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Paraneoplastic autoimmune thrombocytopenia in solid tumors
Critical Reviews in Oncology/Hematology 81 (2012) 75–81
Paraneoplastic autoimmune thrombocytopenia in solid tumors Maria-Theresa Krauth ∗ , Joe Puthenparambil, Klaus Lechner Division Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria Accepted 16 February 2011
Contents 1. 2. 3.
4. 5.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Prevalence of ITP in various cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Temporal relationship of ITP and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. ITP prior to cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. ITP concurrent with cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. ITP at recurrence of cancer or a second/third cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.4. ITP after chemotherapy and/or radiotherapy of the cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Other antibodies in patients with cancer associated ITP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Limitations of this analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
75 76 76 76 77 77 77 77 77 78 78 79 80 80 80 81
Abstract Immune-mediated hematological diseases are rare, but typical paraneoplastic syndromes. We have critically analyzed 68 published cases of an association of autoimmune thrombocytopenia (ITP) and solid cancers. Such cases occurred in a variety of cancers. They were most common in patients with lung and breast cancer, very rare in prostate cancer, but relatively common in renal cell and ovarian cancers. ITP occurred in about half of the patients concurrently with cancer, in about 25% prior to cancer and in others some time after diagnosis and treatment of cancer. In the latter patients ITP was either a sign of recurrence of cancer or had other causes. In most patients ITP responded to steroid treatment. There were only few patients who had a complete response of ITP after surgical removal or chemotherapy of the cancer and there was only one patient (ITP prior to cancer) in whom a long lasting complete remission of ITP after cancer resection could be ascribed solely to cancer resection. We believe that in patients with ITP a cancer-associated ITP has always to be considered, but an extensive search for a present or future cancer is not indicated unless there is laboratory or clinical suspicion of a malignant disease. In patients with cancer associated ITP cancer resection should be done in non-metastatic cases (after appropriate pretreatment). In metastatic cases steroids are probably the treatment of choice. © 2011 Elsevier Ireland Ltd. All rights reserved. Keywords: Autoimmune thrombocytopenia; Paraneoplastic syndrome; Solid tumors; Treatment; Surgery
1. Introduction ∗
Corresponding author. Tel.: +43 1 40400 4410; fax: +43 1 40400 4030. E-mail address: [email protected] (M.-T. Krauth).
1040-8428/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2011.02.004
Thrombocytopenia is common in cancer patients. The main cause is bone marrow aplasia due to cytotoxic
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Table 1 Cancer sites in patients with ITP-associated cancer. Cancer site
Estimated new cancer cases, U.S. (×1000)a
Number of reported cases of an association of cancer with AITP
References
Lung Breast Prostate Colorectal Urinary bladder Kidney Uterus Pancreas Thyroid Liver Ovary Stomach Larynx Cervix Testis Thymic Kaposi syndrome Germ cell cancer Melanoma Oesophagus Gall bladder Others
219 194 192 106 71 58 42 42 37 23 22 21 12 11 8 – – – – – – –
15 15 1 4 1 7 0 2 0 0 5 3 1 3 0 1 1 3 1 1 1 3
[2–15] [1,16–22] [23] [5,23,24] [25] [26–32]
Total a According
[8,33]
[2,34–36] [37–39] [8] [23,40] [41] [42] [5,43] [44] [45] [5] [2,46,47]
68 to [48].
chemotherapy or radiation. Less common causes are bone marrow infiltration by the tumor, drug induced immune thrombocytopenia or disseminated intravascular coagulation. Autoimmune thrombocytopenia (ITP) is a rare cause of thrombocytopenia in solid tumors and has not received much attention in the oncological literature. However, a few small series of patients [1–3] sometimes from one institution [1] and a substantial number of single cases of ITP associated with cancer have been published. We have collected all published cases of a presumed association of cancer and ITP and have carefully analyzed the pathohistology and the stage of these cancers, the severity of ITP, the temporal relationship of ITP and cancer and the response of ITP (and cancer) to various treatments.
2. Methods We performed a Medline database search via pubmed using the search terms “autoimmune thrombocytopenia and cancer” and “autoimmune thrombocytopenia and particular sites of the cancer (breast cancer, prostate cancer, etc.)”. In addition we used pubmed “related links” to identify similar papers on these topics and we screened the reference lists of published reports on ITP and cancer to identify additional cases. The authors independently evaluated the cases and checked the validity of the data. The criteria for the inclusion of cases for the analysis were as follows: (1) Definite diagnosis of a solid malignant cancer including histology and stage (metastatic or non-metastatic). (2) Data on the
temporal relationship between ITP and cancer. (3) Platelet count <100,000/l. (4) High probability that the thrombocytopenia was immune-mediated. An immune-mediated thrombocytopenia was assumed under the following conditions: No massive bone marrow infiltration by the cancer (small focal infiltrates were regarded as compatible with ITP), no chemotherapy within the last 4 weeks, normal or near-normal hemoglobin and leukocyte counts, normal or increased number of megakaryocytes in the bone marrow and no evidence of disseminated intravascular coagulation or drug dependent immune thrombocytopenia. The presence of platelet antibodies was regarded as compatible but not diagnostic for ITP since in almost all cases a relatively nonspecific antibody-test (platelet-IgG) has been used. 19 cases of cancer associated thrombocytopenia were excluded from the analysis, 3 because of possible alternative diagnoses and 16 because of lack of relevant data. Sustained complete remission (CR) was defined as CR of more than 6 months without steroids.
