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Immune thrombocytopenia in patient with clear cell renal

carcinoma: case report and literature review

Journal: Platelets

URL: http://mc.manuscriptcentral.com/cpla E-mail: P.Harrison.1@bham.ac.uk

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Manuscript ID Draft
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5 Manuscript Type: Case Report
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7 Date Submitted by the
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Author:
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9 Complete List of Authors: Martínez-Cordero, Humberto; Instituto Nacional de Cancerologia,
10 Hematology and Bone Marrow Transplantation
11 Salgado-Reyes, Paula; Universidad El Bosque
12 Alcala-Lara, Sebastian ; Instituto Nacional de Cancerologia, Hematology
13 and Bone Marrow Transplantation
Linares-Patiño, Maximo; Instituto Nacional de Cancerologia, Hematology
14 and Bone Marrow Transplantation
15 Mejia , Angie; Instituto Nacional de Cancerologia, Hematology and Bone
16 Marrow Transplantation
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17 Ramos , Robert; Instituto Nacional de Cancerologia, Hematology and
18 Bone Marrow Transplantation
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Keywords: clear cell metastatic renal cell carcinoma, autoimmune thrombocytopenia
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Immune thrombocytopenia in patient with clear
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cell renal carcinoma: case report and literature
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review
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14 Abstract
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Paraneoplastic secondary immune thrombocytopenia is a rare disorder, however,
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22 side effects of therapy. There are few reported cases of immune thrombocytopenia
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24 associated with clear cell renal carcinoma and it is described that they may have a
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good response to glucocorticoids and immunoglobulin. We present here the case of
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27 a 70-year-old patient with a diagnosis of clear cell renal carcinoma with associated
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29 severe thrombocytopenia that was initially diagnosed as disseminated intravascular
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31 coagulation lasting several months without recovering the platelet count and
32 therefore the patient could not initiate anticancer therapy timely. Subsequently, the
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34 diagnosis was redefined to secondary immune thrombocytopenia after a detailed
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36 analysis of the blood count and to achieve a good response with the use of oral
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prednisone. The objective of this report is to describe the association of some solid
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39 neoplasms with immune thrombocytopenia, the potential benefit of systemic
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41 glucocorticoid therapy, which may allow timely directed therapy for these patients.
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46 Introduction:
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Clear cell renal carcinoma corresponds to 80-85% of all primary renal neoplasms,
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50 with an incidence, mortality and prevalence of 5.3, 2.3 and 13.4 per 100,000
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52 inhabitants respectively (1, 2). The incidence varies by region, as being with the
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54 Czech Republic and North America being the areas with the highest incidence and
55 prevalence with around 30.5 and 18.5 per 100,000 inhabitants, while in Colombia
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60 URL: http://mc.manuscriptcentral.com/cpla E-mail: P.Harrison.1@bham.ac.uk
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3 there is a figure of 3.6 per 100,000 inhabitants. It happens more in males than in
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5 female population, with a ratio of 3:1 (3) and occurs mostly in people in the sixth and
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7 eighth decade of life (1, 2). The five-year survival rate has doubled in recent
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decades. This tendency is due to early detection when the primary tumor is in the
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10 early stages (<4 cm) (1, 2).
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The recommended first-line treatment in the advanced stages is tyrosine kinase
14 inhibitors (Sunitinib and Pazopanib) until disease progression or increased toxicity
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16 (4, 5). The use of these medications requires a platelet count between 75,000 -
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18 50,000 cells per microliter and the management should be postponed until the
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recovery of this cell line due to an increased risk of bleeding, however, it is to be
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21 recognized that clear cell renal carcinoma could be associated with paraneoplastic
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23 phenomena including immune thrombocytopenia which correspond to the
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25 production of antibodies that cause platelet destruction (6,7).
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27 We present here a case of a patient with clear cell renal carcinoma that was initially
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29 approached as disseminated intravascular coagulation, however, given the
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characteristics of the blood count, peripheral blood spread and the good response
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32 to the use of systemic corticosteroids, it was determined that he was actually
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34 suffering from paraneoplastic secondary immune thrombocytopenia.
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36 The objective of this case report is to show the association of solid cancers, such as
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38 a clear cell renal carcinoma, with immune thrombocytopenia and the benefit of the
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40 use of systemic steroids that allow the timely initiation of targeted therapy that leads
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to an improvement in the survival.
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46 Case presentation
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48 A 70-year-old man, a native of San Gil - Santander Colombia and living in Bogotá,
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50 who was treated for the first time in the oncology department of the National Cancer
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Institute of Colombia on May 2015 with a diagnosis of advanced clear cell renal
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53 carcinoma T4NXM1 (lung and testicular metastasis) not a candidate for surgery but
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55 a tyrosine kinase inhibitor requirement for disease control. Thrombocytopenia was
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3 found since admission, so the concept of hematology was requested to start
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5 sunitinib. At assessment, mild microcytic and hypochromic anemia and severe
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7 thrombocytopenia were found. A complete bone marrow study was requested, which
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was normal. A low level of vitamin B 12 and ferritin was documented, so it was
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10 replaced waiting for recovery of the platelet count. The response was null requiring
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12 continuous platelet transfusion without allowing the onset of tyrosine kinase inhibitor.
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14 An initial diagnosis of disseminated intravascular coagulation associated with solid
15 neoplasia was made. It was considered that it required treatment of the primary
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17 neoplasm for the improvement of platelet count, however it was considered that
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19 there were some characteristics that suggested associated autoimmune component
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such as normality in other cell lines, large platelet size and absence of bleeding with
22 very low counts. It was then decided to start prednisone at 0.5 mg per kilogram,
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24 achieving a recovery in platelet count at more than 100,000 cells per microliter, which
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26 allowed starting treatment with pazopanib on March 2017. During the course of
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treatment, thrombosis of the inferior vena cava was documented that required full
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29 anticoagulation. The following graph describes the complete trend of platelet count
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31 evolution.
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43 Subsequently, in September 2018, he consulted the emergency department for
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abdominal pain and emetic syndrome. Acute renal failure was documented on the
46 status of chronic kidney disease with emergency dialysis criteria, however, it was
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48 considered that the clinical status with respect to metastatic pathology did not
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50 benefit from renal replacement therapy and also differs from resuscitation
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maneuvers, a wish also accepted by family members. Finally, in October 2018, he
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53 dies because of his underlying illness.
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3 Discussion
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6 Immune thrombocytopenia secondary to renal carcinoma is a rare entity. Its
7 incidence and prevalence are 1 to 5 cases and 8 cases per 100,000 inhabitants
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9 respectively, both increase with age and sex (higher in men) (6, 7). Patients
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11 presenting with this paraneoplastic syndrome may debut with an asymptomatic
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condition (in most cases) or the presence of bleeding, petechiae, purpura, epistaxis
14 and / or fatigue.
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17 Normally, immune thrombocytopenia is a diagnosis of exclusion in which there
18 should be a platelet count of less than 100,000 / uL without being related to anemia
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20 or leukopenia (8), and other causes should be ruled out, so other diagnostic tests
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22 may be requested that help the exclusion of other entities, which usually include the
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24 complete study of bone marrow in certain cases (9, 10).

