Objective: Rare disease Background: Antiphospholipid syndrome (APS) is a rare autoimmune disease characterized by arterial, venous, and small-vessel thrombosis, pregnancy-related morbidity and the presence of antiphospholipid antibodies such as an-ticardiolipin antibody, and/or anti-beta2-glycoprotein I. In the recent years, APS was observed in patients with solid tumors and the renal cancer, lung carcinoma and breast tumors were the most common tumors linked with APS. Case Report: A 53-year-old female presented with pain and pitting edema of left lower extremity that had begun 6 months prior to hospitalization. Deep vein thrombosis (DVT) in the popliteal vein diagnosed by Doppler ultrasonogra-phy and the patient was treated with heparin followed by warfarin. Following subdural hematoma, anticoagu-lant therapy was stopped, and the patient underwent craniotomy. One month later, the patient returned with pain and DVT diagnosed in its right leg. Laboratory tests showed high levels of lupus anticoagulant, IgM and IgG anticardiolipin antibodies. Following a high alkaline phosphatase, diffuse bone marrow involvement was found by whole body bone scan. Looking to find primary tumor, a large infilterable lesion in gastric was seen by endoscopic images, and biopsy histopathology showed a signet ring cell adenocarcinoma. The patient re-fused chemotherapy and died 6 months after diagnosis. Conclusions: APS is associated with gastric signet ring cell adenocarcinoma. Â© Am J Case Rep, 2020

Dadkhah, D.

Ehsani, M.

Shayestehpour, M.

Zamani, B.