3. Results 3.1. Prevalence of ITP in various cancers We identified 68 cases of ITP associated with a solid cancer (Table 1). Cancer associated ITP has been described in almost all types of solid cancers [1–47]. The greatest number of cases of cancer-associated ITP was found in patients with the most common cancers (lung and breast cancer), but ITP
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was unusual in prostate cancer (the third common cancer). In relative terms cancer-associated ITP was more common than expected in renal and ovarian cancers. 3.2. Temporal relationship of ITP and cancer We divided paraneoplastic ITP in four categories according to the temporal relationship to the cancer. 3.2.1. ITP prior to cancer In 17 reported cases (median age 50 years, range 30–75) the ITP antedated the diagnosis of cancer. The cancers were 5 breast [1,16] 6 lung [3,6,8,10,11,15], 2 gastric [37,38], 2 colorectal [5,24], one ovarian [34] and one renal cell cancer [26]. In only three cases the cancer was metastatic at the time of detection. The median time from diagnosis of ITP to cancer diagnosis was 5 years (range 7 months to 40 years). The platelet count was 20,000/L or less in 9 out of 17 cases at diagnosis of ITP. The ITP was ongoing until detection of the cancer in 12 patients. In one case [5] the patient was in complete remission (CR) of ITP (after splenectomy) at the time of cancer diagnosis. In 4 cases there was no information on the status of ITP at cancer diagnosis [4,24,26,38]. In only one case the authors stated that ITP worsened at the time of cancer diagnosis [37]. Among 11 evaluable patients 6 had a response to steroids before cancer diagnosis whereas 5 patients were refractory to steroid therapy. Interestingly, one steroid refractory patient had a CR of ITP after interferon alpha [6]. Five patients were splenectomized before cancer diagnosis. Two had a transient, two had a sustained CR [5,24] and one had no response [6]. Eleven patients underwent elective cancer surgery with or without radiotherapy or adjuvant chemotherapy at the time of detection of cancer. One patient achieved a complete remission of ITP after removal of an ovarian tumor for more than 8 years [34]. Another patient [38] achieved a CR of ITP (sustained for more than 3 years) after simultaneous removal of a gastric cancer and the spleen. One patient had a PR of ITP after lung cancer surgery and radiotherapy for more than 20 months [7] and one [3] had a very short CR of ITP (3 weeks). Two breast cancer patients reported by the same author [16] achieved a CR of ITP after surgery and adjuvant chemotherapy. 3.2.2. ITP concurrent with cancer In 35 cases ITP was concurrent with the diagnosis of cancer (within 6 months before or after cancer diagnosis). There were 7 cases of lung cancer [3,8–13] among them one with small cell lung cancer [12], 6 cases of renal cell [27–32], 5 cases of breast cancer [1,17,18], 3 germcell cancers [5,43], 2 ovarian [2,35] 2 colorectal cancers [5,23], 1 skin [2], 1 oesophageal [45], 1 pancreatic [33], 1 prostate [23], 1 gallbladder cancer [5], 1 Kaposi sarcoma [42], 1 malignant melanoma [44], 1 rhabdomyosarcoma [46] and 1 thymic cancer [41]. 15 cancers were metastatic. The platelet count was ≤30,000/l in 22/35 cases and ≤10,000/l in 13 cases. Response to steroids was evaluable in 26
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patients. 16 patients had some response to steroids. Only five patients achieved a CR which was sustained for some time after withdrawal of steroids [10,11,17,18,33]. Ten patients were steroid-refractory [3,12,13,30,32,41,43,44,46]. Twelve patients underwent cancer surgery. Six patients, all with renal cell cancer, [27–32] achieved at least a short term CR of ITP after resection of the tumor. Of the three patients with tumor resection alone one patient with Evans syndrome [32] had a CR of AIHA and ITP for 210+ days, the other two had an only transient or unknown duration of CR [28,31] Two patients were splenectomized simultaneously. One of these patients [27] had a documented sustained CR of ITP (20 weeks), the other was not followed up [30]. One patient with lung cancer had a very short CR after surgery [3] and another a CR of an Evans syndrome for 11 months [11] after lobectomy and splenectomy. One patient with metastatic breast cancer had a CR of ITP and partial response (PR) of cancer for 7 months after chemotherapy [17]. 3.2.3. ITP at recurrence of cancer or a second/third cancer In 9 patients ITP occurred only at the time of recurrence of cancer [2,19,20,25,36,47] or at the time of a second or third cancer [8,23]. The primary cancers were 2 breast, 2 ovarian, 1 urinary bladder, 1 head and neck, 1 laryngeal, 1 cervix cancer and 1 Kaposi syndrome. The time from primary tumor to recurrence ranged from 6 months to 26 years. The platelet count was ≤30,000 in 6 cases. In four cases ITP was associated with a solitary localized cancer recurrence, in three cases [19,36] in a normal-sized or enlarged spleen (diffuse and nodular cancer infiltration) and one in a skin nodule in the scar after surgery for left sided breast cancer [20]. All four patients achieved a CR of ITP after local treatment (in three cases splenectomy, in one case local radiotherapy). The other patients (n = 3) had a recurrence of cancer at the primary tumor site. ITP responded in all these cases to steroid treatment. 3.2.4. ITP after chemotherapy and/or radiotherapy of the cancer In seven patients (2 uterine/cervix, 2 breast, 2 lung and 1 pancreatic cancer) ITP occurred after intensive radioor chemotherapy [2,8,14,21,22,40]. Thrombocytopenia was severe (≤20,000/l) in all cases in the absence of severe anemia und neutropenia and documented normal or increased numbers of megakaryocytes in the bone marrow. Of particular interest in this group of patients is the case of a patient with lobular breast cancer [22] who underwent autologous stem cell transplantation (conditioning with thiotepa and carboplatin) and developed after full engraftment at day 8 an isolated severe thrombocytopenia with normal hemoglobin and leukocyte values and increased megakaryocytes in the bone marrow. The patient responded to steroids and finally achieved a complete remission of ITP. Another patient with small cell lung cancer [14] developed severe thrombocy-
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topenia one to two months after intensive chemotherapy with cyclophosphamide and paclitaxel before planned stem cell harvest. After full hematologic recovery he developed after one month a severe isolated thrombocytopenia with normocellular bone marrow and increased megakaryocytes. Despite thrombocytopenia autologous stem cell transplantation was performed and the platelet count started to recover spontaneously on day 14 post-transplantation. The remaining patients developed severe isolated thrombocytopenia ten days to two months after the last cycle of intensive but not myeloablative chemo- or radiotherapy. Thrombocytopenia was severe in all cases with otherwise normal blood counts. All patients responded to treatment with steroids. 3.3. Other antibodies in patients with cancer associated ITP The most common additional antibodies in cancer associated ITP are red cell antibodies (Evans syndrome) [11,32,34,37,38,41,42]. A lupus anticoagulant was associated in three cases [9,15,19] and an acetylcholine receptor antibody in one case [38].