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26 If immune thrombocytopenia is secondary to a solid tumor, the first step is to treat
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28 the neoplasm in order to correct the defect (4, 6, 10, 11), however, in cases such as
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the one proposed in this review, where surgical treatment was not possible, the
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31 proposed first-line therapy is the use of glucocorticoids and / or intravenous
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33 immunoglobulin (6).
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35 The use of intravenous immunoglobulin generally presents a faster response,
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37 however, the use of this therapy is only indicated in patients with active bleeding or
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39 who require an invasive emergency intervention (6, 10). A comparative study was
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developed on the use of glucocorticoids versus the use of intravenous
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42 immunoglobulin where both treatments were shown to have a similar response

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44 when supplemented with oral prednisone for three weeks, however, it should be
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46 noted that the use of oral prednisone or dexamethasone in high doses for one or
47 two weeks with a subsequent gradual decrease shows the same efficacy as the
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49 therapy mentioned above (6).
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In addition to the above, the use of splenectomy, rituximab or immunosuppressive
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53 therapy has also been proposed as a second line of treatment, taking into account
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55 that these treatments should only be considered in case the first line does not
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 Platelets Page 6 of 8

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3 demonstrate an adequate response and platelet count persists below 20,000 / uL
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5 (10).
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7 Conclusions:
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10 It is very important, not only in the case of renal carcinoma, but in general in all
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malignant pathologies, to make an early diagnosis to offer a curative therapy. In
13 addition, it is important to consider all the paraneoplastic phenomena or syndromes
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15 that may occur during the course of the disease to reduce complications and offer
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19 In the specific case of immune thrombocytopenia secondary to clear cell renal
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21 carcinoma, rapid onset of glucocorticoids gives an important benefit and, as
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demonstrated in the proposed case, a complete resolution of thrombocytopenia
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26 requirements and / or due to complications associated with the presentation of
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28 decreased platelet values, in addition to being able to provide the recommended
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therapy according to oncological guidelines.
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32 Thanks:
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34 We appreciate the collaboration with the Pathology Department of the National
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36 Cancer Institute for their great work in the study of patients and the contribution
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Note of reservation:
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45 The National Cancer Institute is not responsible for the concepts issued by
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researchers in their work, it will only ensure scientific rigor. The same
48 methodological and ethical for the search of truth and justice.
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Page 7 of 8 Platelets

