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CASE REPORT
Year : 2022  |  Volume : 25  |  Issue : 2  |  Page : 211-214

Signet ring cell carcinoma metastasis in the bone marrow accompanied by cancer related thrombotic microangiopathy as a first presentation


1 Department of Hematology, Bursa City Hospital, Bursa, Turkey
2 Department of Pathology, Bursa City Hospital, Bursa, Turkey

Date of Submission11-Oct-2020
Date of Acceptance17-Jun-2021
Date of Web Publication16-Feb-2022

Correspondence Address:
Dr. M Baysal
Department of Hematology, Bursa City Hospital, Bursa
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_622_20

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   Abstract 


Cancer related thrombotic microangiopathies usually cause a diagnostic dilemma for hematologists and clinicians. In this case report, we presented a fifty-nine-year-old man who was admitted to our hospital with microangiopathic hemolytic anemia and thrombocytopenia due to the carcinoma metastasis to the bone marrow. As a result of rapid evaluations, it was revealed that the histological subtype of the cancer was signet ring cell carcinoma, and despite all the interventions, the patient died at a very short time after the initial presentation. Regardless of all the innovations in the diagnosis and treatment of thrombotic microangiopathies, cancer-associated thrombotic microangiopathy is still fatal and deadly today.

Keywords: Cancer related TMA, PLASMIC score, signet ring cell, thrombotic microangiopathy


How to cite this article:
Baysal M, Alkış N, Tosun S. Signet ring cell carcinoma metastasis in the bone marrow accompanied by cancer related thrombotic microangiopathy as a first presentation. Niger J Clin Pract 2022;25:211-4

How to cite this URL:
Baysal M, Alkış N, Tosun S. Signet ring cell carcinoma metastasis in the bone marrow accompanied by cancer related thrombotic microangiopathy as a first presentation. Niger J Clin Pract [serial online] 2022 [cited 2022 Dec 2];25:211-4. Available from: https://www.njcponline.com/text.asp?2022/25/2/211/337767




   Introduction Top


Thrombotic microangiopathies (TMA) consist of Thrombotic Thrombocytopenic Purpura (TTP) and other disorders associated with microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. Disorders other than TTP are Hemolytic Uremic Syndrome, Complemant Mediated Thrombotic Microangiopathy, Drug-induced Thrombotic Microangiopathy, Hereditary TTP, Malignancy associated TMA, Pregnancy-associated syndromes, organ transplantation-associated TTP, Rheumatologic disease and infection associated TMAs.[1],[2],[3] TTP pathogenesis is described as deficiency of ADAMTS13 (A Disintegrin and Metalloprotease with a Thrombospondin type 1 motif, member 13) which cleaves ultra large von Willebrand factor (VWF) molecules therefore, these molecules could not be cleaved and constitute the clinical picture of TTP.[4] ADAMTS13 activity level <10% is associated with TTP.[5] TMAs other than TTP have a more complex and different pathogenesis and endothelial dysfunction, platelet activation probably are the main underlying alterations.[1],[3] Malignancy associated TMAs are rarely reported in the literature and these cases do not respond to plasma exchange therapy which was used in TTP and have a poor prognosis.[6],[7] Besides malignancy associated TMAs Drug-induced thrombotic microangiopathy (DITMA) has entered into the literature in the last twenty years.[8] In this case report, we present a metastatic signet ring cell carcinoma in the bone marrow accompanied by TMA.