4. Discussion Immune-mediated hematological paraneoplastic syndromes (PNS) include autoimmune hemolytic anemia [49], anti-FVIII antibodies [50], antiphospholipid antibodies [51], autoimmune thrombocytopenia and others. The occurrence of these PNS is well known in lymphomas [52] but is also not uncommon in solid tumors but has received less attention. In this paper we show that autoimmune thrombocytopenia is not an uncommon complication in solid tumors. According to the recent proposal for the standardization of terminology of immune thrombocytopenias this of type ITP should be classified as “secondary ITP (paraneoplastic)” [53]. As in other PNS ITP may occur in a variety of solid tumors including common and rare malignancies. The two most common cancers associated with ITP were breast and lung cancers (not unexpected since they are the most common cancers). On the other hand there was only one case of ITPassociated prostate cancer although this cancer has almost the same prevalence as lung and breast cancer (Table 1). Thus, there is no correlation between the frequencies of cancers and ITP (at least on the basis of reported cases). This is a phenomenon which has also been observed in other PNS. The most common solid cancers in patients with paraneoplastic autoimmune hemolytic anemia (AIHA) were lung cancer, renal cell cancer and Kaposi’s syndrome [49]. In patients with acquired factor-VIII inhibitors the most common cancers are prostate, lung and colon cancers [50] and in patients with lupus anticoagulant renal cell carcinoma, lung cancer and malignant melanoma [51]. The same lack of correlation is also seen in lymphomas. PNS are almost absent in mantle cell lymphoma, but very common in the very rare splenic marginal
zone lymphoma [52]. The reasons for the differences in these PNS associations are unknown. One interesting phenomenon in patients with paraneoplastic ITP is the observation of a relatively high prevalence of double cancers (7 patients out of 68). Autoimmune paraneoplastic diseases in general may occur prior to the diagnosis of cancer, concurrent with cancer or after treatment of cancer either as a sign of recurrence or in CR of cancer. In our analysis of cancer-associated ITP we found a considerable number of cases in which ITP preceded the diagnosis of cancer, often for many years. In such cases it is uncertain whether this is a coincidence or whether there is a causal relationship between the two conditions. Prospective studies on the risk of solid tumors in patients with ITP have not been performed so far. However, from population- based studies it is known that patients with ITP have an increased incidence of Hodgkin’s lymphoma [54]. There are other examples of PNS in which an antibody or an immune disease definitely precedes a malignant disease. Patients with AIHA have an increased incidence of diffuse large cell lymphoma [55] and onconeural antibodies may be detectable often several years before diagnosis of a malignancy [56–58]. Thus, a causal relationship between preceding ITP and solid tumors cannot be excluded. In favor of a specific association is the fact that most ITPs were ongoing until the time of detection of the cancer. On the other hand there was only one instance in which the appearance of the cancer had an adverse effect on thrombocytopenia. Patients with ITP preceding cancer seem to have the same response to steroids and splenectomy as primary ITP. Interestingly, in one patient with ITP preceding cancer radical cancer surgery led to long lasting remission of ITP (and cancer). It has been speculated that paraneoplastic antibodies may have a favorable influence on tumor progression. This assumption is based mainly on observations in onconeural antibodies [59]. Our data cannot support this assumption, but it should be noted that 14 out of 17 patients with cancer after preceding ITP were non-metastatic. In the vast majority of cases, ITP occurred concurrent with the diagnosis of the tumor (no documented thrombocytopenia or bleeding tendency before detection of the tumor). A substantial number of these patients responded to standard treatment of primary ITP e.g. steroids and splenectomy. Of greatest practical and theoretical interest is the question, whether the removal of the tumor or chemotherapy led to documented sustained steroid-free remissions of ITP. Eleven patients with concurrent ITP who underwent surgery with curative intent had some response of ITP (Table 2). There were some patients with short-lived CR which were probably due to postoperative acute phase reaction. However, we could identify only one single patient (a non-metastatic renal cell cancer with Evans syndrome) who achieved a sustained complete remission of ITP (and AIHA) after cancer surgery alone [32]. Two patients had sustained remissions after tumor resection with simultaneous splenectomy [27,38]. The remission in these cases may rather be due to the known efficacy of
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Table 2 Responses of paraneoplastic ITP to various cancer treatments (only cases with some response). Reference
Cancer site
Stage
Temporal relationship
Primary cancer treatment
Additional treatments for ITP
Response of ITP (platelet count × 1000/l before/after therapy
Duration of ITP response
[16] [19] (case 1) [19] (case 2) [11] [3] [7] [28] [32] [27] [30] [31] [34] [38] [20] [17] [36]
Breast Breast Breast Lung Lung Lung RCC RCC RCC RCC RCC Ovary Gastric Breast Breast Ovary
nm m m nm m nm m nm nm nm m nm nm m m m
Prior Recurrence Recurrence Prior Prior Prior conc. conc. conc. conc. conc. Prior Prior Recurrence conc. Recurrence
Surgery CT (FEC) Splenectomy Splenectomy Surgery Surgery Surgery RT Surgery Surgery Surgery Surgery Surgery Surgery Surgery RT Tamoxifen CT SE
None None None SE None None Steroids None SE SE None None SE None None None
CR (20/100) CR (26/500) CR (8/167) CR (5/293) CR (10/119) PR (25/50) CR (18/131) CR (10/“normal”) CR CR (1/500) CR CR (80/“normal”) CR (1/244) CR (26/170) CR (2/”normal”) CR (50/120)
Unknown Unknown Unknown 2 months 3 weeks 20+ months Unknown 210+ days 20+ weeks Unknown 2 weeks 8+ years 3+ years 2.5 years 7+ months 8+ months
SE, splenectomy; RT, radiotherapy; CT, chemotherapy; RCC, renal cell cancer; m, metastatic; nm, non-metastatic; conc., concurrent.
splenectomy than to the removal of the tumor. There is only one patient with metastatic breast cancer who had a remission of ITP (seven months) after chemotherapy alone. Thus, there is only little evidence that the control of the underlying malignancy has any long term beneficial effect on paraneoplastic ITP in most cases. We found only one case in which chemotherapy had some effect on ITP [17]. This is certainly due to the fact that there are no highly effective curative chemotherapies available for these cancers. A special case is a patient with amegakaryocytic ITP (presumably immunological) in a small cell lung cancer in whom a CR was achieved with chemotherapy [60]. Of particular interest are the seven patients who had ITP only at the time of recurrence of the primary cancer. This indicates that the biology of the cancer may have changed, although the histology of the primary and the recurrent cancer were not different. Most exciting is the high efficacy of the removal of distant metastases in the spleen by splenectomy without systemic treatment in three patients [19,36]. The remission of ITP may have been due to reduction of antibody production by the spleen. It might also be possible that the diffuse metastasis in the spleen increased the platelet trapping activity of the spleen. This might be a similar mechanism as in hairy cell leukemia, where the infiltration of the spleen with hairy cells increases the splenic platelet trapping and splenectomy is highly effective for treatment of cytopenia. The patient with local recurrence and ITP [20] and complete remission of ITP after local irradiation is a second (even more impressive) example that paraneoplastic ITP could be completely controlled by local treatment of the tumor. Severe isolated immune thrombocytopenia after myeloablative chemotherapy is a well known phenomenon in patients after autologous stem cell transplantation for lymphomas [61–63]. It occurs after full recovery of the bone marrow and responds to steroid treatment. The two cases of ITP
after myeloablative chemotherapy in solid cancer may belong to this category of immune thrombocytopenias. The development of severe thrombocytopenia late after intensive but non-myeloablative chemotherapy is a peculiar phenomenon which has been observed only after chemotherapy in Hodgkin lymphomas [64]. It is uncertain whether there is really a pathogenetic association with chemo/radiotherapy. Virus infections could also be a cause for these thrombocytopenias but have not been studied extensively in these patients.