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3 Bibliography:
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6 (1) Ariana Znaor, Joannie Lortet-Tieulentb, Mathieu Laversannea, Ahmedin
7 Jemalb, Freddie Bray. International Variations and Trends in Renal Cell Carcinoma
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9 Incidence and Mortality. European Urology 2015 March;67(3).
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(2) J. Ferlay, E. Steliarova-Fouchera, J. Lortet-Tieulenta, S. Rossob, J.W.W.
13 Coeberghc,d, H. Combere, D. Formana, F. Bray. Cancer incidence and mortality
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15 patterns in Europe: Estimates for 40 countries in 2012. European Journal of
16
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17 Cancer 2013 April;49(6).
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19 (3) World Health Organization. International Agency for Research on Cancer.
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21 2018; Available at: https://gco.iarc.fr/today/online-analysis-
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table?v=2018&mode=population&mode_population=continents&population=900&p
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24 opulations=900&key=asr&sex=2&cancer=29&type=0&statistic=5&prevalence=0&p
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26 opulation_group=0&ages_group%5B%5D=0&ages_group%5B%5D=17&nb_items
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28 =5&group_cancer=0&include_nmsc=0&include_nmsc_other=0. Accessed 26/09/,
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2019.
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32 (4) Instituto Nacional del Cancer. Tratamiento del cáncer de células renales –
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Versión para profesionales de salud. 2019; Available at:
35 https://www.cancer.gov/espanol/tipos/rinon/pro/tratamiento-rinon-pdq. Accessed
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37 26/09/, 2019.
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39 (5) Cancer Insititute N. Renal cell metastatic sunitinib. 2019; Available at:
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41 https://www.eviq.org.au/medical-oncology/urogenital/renal/322-renal-cell-
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43 metastatic-sunitinib#. Accessed 26/09/, 2019.
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45 (6) Anam Rehan, Aakash Desai, Corina Iorgoveanu, and Jim C Lee. Secondary
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47 Immune Thrombocytopenic Purpura in Renal Cell Cancer: A Paraneoplastic
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49 Syndrome. Cureus 11(4): e4398 2019 Apr 5.
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51 (7) Shigekatsu Maekawa, Masayoshi Nagata, Hiroshi Watanabe, Keina Nozaki,
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53 Atsuko Takahashi, Shigeru Minowada, Yukio Homma. Complete Response of
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severe idiopathic thrombocytopenic purpura after resection of bulky chromophobe
56 renal cell carcinoma. 2016 January 18.
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3 (8) Kevin R. Melnick, Courtney Chang, Ana Antun, Shishir K. Maithel, and Viraj A.
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5 Master Show More. Paraneoplastic Thrombocytopenia Cured With Nephrectomy
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7 and Vena Cava Thrombectomy: Concurrent Hematology and Oncology
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Management Conundrums. Emory University School of Medicine, Atlanta, GA
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10 2017 August 15,;13(11).
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(9) Cindy Neunert, Wendy Lim, Mark Crowther, Alan Cohen, Lawrence Solberg Jr,
14 and Mark A. Crowther. The American Society of Hematology 2011 evidence-based
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16 practice guideline for immune thrombocytopenia. Blood Journal 2011 21
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18 APRIL;117(16).
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20 (10) American Society of Hematology. ASH Pocket Guides. 2011; Available at:
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22 https://www.hematology.org/Clinicians/Guidelines-Quality/Quick-Reference.aspx.
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24 Accessed 26/09/, 2019.

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26 (11) Eun Ju Cho, Ha Jung Lee, Kyung Un Park, Uk-Yeon Kim, Hak Jong Lee, and
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28 Soo Mee Bang. Immune thrombocytopenic purpura in a patient with renal cell
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carcinoma. 2014 Aug 28.
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32 (12) American Society of Hematology. Don’t treat patients with immune
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thrombocytopenic purpura (ITP) in the absence of bleeding or a very low platelet
35 count. 2014; Available at: http://www.choosingwisely.org/clinician-lists/american-
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