English

kashan university of medical sciences

Received: 2019.07.27
Accepted: 2019.11.06
Published: 2020.01.18
 1432   —   2   9
A Case of Antiphospholipid Syndrome Following 
Gastric Signet Ring Cell Adenocarcinoma
 BEF 1,2 Mohammad Shayestehpour
 AC 1 Majid Ehsani
 B 1 Davood Dadkhah
 AC 1 Batool Zamani
 Corresponding Author: Batool Zamani, e-mail: batol_zamani2007@yahoo.com
 Conflict of interest: None declared
 Patient: Female, 53-year-old
 Final Diagnosis: —
 Symptoms: Antiphospholipid syndrome (APS)
 Medication: —
 Clinical Procedure: —
 Specialty: Oncology
 Objective: Rare disease
 Background: Antiphospholipid syndrome (APS) is a rare autoimmune disease characterized by arterial, venous, and small-
vessel thrombosis, pregnancy-related morbidity and the presence of antiphospholipid antibodies such as an-
ticardiolipin antibody, and/or anti-beta2-glycoprotein I. In the recent years, APS was observed in patients with 
solid tumors and the renal cancer, lung carcinoma and breast tumors were the most common tumors linked 
with APS.
 Case Report: A 53-year-old female presented with pain and pitting edema of left lower extremity that had begun 6 months 
prior to hospitalization. Deep vein thrombosis (DVT) in the popliteal vein diagnosed by Doppler ultrasonogra-
phy and the patient was treated with heparin followed by warfarin. Following subdural hematoma, anticoagu-
lant therapy was stopped, and the patient underwent craniotomy. One month later, the patient returned with 
pain and DVT diagnosed in its right leg. Laboratory tests showed high levels of lupus anticoagulant, IgM and 
IgG anticardiolipin antibodies. Following a high alkaline phosphatase, diffuse bone marrow involvement was 
found by whole body bone scan. Looking to find primary tumor, a large infilterable lesion in gastric was seen 
by endoscopic images, and biopsy histopathology showed a signet ring cell adenocarcinoma. The patient re-
fused chemotherapy and died 6 months after diagnosis.
 Conclusions: APS is associated with gastric signet ring cell adenocarcinoma.
 MeSH Keywords:	 Antibodies,	Anticardiolipin	•	Antiphospholipid	Syndrome	•	Stomach	Neoplasms
 Full-text PDF: https://www.amjcaserep.com/abstract/index/idArt/919037
Authors’ Contribution: 
Study Design A
 Data Collection B
 Statistical Analysis C
Data Interpretation D
 Manuscript Preparation E
 Literature Search F
Funds Collection G
1 Autoimmune Diseases Research Center, Kashan University of Medical Sciences, 
Kashan, I.R. Iran
2 Department of Microbiology and Immunology, Faculty of Medicine, Kashan 
University of Medical Sciences, Kashan, I.R. Iran
e-ISSN 1941-5923
© Am J Case Rep, 2020; 21: e919037 
DOI: 10.12659/AJCR.919037
e919037-1 Indexed in: [PMC] [PubMed] [Emerging Sources Citation Index (ESCI)][Web of Science by Clarivate]
This work is licensed under Creative Common Attribution-
NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Background
Antiphospholipid syndrome (APS) is a rare autoimmune disease 
characterized by arterial, venous, and small-vessel thrombosis, 
pregnancy-related morbidity and the presence of antiphospho-
lipid antibodies such as anticardiolipin antibody, lupus antico-
agulant, and/or anti-beta2-glycoprotein I [1]. There are several 
reports on the association between APS and malignancies [2]. 
The presence of APS in patients with solid tumor is linked with 
thrombotic complications. The review of cases with APS and tu-
mor revealed that the renal cancer, lung carcinoma and breast 
tumors were the most common tumors linked with APS. Only 
1 case of stomach cancer with APS was found in the litera-
ture [3]. Here, we report a case of APS following gastric signet 
ring cell adenocarcinoma.
Case Report
A 53-year-old female was referred to our hospital with pain 
and pitting edema of left lower extremity that had begun 6 
months prior to hospitalization. Deep vein thrombosis (DVT) 
in the popliteal vein diagnosed by color Doppler ultrasonog-
raphy. The patient treated with 1100 U/hour heparin and dis-
charged from the hospital on warfarin 5 mg daily with interna-
tional normalized ratio (INR) 2.2 after pain relief. The patient 
returned 1 month later, and a cerebral computed tomography 
(CT) scan revealed a subdural hematoma in hemisphere. This 
hematoma caused mass effect to lateral ventricle and subfal-
cine herniation. Following subdural hematoma, anticoagulant 
therapy was stopped, and the patient underwent craniotomy. 
One month after the craniotomy, the patient returned with 
pain and swelling of right leg. She had anorexia and weight 
loss of 4 kg over the last 4 months. On examination, body 
temperature, blood pressure, pulse rate, and respiratory rate 
were 36.5°C, 120/80 mm Hg, 78 beats, and 14 breaths per 
minute, respectively. Heart and lung auscultation were normal. 
The patient had mild epigastric tenderness without rebound. 
Difference between distal and proximal of right and left low-