5. Limitations of this analysis Our analysis of case reports has important limitations. All numerical data should be regarded with caution because of possible reporting bias. Whereas the diagnosis and the stage of disease (metastatic/non-metastatic) was well established in most analyzed cases the diagnosis of ITP was highly probable but not definitive because for diagnosis of ITP no laboratory test with a very high positive predictive power is available. We took great care to exclude patients with other causes of thrombocytopenia but we could not exclude viral infections as a possible cause of thrombocytopenia in these often immune-compromised patients. The most useful finding was an increased number of megakaryocytes in the bone marrow, while the platelet antibody tests which measured in almost all cases only the IgG concentration on platelets is known to be neither sensitive nor specific for ITP. However, we believe that the diagnosis was valid in the vast majority of cases. Another problem was the lack of short and long term follow up in many patients which made it difficult to determine the duration of remissions. Although we believe that most of the ITP were causally related to the cancer we are aware of the fact, that association does not mean causality. The lack of response of ITP after curative surgery in most of the cancers is disappointing. On the other hand, the convincing effects
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of surgery and chemotherapy in some cases suggest a causal relationship. It may be that the pathogenesis is not the same in all cases of cancer associated ITP. We believe that in patients with cancer associated ITP cancer resection should be done in non-metastatic cases (after appropriate pretreatment). In metastatic cases steroids are probably the best choice. In practical terms we believe that in patients with ITP a cancer-associated ITP has always to be considered, but an extensive search for a present or future cancer is not indicated unless there is laboratory or clinical suspicion of a malignant disease. There are many unanswered questions in PNS. We believe that careful laboratory studies in patients with PNS may provide interesting insights into the biology of malignant tumors in particular the interaction of the tumor with the immune system and may provide some clues to immune therapy of solid cancers.
Reviewer Hans-Joachim Schmoll, M.D., Ph.D., Martin-LutherUniversitat Halle-Wittenberg, Innere Med. IV, Ernst-GrubeStrasse 40, D-06120 Halle, Germany.
Conflict of interest The authors declare no conflict of interest.
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M.-T. Krauth et al. / Critical Reviews in Oncology/Hematology 81 (2012) 75–81 [32] Kamra D, Boselli J, Sloane BB, Gladstone DE. Renal cell carcinoma induced Coombs negative autoimmune hemolytic anemia and severe thrombocytopenia responsive to nephrectomy. J Urol 2002;167:1395. [33] Bir A, Bshara W, George M, Fakih MG. Idiopathic thrombocytopenic purpura in a newly diagnosed pancreatic adenocarcinoma. JOP 2006;7:647–50. [34] Bellucci S, Dosquet C, Boval B, Wautier JL, Caen J. Association of autoimmune thrombocytopenic purpura (AITP), Graves’ disease and ovarian carcinoma. Nouv Rev Fr Hematol 1991;33:307–9. [35] Chehal A, Taher A, Seoud M, Shamseddine A. Idiopathic thrombocytopenic purpura and ovarian cancer. Eur J Gynaecol Oncol 2003;24:539–40. [36] Tarraza HM, Carroll R, De Cain M, Jones M. Recurrent ovarian carcinoma: presentation as idiopathic thrombocytopenic purpura and a splenic mass. Eur J Gynaecol Oncol 1991;12:439–43. [37] Inoue Y, Kaku K, Kaneko T, Matsumoto N. Autoimmune hemolytic anemia and gastric cancer: case report and review of the literature. Nippon Ketsueki Gakkai Zasshi 1983;46:836–41. [38] Wakata N, Kiyozuka T, Konno S, et al. Autoimmune thrombocytopenic purpura, autoimmune hemolytic anemia and gastric cancer appeared in a patient with myasthenia gravis. Intern Med 2006;45:479–81. [39] Villias C, Gourgiotis S, Veloudis G, Sampaziotis D, Moreas H. Synchronous early gastric cancer and gastrointestinal stromal tumor in the stomach of a patient with idiopathic thrombocytopenic purpura. J Dig Dis 2008;9:104–7. [40] Mitsuhashi A, Yamazawa K, Tanaka N, Sekiya S. Autoimmune thrombocytopenia in women with carcinoma of the uterine cervix developing after cisplatin and radiation therapy. BJOG 2002;109:103–4. [41] Rubinstein I, Langevitz P, Hirsch R, Berkowicz M, Lieberman Y, Shibi G. Autoimmune hemolytic anemia as the presenting manifestation of malignant thymoma. Acta Haematol 1985;74:40–2. [42] Thomas P, Rotteleur G, Gosset D, et al. Kaposi’s angiosarcoma associated with Evans syndrome. Nouv Presse Med 1980;9:1710. [43] Garnick MB, Griffin JD. Idiopathic thrombocytopenia in association with extragonadal germ cell cancer. Ann Intern Med 1983;98:926–7. [44] Castro Ríos MA, Sánchez Avalos JC, Molinas F, Barcat JA, Macchi AE. Idiopathic thrombocytopenic purpura and melanoma. Medicina (B Aires) 1984;44:282–6. [45] Shutt JD, Mainwaring CJ, Davis AJ, James CM, Shepherd HA. Oesophageal carcinoma and refractory idiopathic thrombocytopenic purpura: a challenging combination. Eur J Gastroenterol Hepatol 2004;16:791–3. [46] Semino A, Danova M, Perlini S, Palladini G, Riccardi A, Perfetti V. Unusual manifestations of disseminated neoplasia at presentation: right-sided heart failure due to a massive cardiac metastasis and autoimmune thrombocytopenia in pleomorphic rhabdomyosarcoma of the adult. Am J Clin Oncol 2006;29:102–3. [47] Jubelirer SJ, Goodloe-Greens L, Deykin D. Autoimmune thrombocytopenic purpura-like syndrome in a patient with head and neck cancer. Laryngoscope 1981;91:408–9. [48] Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin 2009;59:225–49. [49] Puthenparambil J, Lechner K, Kornek G. Autoimmune hemolytic anemia as a paraneoplastic phenomenon in solid tumors: a critical analysis of 52 cases reported in the literature. Wien Klin Wochenschr 2010;122:229–36. [50] Hauser I, Lechner K. Solid tumors and factor VIII antibodies. Thromb Haemost 1999;82:1005–7.