   Case Report Top


A Fifty-nine-year-old man with no history of chronic disease presented to our hospital with fatigue and shortness of breath. The patient denied any medication or illicit drug use, he is an ex-smoker who quit smoking 20 years before smoking 20 packet years. Upon his physical examination, the patient is alert and oriented. He had a sub febrile fever with a temperature of 37.6°C. His blood pressure was 120/80 mmHg. His peripheral pulses were palpable. In his general examination conjunctivae were found subicteric, He had a respiratory rate of 18 breaths/min, with vesicular breath sounds, other system examinations were found to be normal and no lymphadenopathy or organomegaly were observed. His laboratory workup revealed anemia with thrombocytopenia; his Hemoglobin level was 7.6 g/dl and platelet count was 24 × 109/L. Leucocyte count and differentials were normal. His LDH (lactate dehydrogenase) level was elevated with 2256 IU/L and indirect bilirubin level was found elevated with 3.3 mg/dl. Besides these findings corrected reticulocyte count was found 4.21%. The Creatinine level was found to be 1.1 mg/dl, INR was 1.6, and Mean Corpuscular Volume (MCV) was 92 FL. In his other baseline laboratory tests such as blood glucose level, erythrocyte sedimentation rate, electrolyte levels, B12 vitamin, and serum folate levels were normal. Direct and indirect Coombs' tests were negative. C-reactive protein level was slightly elevated and broad-spectrum antibiotics were started after obtaining the necessary cultures. In peripheral blood smear examination, numerous schistocytes, fragmented erythrocytes, and nucleated erythrocytes were observed [Figure 1]. Based on these findings our patient was diagnosed with thrombocytopenia and microangiopathic hemolytic anemia. Hemolytic uremic syndrome was not considered due to the absence of an increase in creatinine and accompanying diarrhea. Thoracic and Abdomen CT scans performed because of malignancy can always be included in this type of picture among the differential diagnoses. On imaging results, a diffuse increase in wall thickness was noticed in the stomach. From tumor markers CA 19-9 level was found to be highly elevated with 31697 IU/ml (normal range 0-39) also Carcinoembryonic antigen (CEA) level was quietly elevated with 410 IU/ml. PLASMIC score was evaluated and it was found to be low risk with three points. Plasmapheresis treatment was not initiated considering that the patient would not benefit from plasmapheresis because of the low risk found in the PLASMIC score. With this result, ADAMTS13 deficiency and Thrombotic thrombocytopenic purpura (TTP) were not considered. However, we have sampled for ADAMTS13 activity level and found it to be normal at 56.8%. A Bone marrow biopsy was performed for differential diagnosis. Bone marrow trephine biopsy revealed signet ring cell carcinoma infiltration [Figure 2] and [Figure 3]. Patient diagnosed with signet ring cell carcinoma metastasis in the bone marrow. Despite the supportive treatments, the patient progressed rapidly and died in a very short time.
Figure 1: Numerous schistocytes and one nucleated red cell on peripheral blood smear

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Figure 2: Signet Ring Cell Infiltration in the Bone Marrow; (Hematoxylin Eosin Stain 40× magnification)

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Figure 3: Pancytokeratin stain on bone marrow biopsy

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   Discussion Top


Microangiopathic hemolytic anemia and thrombocytopenia can be seen in patients with cancer and it was first reported years ago.[9] Thrombotic microangiopathies in systemic malignancies could be due to the disease itself or could be due to the treatment agents; the latter one is called Drug-induced thrombotic microangiopathy; Immune mechanisms and dose-related toxicities come out in the pathogenesis of DITMA.[9],[10] However, the exact mechanism in DITMA is still unidentified clearly. Chemotherapeutic agents, monoclonal antibodies, immune checkpoint inhibitors, vascular endothelial growth factor inhibitors, and several other drugs are reported as a cause of DITMA.[11],[12],[13] TMA can rarely be seen as the first sign or manifestation of systemic malignancy.[14],[15],[16],[17] Patients on rare occasions present with an onset of malignancy. The pathogenesis of patients who initially presented with TMA due to cancer is unclear. However, in the majority of cases bone marrow infiltration with cancer wells was found.[7] Another explanation may be cancer related paraneoplastic syndrome. Gastric, breast, and prostate cancer are the three most common types of cancers associated with TMA.[7] The most frequently accused cancer histology is adenocarcinomas, especially mucinous types.[7] Mucin producing signet ring cell carcinomas can present with TMA as an initial presentation. In a recent case report TMA due to mucin producing signet ring cell carcinoma was found as an initial presentation of cancer.[18]

Treatment options for such patients are limited; the benefit from plasmapheresis as seen in the treatment of TTP is not seen.[3] One possible explanation for this argument is that plasmapheresis may cause microcirculatory damage and this may enhance microthrombi formation.[19] The best option amongst treatment agents for cancer associated TMA patients is systemic chemotherapy. Therefore systemic chemotherapeutic agents should be started as soon as possible. However, as in our case; some patients may progress rapidly before starting treatment. Cancer related TMA demonstrating as an initial presentation can rarely be encountered. However, cancer related TMA should be in clinicians' minds in patients who cannot fulfill the diagnostic criteria of TTP or who do not respond to plasma treatment after being diagnosed with TTP.[20] As an example of this, we can give the Oklahoma TTP registry, in which 10 out of 301 patients treated as TTP had been found to be systemic malignancies as a final diagnosis.[21] In a systemic review that included disseminated malignancies misdiagnosed as TTP, the authors report that disseminated malignancy patients had higher LDH levels, more respiratory symptoms, and more failure to plasma exchange treatment compared to TTP patients.[20]