er extremity was about 4 cm. Color Doppler ultrasonography 
showed DVT in the popliteal vein. Inferior vena cava (IVC) fil-
ter placed in the patient because of the history of intra-cra-
nial bleeding. Follow-up laboratory tests showed a thrombo-
cytopenia and a prolonged partial thromboplastin time (PTT) 
despite stopping the anticoagulants. Hemoglobin concentra-
tion was reduced to 8.6 g/dL (normal: 11.3–14.5 g/dL) and 
platelet count was 47 000/μL that was below normal range 
(150 000–450 000/μL). The C-reactive protein was 51 mg/dL 
(normal <0.2 mg/dL) and erythrocyte sedimentation rate (ESR) 
was 114 mm/hour (normal <15 mm/hour). C3 (90–180 mg/dL), 
C4 (13–75 mg/dL), and total complement activity (CH50) were 
in normal level. APS was suspected so serology was sent and it 
showed a high titer (45 U/mL) of IgM anticardiolipin antibodies 
(normal <18 U/mL), IgG anticardiolipin antibodies equal to 
55 U/mL (normal <18 U/mL), and lupus anticoagulant equal 
to 48 U/mL (normal <35 U/mL). Anti-double stranded DNA 
(anti-dsDNA), and antinuclear antibody (ANA) were negative. 
Alkaline phosphatase (ALP) was increased to 3783 U/L (nor-
mal: 20–70 U/L), and the level of gamma glutamyl transferase 
(GGT) was 35 U/L (6–37 U/L). Therefore, the whole-body bone 
scan was performed to detect infiltrative bone disease in the 
patient suspected to APS. The scan showed nonhomogeneous 
radiotracer uptake in the skull, spine, pelvic, and faint foci of 
increased radiotracer uptake in the proximal portion of both 
femurs. This result suggested bone metastasis. Upper endos-
copy was performed as a part of work up for the primary tu-
mor, which revealed a large infilterable lesion (4×3 cm) in the 
stomach (Figure 1). A biopsy was taken which showed adeno-
carcinoma with signet ring cell component. Histologic analysis 
of the gastric biopsy shows atypical cells with hyperchromat-
ic nuclei and eosinophilic cytoplasm are arranged as glandu-
lar structures. (Figure 2). Other organs were checked for me-
tastasis. Triphasic CT scan of the abdomen showed hypodense 
lesions in the liver resembling metastases. In chest CT scan, 
small nodules seen in right lung and metastatic lesions in the 
vertebra. Thyroid sonography revealed multiple calcified nod-
ules in both lobes. The patient refused chemotherapy and died 
6 months after diagnosis.
Discussion
The APS is diagnosed when the patient has least one clinical 
and one laboratory criterion. Vascular thrombosis and preg-
nancy morbidity are clinical criteria. Lupus anticoagulant, an-
ticardiolipin-antibodies (with titer >99th percentile), anti-b2 
Figure 1.  Upper gastrointestinal endoscopy showing a large 
infilterable lesion (4×3 cm) located in the body of 
stomach (arrow). The surrounding mucosa was not 
combined with atrophy or intestinal metaplasia.
Shayestehpour M. et al.: 
A case of antiphospholipid syndrome following gastric cancer
© Am J Case Rep, 2020; 21: e919037 
e919037-2 Indexed in: [PMC] [PubMed] [Emerging Sources Citation Index (ESCI)][Web of Science by Clarivate]
This work is licensed under Creative Common Attribution-
NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
glycoprotein-I-antibodies (with titer >99th percentile) that is 
confirmed by repeat testing with an interval of at least 12 
weeks are laboratory criteria. In the present case, the patient 
had an ultrasound confirmed DVT and high titer of IgM/IgG 
anticardiolipin and lupus anticoagulant. The presence of lu-
pus anticoagulant is a strong risk factor for venous thrombosis 
in APS, while the association between levels of anticardiolip-
in-antibodies antibodies and thrombosis is less clear. Several 
studies have reported that the risk of venous thrombosis in-
creases with the number of positive tests for antiphospho-
lipid antibodies. APS can be associated with the non-criteria 
manifestations, such as heart valve disease, livedo reticularis, 
thrombocytopenia, superficial vein thrombosis, renal microan-
giopathy, seizures, chorea, myelitis, and systemic lupus erythe-
matosus (SLE)-like symptoms (e.g., alopecia, aphthous ulcers). 
In this case, the patient had thrombocytopenia (PLT <50 000) 
as a non-criterion clinical manifestation of APS.
Previous studies have shown that antiphospholipid antibod-
ies can be associated with malignancies [2]. In this case, titer 
of lupus anticoagulant, IgM and IgG anticardiolipin antibodies 
were moderate to high in a patient with DVT and gastric cancer. 
Ozguroglue et al. showed an association between high level of 
anticardiolipin antibody and thromboembolic events in patients 
with colorectal, breast, ovarian, lung, and pancreatic cancer [4].
The literature review of cases with APS and solid tumors showed 
that kidney cancer, tumors with unknown origin, lung adeno-
carcinoma, and breast cancer were the common tumors relat-
ed with antiphospholipid antibodies [1]. Only 1 case of stom-