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[51] Gómez-Puerta JA, Cervera R, Espinosa G, et al. Antiphospholipid antibodies associated with malignancies: clinical and pathological characteristics of 120 patients. Semin Arthritis Rheum 2006;35:322– 32. [52] Hauswirth AW, Skrabs C, Schützinger C, et al. Autoimmune thrombocytopenia in non-Hodgkin’s lymphomas. Haematologica 2008;93:447–50. [53] Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 2009;113:2386–93. [54] Landgren O, Engels EA, Pfeiffer RM, et al. Autoimmunity and susceptibility to Hodgkin lymphoma: a population-based case-control study in Scandinavia. J Natl Cancer Inst 2006;98:1321–30. [55] Anderson LA, Gadalla S, Morton LM, et al. Population-based study of autoimmune conditions and the risk of specific lymphoid malignancies. Int J Cancer 2009;125:398–405. [56] Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003;349:1543–54. [57] Braik T, Evans AT, Telfer M, McDunn S. Paraneoplastic neurological syndromes: unusual presentations of cancer. A practical review. Am J Med Sci 2010 [Epub ahead of print]. [58] Ropper AH, Gorson KC. Neuropathies associated with paraproteinemia. N Engl J Med 1998;338:1601–7. [59] Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol 2008;7:327–40. [60] Zoppoli G, Balleari E, Bruzzone A, Mastracci L, Ghio R. Purpura as the initial presentation for small-cell lung cancer. Onkologie 2009;32:277–9. [61] Hequet O, Salles G, Ketterer N, et al. Autoimmune thrombocytopenic purpura after autologous stem cell transplantation. Bone Marrow Transplant 2003;32:89–95. [62] Kamezaki K, Fukuda T, Makino S, Harada M. Evans’ syndrome following autologous peripheral blood stem cell transplantation for non-Hodgkin’s lymphoma. Clin Lab Haematol 2004;26: 291–3. [63] Keung YK, Cobos E, Bolanos-Meade J, Issarachai S, Brideau A, Morgan D. Evans syndrome after autologous bone marrow transplant for recurrent Hodgkin’s disease. Bone Marrow Transplant 1997;20:1099–101. [64] Lechner K, Chen YA. Paraneoplastic autoimmune cytopenias in Hodgkin lymphoma. Leuk Lymphoma 2010;51:469–74.
Biographies Maria-Theresa Krauth graduated from the medical University of Vienna in 2002. She is currently assistant professor at the Division of Hematology and Hemostaseology. Joe Puthenparambil graduated from the medical University of Vienna in 2010. Klaus Lechner graduated from the University of Vienna in 1960. He is former head of the Division of Hematology and Hemostaseology.
Paraneoplastic autoimmune thrombocytopenia in solid tumors Maria-Theresa Krauth ∗ , Joe Puthenparambil, Klaus Lechner Division Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria Accepted 16 February 2011
Contents 1. 2. 3.
4. 5.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Prevalence of ITP in various cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Temporal relationship of ITP and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. ITP prior to cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. ITP concurrent with cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. ITP at recurrence of cancer or a second/third cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.4. ITP after chemotherapy and/or radiotherapy of the cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Other antibodies in patients with cancer associated ITP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Limitations of this analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
75 76 76 76 77 77 77 77 77 78 78 79 80 80 80 81
Abstract Immune-mediated hematological diseases are rare, but typical paraneoplastic syndromes. We have critically analyzed 68 published cases of an association of autoimmune thrombocytopenia (ITP) and solid cancers. Such cases occurred in a variety of cancers. They were most common in patients with lung and breast cancer, very rare in prostate cancer, but relatively common in renal cell and ovarian cancers. ITP occurred in about half of the patients concurrently with cancer, in about 25% prior to cancer and in others some time after diagnosis and treatment of cancer. In the latter patients ITP was either a sign of recurrence of cancer or had other causes. In most patients ITP responded to steroid treatment. There were only few patients who had a complete response of ITP after surgical removal or chemotherapy of the cancer and there was only one patient (ITP prior to cancer) in whom a long lasting complete remission of ITP after cancer resection could be ascribed solely to cancer resection. We believe that in patients with ITP a cancer-associated ITP has always to be considered, but an extensive search for a present or future cancer is not indicated unless there is laboratory or clinical suspicion of a malignant disease. In patients with cancer associated ITP cancer resection should be done in non-metastatic cases (after appropriate pretreatment). In metastatic cases steroids are probably the treatment of choice. © 2011 Elsevier Ireland Ltd. All rights reserved. Keywords: Autoimmune thrombocytopenia; Paraneoplastic syndrome; Solid tumors; Treatment; Surgery
1. Introduction ∗
Corresponding author. Tel.: +43 1 40400 4410; fax: +43 1 40400 4030. E-mail address: [email protected] (M.-T. Krauth).
1040-8428/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2011.02.004
Thrombocytopenia is common in cancer patients. The main cause is bone marrow aplasia due to cytotoxic
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Table 1 Cancer sites in patients with ITP-associated cancer. Cancer site
Estimated new cancer cases, U.S. (×1000)a
Number of reported cases of an association of cancer with AITP
References
Lung Breast Prostate Colorectal Urinary bladder Kidney Uterus Pancreas Thyroid Liver Ovary Stomach Larynx Cervix Testis Thymic Kaposi syndrome Germ cell cancer Melanoma Oesophagus Gall bladder Others
219 194 192 106 71 58 42 42 37 23 22 21 12 11 8 – – – – – – –
15 15 1 4 1 7 0 2 0 0 5 3 1 3 0 1 1 3 1 1 1 3
[2–15] [1,16–22] [23] [5,23,24] [25] [26–32]
Total a According
[8,33]
[2,34–36] [37–39] [8] [23,40] [41] [42] [5,43] [44] [45] [5] [2,46,47]
68 to [48].
chemotherapy or radiation. Less common causes are bone marrow infiltration by the tumor, drug induced immune thrombocytopenia or disseminated intravascular coagulation. Autoimmune thrombocytopenia (ITP) is a rare cause of thrombocytopenia in solid tumors and has not received much attention in the oncological literature. However, a few small series of patients [1–3] sometimes from one institution [1] and a substantial number of single cases of ITP associated with cancer have been published. We have collected all published cases of a presumed association of cancer and ITP and have carefully analyzed the pathohistology and the stage of these cancers, the severity of ITP, the temporal relationship of ITP and cancer and the response of ITP (and cancer) to various treatments.
