-HUS Registry, 10 (3%) of 351 patients who were initially diagnosed as having TTP and treated with plasma exchange were subsequently and unexpectedly diagnosed with disseminated malignancy. Only systemic infections have been a more common cause of an incorrect initial diagnosis of TTP in the Oklahoma Registry [2]. Many different malignancies may mimic TTP; there were 14 different malignant disorders (Tables 1, 3) in the 29 patients described in this report.

The importance of prompt diagnosis of the systemic malignancy is to provide an opportunity for treatment with appropriate chemotherapy. Early recognition of cancer may not benefit many patients who present with microangiopathic hemolytic anemia and thrombocytopenia since these patients often have widely disseminated cancer. This is evident from our experience, in which only 1 of 10 patients received chemotherapy, and even that one patient died soon after beginning treatment. Nine of 19 previously reported patients received chemotherapy and five achieved remission, but selection bias for reporting favorable outcomes may have influenced these data. Even though treatment success may be limited, prompt diagnosis is important for appropriate management.

Prompt diagnosis of systemic malignancy is also important in avoiding unnecessary risks of plasma exchange treatment for TTP. In a recent 9-year cohort study of 206 consecutive patients treated with plasma exchange for TTP, five patients died due to complications of the central venous catheter insertion or catheter-related sepsis; an additional 53 (26%) patients had nonfatal major complications, such as sepsis, venous thrombosis, and pericardial tamponade [8].

The difficulty of diagnosing a systemic malignancy presenting with microangiopathic hemolytic anemia and thrombocytopenia is apparent from the presentations of our 10 patients. The onset of symptoms may be abrupt. The severity of anemia, thrombocytopenia, and neurologic and renal abnormalities were not different from patients with idiopathic TTP. In 8 of the 29 patients, malignancy was not discovered until an autopsy was done; in three of these eight patients, malignancy was apparent only when microscopic sections from the autopsy were examined. Therefore, other patients with presumed idiopathic TTP who do not have an autopsy may have also had occult disseminated malignancy.

The diagnosis of disseminated malignancy excludes the diagnosis of TTP or HUS; these patients should not be considered to have "cancer-associated TTP" [31–33]. Although multiple etiologies may contribute to the syndromes recognized as TTP and HUS, disseminated malignancy is a pathologically and clinically distinct disorder. Disseminated malignancy can cause microangiopathic hemolytic anemia and thrombocytopenia, in the absence of DIC, by microvascular tumor emboli [7]. This has been most frequently observed with diffuse microscopic pulmonary involvement [20, 34]. ADAMTS13 activity is not severely deficient [35] but may be lower than normal in some patients with disseminated malignancy due to high plasma levels of von Willebrand factor [35, 36]. Plasma exchange has no role in management when a malignant disorder is recognized.

Clues that may suggest the presence of an occult systemic malignancy include presenting symptoms of dyspnea, cough, and pain other than abdominal pain. These symptoms were not common in our patients with idiopathic TTP but were common among the patients with malignancies. Although increased serum LDH is characteristic of patients with TTP, extreme elevations are not typical and may suggest tumor lysis. The presence of many nucleated red cells plus immature granulocytes may also create a suspicion of metastatic malignancy in the marrow [37]. Although many patients with systemic malignancy causing microangiopathic hemolytic anemia and thrombocytopenia may have DIC, the absence of evidence for DIC does not exclude the possibility of malignancy [7]. DIC was considered in only 1 of the 10 patients from Oklahoma and, by our selection criteria, in none of the previously reported patients. History of previous malignancy would be an obvious clue for the possibility of disseminated malignancy. However, 23 of 29 patients had no previous cancer history, suggesting that this presentation reflects a biologic property that accelerates systemic invasiveness. Perhaps the most convincing clue that a patient with presumed TTP may have a disseminated malignancy is failure to respond to plasma exchange.

If systematic malignancy is suspected, bone marrow biopsy is appropriate. Twenty-three of the 29 patients had a bone marrow biopsy, and it provided the diagnosis in 12 patients. Perhaps immunohistochemistry could have increased the diagnostic sensitivity of bone marrow biopsies. CT or bone scans provided the diagnosis in four additional patients. In eight patients, the diagnosis of malignancy was not made until autopsy.

	SUMMARY

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The evaluation and management of patients who present with an acute onset of microangiopathic hemolytic anemia and thrombocytopenia remain critical challenges for clinicians. Although the diagnosis of TTP and urgent treatment with plasma exchange must be considered in patients with microangiopathic hemolytic anemia and thrombocytopenia, the possibility that all of the clinical features of TTP may be caused by an occult disseminated malignancy must be appreciated. With increased awareness of the possible diagnosis of disseminated malignancy, the diagnosis can be made sooner, avoiding unnecessary plasma exchange treatment and allowing appropriate chemotherapy treatment.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicate no potential conflicts of interest.

	ACKNOWLEDGMENT

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This work was supported by The Hematology Research Fund, University of Oklahoma Health Sciences Center.

	REFERENCES

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This Article Abstract Full Text (PDF) CME: Take the course for this article: Disseminated Malignancy Misdiagnosed as Thrombotic Thrombocytopenic Purpura... eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Francis, K. K. Articles by George, J. N. Search for Related Content PubMed PubMed Citation Articles by Francis, K. K. Articles by George, J. N.