ach cancer linked with APS was found among the published 
articles [3]. They were detected anticardiolipin and anti-beta-2 
glycoprotein I antibodies in the serum of a 45-year-old fe-
male with gastric cancer. Their case had only hypertension 
in her medical history without other illnesses, miscarriages, 
or thrombotic events. A history of SLE was in her family and 
her daughter had died with SLE, but in the present case, the 
patient did not have a family history of SLE. The first finding 
in their case was lesions resembling metastases in the liver, 
spleen, and kidney, then antiphospholipid antibodies detected 
in serum, whereas we first detected APS and then found the 
cancer. Despite the findings in this case and previous data on 
the possible pathogenic role of antiphospholipid antibodies, 
proving a direct association between APS and the cancer is 
difficult. However, the clinical findings described in our pres-
ent case and the positivity of antiphospholipid antibodies sug-
gested an association between the 2 disorders.
Thrombosis is one of the first manifestations of malignancy. 
Cancer patients are at high risk of thromboembolic events [5]. 
The association between antiphospholipid antibodies and 
thrombotic events was found since the 1980s [6]. During the 
last decades, several case reports of APS in patients with throm-
bosis and various types of cancer such as non-Hodgkin lym-
phoma, breast, colorectal, ovarian, and lung carcinoma have 
been published [7]. Therefore, antiphospholipid antibodies 
may be linked to tumor-related thrombosis. These antibod-
ies may be increased due to cancer immunotherapy by inter-
feron a or immune response to tumor antigens [2]. Cancers 
can increase the production of antiphospholipid antibodies 
by several mechanisms including the following: 1) autoanti-
body production in response to tumor antigens; 2) secretion 
of anticardiolipin antibodies from tumor cells; and 3) produc-
tion of monoclonal immunoglobulins with lupus anticoagulant 
and anticardiolipin-antibodies activities.
In the present case, heparin was first used for treatment of 
DVT followed by warfarin. Anticoagulation therapy was stopped 
following subdural hematoma. Low molecular weight heparin 
and subsequent vitamin K antagonists are first-line treatments 
for venous thrombotic event. The use of direct oral anticoag-
ulants for treatment is not recommended. After low molec-
ular weight heparin therapy in the acute phase, treatment 
can be switched to vitamin K antagonists (INR target range 
of 2.0–3.0). Treatment with an INR more than 3.0 after a first 
venous thrombosis is not recommended.
Unfortunately, the patient reported in this study refused che-
motherapy and died 6 months after diagnosis. In several pre-
vious reports, patients underwent chemotherapy or checkpoint 
inhibitor therapy, and survived. In recent years, immune check-
point inhibitors (ICIs) have been recommended for treatment 
of advanced cancers. Anti-PD-1/PD-L1 antibodies have shown 
an acceptable clinical activity in gastric cancer and can be a 
new treatment option [8,9].
Figure 2.  Histologic analysis of the gastric biopsy shows signet 
ring cell carcinoma. Atypical cells with hyperchromatic 
nuclei and eosinophilic cytoplasm are arranged as 
glandular structures. Some neoplastic cells have lateral 
nucleus and cytoplasmic mucin vacuoles matched with 
ring cells (arrows) that invaded the lamina propria.
Shayestehpour M. et al.: 
A case of antiphospholipid syndrome following gastric cancer
© Am J Case Rep, 2020; 21: e919037 
e919037-3 Indexed in: [PMC] [PubMed] [Emerging Sources Citation Index (ESCI)][Web of Science by Clarivate]
This work is licensed under Creative Common Attribution-
NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Conclusions
In this present case, we found an APS associated with gastric 
signet ring cell adenocarcinoma. Despite the findings in this 
case and previous data on APS and cancer, proving a direct as-
sociation between APS and the cancer was difficult. However, 
the clinical findings described in the present case and the pos-
itivity of antiphospholipid antibodies suggested an association 
between the 2 disorders.
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Conflicts of interest
None.
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Shayestehpour M. et al.: 
A case of antiphospholipid syndrome following gastric cancer
© Am J Case Rep, 2020; 21: e919037 
e919037-4 Indexed in: [PMC] [PubMed] [Emerging Sources Citation Index (ESCI)][Web of Science by Clarivate]
This work is licensed under Creative Common Attribution-
NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)


A case of antiphospholipid syndrome following gastric signet ring cell adenocarcinoma

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A case of antiphospholipid syndrome following gastric signet ring cell adenocarcinoma

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