2. Methods We performed a Medline database search via pubmed using the search terms “autoimmune thrombocytopenia and cancer” and “autoimmune thrombocytopenia and particular sites of the cancer (breast cancer, prostate cancer, etc.)”. In addition we used pubmed “related links” to identify similar papers on these topics and we screened the reference lists of published reports on ITP and cancer to identify additional cases. The authors independently evaluated the cases and checked the validity of the data. The criteria for the inclusion of cases for the analysis were as follows: (1) Definite diagnosis of a solid malignant cancer including histology and stage (metastatic or non-metastatic). (2) Data on the
temporal relationship between ITP and cancer. (3) Platelet count <100,000/l. (4) High probability that the thrombocytopenia was immune-mediated. An immune-mediated thrombocytopenia was assumed under the following conditions: No massive bone marrow infiltration by the cancer (small focal infiltrates were regarded as compatible with ITP), no chemotherapy within the last 4 weeks, normal or near-normal hemoglobin and leukocyte counts, normal or increased number of megakaryocytes in the bone marrow and no evidence of disseminated intravascular coagulation or drug dependent immune thrombocytopenia. The presence of platelet antibodies was regarded as compatible but not diagnostic for ITP since in almost all cases a relatively nonspecific antibody-test (platelet-IgG) has been used. 19 cases of cancer associated thrombocytopenia were excluded from the analysis, 3 because of possible alternative diagnoses and 16 because of lack of relevant data. Sustained complete remission (CR) was defined as CR of more than 6 months without steroids.
3. Results 3.1. Prevalence of ITP in various cancers We identified 68 cases of ITP associated with a solid cancer (Table 1). Cancer associated ITP has been described in almost all types of solid cancers [1–47]. The greatest number of cases of cancer-associated ITP was found in patients with the most common cancers (lung and breast cancer), but ITP
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was unusual in prostate cancer (the third common cancer). In relative terms cancer-associated ITP was more common than expected in renal and ovarian cancers. 3.2. Temporal relationship of ITP and cancer We divided paraneoplastic ITP in four categories according to the temporal relationship to the cancer. 3.2.1. ITP prior to cancer In 17 reported cases (median age 50 years, range 30–75) the ITP antedated the diagnosis of cancer. The cancers were 5 breast [1,16] 6 lung [3,6,8,10,11,15], 2 gastric [37,38], 2 colorectal [5,24], one ovarian [34] and one renal cell cancer [26]. In only three cases the cancer was metastatic at the time of detection. The median time from diagnosis of ITP to cancer diagnosis was 5 years (range 7 months to 40 years). The platelet count was 20,000/L or less in 9 out of 17 cases at diagnosis of ITP. The ITP was ongoing until detection of the cancer in 12 patients. In one case [5] the patient was in complete remission (CR) of ITP (after splenectomy) at the time of cancer diagnosis. In 4 cases there was no information on the status of ITP at cancer diagnosis [4,24,26,38]. In only one case the authors stated that ITP worsened at the time of cancer diagnosis [37]. Among 11 evaluable patients 6 had a response to steroids before cancer diagnosis whereas 5 patients were refractory to steroid therapy. Interestingly, one steroid refractory patient had a CR of ITP after interferon alpha [6]. Five patients were splenectomized before cancer diagnosis. Two had a transient, two had a sustained CR [5,24] and one had no response [6]. Eleven patients underwent elective cancer surgery with or without radiotherapy or adjuvant chemotherapy at the time of detection of cancer. One patient achieved a complete remission of ITP after removal of an ovarian tumor for more than 8 years [34]. Another patient [38] achieved a CR of ITP (sustained for more than 3 years) after simultaneous removal of a gastric cancer and the spleen. One patient had a PR of ITP after lung cancer surgery and radiotherapy for more than 20 months [7] and one [3] had a very short CR of ITP (3 weeks). Two breast cancer patients reported by the same author [16] achieved a CR of ITP after surgery and adjuvant chemotherapy. 3.2.2. ITP concurrent with cancer In 35 cases ITP was concurrent with the diagnosis of cancer (within 6 months before or after cancer diagnosis). There were 7 cases of lung cancer [3,8–13] among them one with small cell lung cancer [12], 6 cases of renal cell [27–32], 5 cases of breast cancer [1,17,18], 3 germcell cancers [5,43], 2 ovarian [2,35] 2 colorectal cancers [5,23], 1 skin [2], 1 oesophageal [45], 1 pancreatic [33], 1 prostate [23], 1 gallbladder cancer [5], 1 Kaposi sarcoma [42], 1 malignant melanoma [44], 1 rhabdomyosarcoma [46] and 1 thymic cancer [41]. 15 cancers were metastatic. The platelet count was ≤30,000/l in 22/35 cases and ≤10,000/l in 13 cases. Response to steroids was evaluable in 26
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patients. 16 patients had some response to steroids. Only five patients achieved a CR which was sustained for some time after withdrawal of steroids [10,11,17,18,33]. Ten patients were steroid-refractory [3,12,13,30,32,41,43,44,46]. Twelve patients underwent cancer surgery. Six patients, all with renal cell cancer, [27–32] achieved at least a short term CR of ITP after resection of the tumor. Of the three patients with tumor resection alone one patient with Evans syndrome [32] had a CR of AIHA and ITP for 210+ days, the other two had an only transient or unknown duration of CR [28,31] Two patients were splenectomized simultaneously. One of these patients [27] had a documented sustained CR of ITP (20 weeks), the other was not followed up [30]. One patient with lung cancer had a very short CR after surgery [3] and another a CR of an Evans syndrome for 11 months [11] after lobectomy and splenectomy. One patient with metastatic breast cancer had a CR of ITP and partial response (PR) of cancer for 7 months after chemotherapy [17]. 3.2.3. ITP at recurrence of cancer or a second/third cancer In 9 patients ITP occurred only at the time of recurrence of cancer [2,19,20,25,36,47] or at the time of a second or third cancer [8,23]. The primary cancers were 2 breast, 2 ovarian, 1 urinary bladder, 1 head and neck, 1 laryngeal, 1 cervix cancer and 1 Kaposi syndrome. The time from primary tumor to recurrence ranged from 6 months to 26 years. The platelet count was ≤30,000 in 6 cases. In four cases ITP was associated with a solitary localized cancer recurrence, in three cases [19,36] in a normal-sized or enlarged spleen (diffuse and nodular cancer infiltration) and one in a skin nodule in the scar after surgery for left sided breast cancer [20]. All four patients achieved a CR of ITP after local treatment (in three cases splenectomy, in one case local radiotherapy). The other patients (n = 3) had a recurrence of cancer at the primary tumor site. ITP responded in all these cases to steroid treatment. 3.2.4. ITP after chemotherapy and/or radiotherapy of the cancer In seven patients (2 uterine/cervix, 2 breast, 2 lung and 1 pancreatic cancer) ITP occurred after intensive radioor chemotherapy [2,8,14,21,22,40]. Thrombocytopenia was severe (≤20,000/l) in all cases in the absence of severe anemia und neutropenia and documented normal or increased numbers of megakaryocytes in the bone marrow. Of particular interest in this group of patients is the case of a patient with lobular breast cancer [22] who underwent autologous stem cell transplantation (conditioning with thiotepa and carboplatin) and developed after full engraftment at day 8 an isolated severe thrombocytopenia with normal hemoglobin and leukocyte values and increased megakaryocytes in the bone marrow. The patient responded to steroids and finally achieved a complete remission of ITP. Another patient with small cell lung cancer [14] developed severe thrombocy-