Another issue we want to underline with this case is the value of the PLASMIC score in daily practice and emergency plasmapheresis evaluation. PLASMIC score was developed to predict the severe ADAMTS13 deficiency in patients with suspected TTP.[22] Severe ADAMTS 13 deficiency which is specific for diagnosing TTP is defined as having an ADAMTS13 level below 10%.[5] PLASMIC score divides patients into three groups as high risk, intermediate risk, and low risk. It is suggested that in high risk patients Plasmapheresis should be started as soon as possible while waiting for ADAMTS13 activity levels which will take a turnaround time.[22] The PLASMIC score is a handy and useful tool for evaluating suspected TMA patients. If we go back to our patient from this assessment Plasmapheresis treatment was not initiated because the PLASMIC score was found to be at low risk. Although plasmapheresis treatment is life-saving, it can also cause fatal complications.[23] With the initial PLASMIC score evaluation, we think that these fatal complications may also decrease.

To conclude; bone marrow cancer metastasis or infiltration presenting with TMA displays a devastating and challenging clinical scenario to the physicians and clinicians. Cancer associated TMA has deadly and heavy consequences which cause a troublesome burden to the patients and caregivers. We have to be more alert and show increased awareness to this deadly enemy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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George JN, Raskob GE, Shah SR, Rizvi MA, Hamilton SA, Osborne S, et al. Drug-induced thrombocytopenia: A systematic review of published case reports. Ann Intern Med 1998;129:886-90.  Back to cited text no. 8
    
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Falsetti L, Sampaolesi M, Riccomi F, Nitti C. Adalimumab as a potential cause of drug-induced thrombocytopaenic microangiopathy. BMJ Case Rep 2020;13:e233526.  Back to cited text no. 13
    
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Kadikoylu G, Barutca S, Tataroglu C, Kafkas S, Erpek H, Meydan N, et al. Thrombotic thrombocytopenic purpura as the first manifestation of metastatic adenocarcinoma in a young woman. Transfus Apher Sci 2010;42:39-42.  Back to cited text no. 14
    
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Koroglu M, Erkurt MA, Berber I, Kuku I, Kaya E, Ozkahraman A, et al. Primarily unknown origin adenocarcinoma metastasis in bone marrow presenting with thrombotic thrombocytopenic purpura: A case report. Transfus Apher Sci 2013;49:341-4.  Back to cited text no. 16
    
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Dirweesh A, Siddiqui W, Khan M, Iyer P, Seelagy M. Adenocarcinoma of the lung presenting as thrombotic thrombocytopenic purpura. Respir Med Case Rep 2017;21:82-3.  Back to cited text no. 17
    
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Malkan UY, Albayrak M, Ozturk HB, Reis Aras M, Saglam B, Dogan K. A signet ring cell carcinoma presented as refractory acquired thrombotic thrombocytopenic purpura. Case Rep Oncol 2020;13:1368-72.  Back to cited text no. 18
    
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Vasko R, Koziolek M, Fuzesi L, Konig F, Strutz F, Muller GA. Fulminant plasmapheresis-refractory thrombotic microangiopathy associated with advanced gastric cancer. Ther Apher Dial 2010;14:222-5.  Back to cited text no. 19
    
20.
Francis KK, Kalyanam N, Terrell DR, Vesely SK, George JN. Disseminated malignancy misdiagnosed as thrombotic thrombocytopenic purpura: A report of 10 patients and a systematic review of published cases. Oncologist 2007;12:11-9.  Back to cited text no. 20
    
21.
George JN, Vesely SK, Terrell DR. The oklahoma Thrombotic thrombocytopenic purpura-Hemolytic uremic syndrome (TTP-HUS) registry: A community perspective of patients with clinically diagnosed TTP-HUS. Semin Hematol 2004;41:60-7.  Back to cited text no. 21
    
22.
Bendapudi PK, Hurwitz S, Fry A, Marques MB, Waldo SW, Li A, et al. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: A cohort study. Lancet Haematol 2017;4:e157-64.  Back to cited text no. 22
    
23.
Page EE, Kremer Hovinga JA, Terrell DR, Vesely SK, George JN. Thrombotic thrombocytopenic purpura: Diagnostic criteria, clinical features, and long-term outcomes from 1995 through 2015. Blood Adv 2017;1:590-600.  Back to cited text no. 23
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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