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topenia one to two months after intensive chemotherapy with cyclophosphamide and paclitaxel before planned stem cell harvest. After full hematologic recovery he developed after one month a severe isolated thrombocytopenia with normocellular bone marrow and increased megakaryocytes. Despite thrombocytopenia autologous stem cell transplantation was performed and the platelet count started to recover spontaneously on day 14 post-transplantation. The remaining patients developed severe isolated thrombocytopenia ten days to two months after the last cycle of intensive but not myeloablative chemo- or radiotherapy. Thrombocytopenia was severe in all cases with otherwise normal blood counts. All patients responded to treatment with steroids. 3.3. Other antibodies in patients with cancer associated ITP The most common additional antibodies in cancer associated ITP are red cell antibodies (Evans syndrome) [11,32,34,37,38,41,42]. A lupus anticoagulant was associated in three cases [9,15,19] and an acetylcholine receptor antibody in one case [38].
4. Discussion Immune-mediated hematological paraneoplastic syndromes (PNS) include autoimmune hemolytic anemia [49], anti-FVIII antibodies [50], antiphospholipid antibodies [51], autoimmune thrombocytopenia and others. The occurrence of these PNS is well known in lymphomas [52] but is also not uncommon in solid tumors but has received less attention. In this paper we show that autoimmune thrombocytopenia is not an uncommon complication in solid tumors. According to the recent proposal for the standardization of terminology of immune thrombocytopenias this of type ITP should be classified as “secondary ITP (paraneoplastic)” [53]. As in other PNS ITP may occur in a variety of solid tumors including common and rare malignancies. The two most common cancers associated with ITP were breast and lung cancers (not unexpected since they are the most common cancers). On the other hand there was only one case of ITPassociated prostate cancer although this cancer has almost the same prevalence as lung and breast cancer (Table 1). Thus, there is no correlation between the frequencies of cancers and ITP (at least on the basis of reported cases). This is a phenomenon which has also been observed in other PNS. The most common solid cancers in patients with paraneoplastic autoimmune hemolytic anemia (AIHA) were lung cancer, renal cell cancer and Kaposi’s syndrome [49]. In patients with acquired factor-VIII inhibitors the most common cancers are prostate, lung and colon cancers [50] and in patients with lupus anticoagulant renal cell carcinoma, lung cancer and malignant melanoma [51]. The same lack of correlation is also seen in lymphomas. PNS are almost absent in mantle cell lymphoma, but very common in the very rare splenic marginal
zone lymphoma [52]. The reasons for the differences in these PNS associations are unknown. One interesting phenomenon in patients with paraneoplastic ITP is the observation of a relatively high prevalence of double cancers (7 patients out of 68). Autoimmune paraneoplastic diseases in general may occur prior to the diagnosis of cancer, concurrent with cancer or after treatment of cancer either as a sign of recurrence or in CR of cancer. In our analysis of cancer-associated ITP we found a considerable number of cases in which ITP preceded the diagnosis of cancer, often for many years. In such cases it is uncertain whether this is a coincidence or whether there is a causal relationship between the two conditions. Prospective studies on the risk of solid tumors in patients with ITP have not been performed so far. However, from population- based studies it is known that patients with ITP have an increased incidence of Hodgkin’s lymphoma [54]. There are other examples of PNS in which an antibody or an immune disease definitely precedes a malignant disease. Patients with AIHA have an increased incidence of diffuse large cell lymphoma [55] and onconeural antibodies may be detectable often several years before diagnosis of a malignancy [56–58]. Thus, a causal relationship between preceding ITP and solid tumors cannot be excluded. In favor of a specific association is the fact that most ITPs were ongoing until the time of detection of the cancer. On the other hand there was only one instance in which the appearance of the cancer had an adverse effect on thrombocytopenia. Patients with ITP preceding cancer seem to have the same response to steroids and splenectomy as primary ITP. Interestingly, in one patient with ITP preceding cancer radical cancer surgery led to long lasting remission of ITP (and cancer). It has been speculated that paraneoplastic antibodies may have a favorable influence on tumor progression. This assumption is based mainly on observations in onconeural antibodies [59]. Our data cannot support this assumption, but it should be noted that 14 out of 17 patients with cancer after preceding ITP were non-metastatic. In the vast majority of cases, ITP occurred concurrent with the diagnosis of the tumor (no documented thrombocytopenia or bleeding tendency before detection of the tumor). A substantial number of these patients responded to standard treatment of primary ITP e.g. steroids and splenectomy. Of greatest practical and theoretical interest is the question, whether the removal of the tumor or chemotherapy led to documented sustained steroid-free remissions of ITP. Eleven patients with concurrent ITP who underwent surgery with curative intent had some response of ITP (Table 2). There were some patients with short-lived CR which were probably due to postoperative acute phase reaction. However, we could identify only one single patient (a non-metastatic renal cell cancer with Evans syndrome) who achieved a sustained complete remission of ITP (and AIHA) after cancer surgery alone [32]. Two patients had sustained remissions after tumor resection with simultaneous splenectomy [27,38]. The remission in these cases may rather be due to the known efficacy of
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Table 2 Responses of paraneoplastic ITP to various cancer treatments (only cases with some response). Reference
Cancer site
Stage
Temporal relationship
Primary cancer treatment
Additional treatments for ITP
Response of ITP (platelet count × 1000/l before/after therapy
Duration of ITP response
[16] [19] (case 1) [19] (case 2) [11] [3] [7] [28] [32] [27] [30] [31] [34] [38] [20] [17] [36]
Breast Breast Breast Lung Lung Lung RCC RCC RCC RCC RCC Ovary Gastric Breast Breast Ovary
nm m m nm m nm m nm nm nm m nm nm m m m
Prior Recurrence Recurrence Prior Prior Prior conc. conc. conc. conc. conc. Prior Prior Recurrence conc. Recurrence
Surgery CT (FEC) Splenectomy Splenectomy Surgery Surgery Surgery RT Surgery Surgery Surgery Surgery Surgery Surgery Surgery RT Tamoxifen CT SE
None None None SE None None Steroids None SE SE None None SE None None None
CR (20/100) CR (26/500) CR (8/167) CR (5/293) CR (10/119) PR (25/50) CR (18/131) CR (10/“normal”) CR CR (1/500) CR CR (80/“normal”) CR (1/244) CR (26/170) CR (2/”normal”) CR (50/120)
Unknown Unknown Unknown 2 months 3 weeks 20+ months Unknown 210+ days 20+ weeks Unknown 2 weeks 8+ years 3+ years 2.5 years 7+ months 8+ months
SE, splenectomy; RT, radiotherapy; CT, chemotherapy; RCC, renal cell cancer; m, metastatic; nm, non-metastatic; conc., concurrent.
splenectomy than to the removal of the tumor. There is only one patient with metastatic breast cancer who had a remission of ITP (seven months) after chemotherapy alone. Thus, there is only little evidence that the control of the underlying malignancy has any long term beneficial effect on paraneoplastic ITP in most cases. We found only one case in which chemotherapy had some effect on ITP [17]. This is certainly due to the fact that there are no highly effective curative chemotherapies available for these cancers. A special case is a patient with amegakaryocytic ITP (presumably immunological) in a small cell lung cancer in whom a CR was achieved with chemotherapy [60]. Of particular interest are the seven patients who had ITP only at the time of recurrence of the primary cancer. This indicates that the biology of the cancer may have changed, although the histology of the primary and the recurrent cancer were not different. Most exciting is the high efficacy of the removal of distant metastases in the spleen by splenectomy without systemic treatment in three patients [19,36]. The remission of ITP may have been due to reduction of antibody production by the spleen. It might also be possible that the diffuse metastasis in the spleen increased the platelet trapping activity of the spleen. This might be a similar mechanism as in hairy cell leukemia, where the infiltration of the spleen with hairy cells increases the splenic platelet trapping and splenectomy is highly effective for treatment of cytopenia. The patient with local recurrence and ITP [20] and complete remission of ITP after local irradiation is a second (even more impressive) example that paraneoplastic ITP could be completely controlled by local treatment of the tumor. Severe isolated immune thrombocytopenia after myeloablative chemotherapy is a well known phenomenon in patients after autologous stem cell transplantation for lymphomas [61–63]. It occurs after full recovery of the bone marrow and responds to steroid treatment. The two cases of ITP
after myeloablative chemotherapy in solid cancer may belong to this category of immune thrombocytopenias. The development of severe thrombocytopenia late after intensive but non-myeloablative chemotherapy is a peculiar phenomenon which has been observed only after chemotherapy in Hodgkin lymphomas [64]. It is uncertain whether there is really a pathogenetic association with chemo/radiotherapy. Virus infections could also be a cause for these thrombocytopenias but have not been studied extensively in these patients.
5. Limitations of this analysis Our analysis of case reports has important limitations. All numerical data should be regarded with caution because of possible reporting bias. Whereas the diagnosis and the stage of disease (metastatic/non-metastatic) was well established in most analyzed cases the diagnosis of ITP was highly probable but not definitive because for diagnosis of ITP no laboratory test with a very high positive predictive power is available. We took great care to exclude patients with other causes of thrombocytopenia but we could not exclude viral infections as a possible cause of thrombocytopenia in these often immune-compromised patients. The most useful finding was an increased number of megakaryocytes in the bone marrow, while the platelet antibody tests which measured in almost all cases only the IgG concentration on platelets is known to be neither sensitive nor specific for ITP. However, we believe that the diagnosis was valid in the vast majority of cases. Another problem was the lack of short and long term follow up in many patients which made it difficult to determine the duration of remissions. Although we believe that most of the ITP were causally related to the cancer we are aware of the fact, that association does not mean causality. The lack of response of ITP after curative surgery in most of the cancers is disappointing. On the other hand, the convincing effects
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of surgery and chemotherapy in some cases suggest a causal relationship. It may be that the pathogenesis is not the same in all cases of cancer associated ITP. We believe that in patients with cancer associated ITP cancer resection should be done in non-metastatic cases (after appropriate pretreatment). In metastatic cases steroids are probably the best choice. In practical terms we believe that in patients with ITP a cancer-associated ITP has always to be considered, but an extensive search for a present or future cancer is not indicated unless there is laboratory or clinical suspicion of a malignant disease. There are many unanswered questions in PNS. We believe that careful laboratory studies in patients with PNS may provide interesting insights into the biology of malignant tumors in particular the interaction of the tumor with the immune system and may provide some clues to immune therapy of solid cancers.
Reviewer Hans-Joachim Schmoll, M.D., Ph.D., Martin-LutherUniversitat Halle-Wittenberg, Innere Med. IV, Ernst-GrubeStrasse 40, D-06120 Halle, Germany.
Conflict of interest The authors declare no conflict of interest.
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Biographies Maria-Theresa Krauth graduated from the medical University of Vienna in 2002. She is currently assistant professor at the Division of Hematology and Hemostaseology. Joe Puthenparambil graduated from the medical University of Vienna in 2010. Klaus Lechner graduated from the University of Vienna in 1960. He is former head of the Division of Hematology and Hemostaseology.