A case of lung cancer-associated pulmonary embolism mimicking Kimura disease: a case report

Abstract

Background

Lung cancer-associated pulmonary embolism (PE) is an acute and fatal clinical syndrome. Kimura disease is defined as a rare, chronic inflammatory disease, primarily characterized by swollen lymph nodes in the head and neck, elevated levels of eosinophils and immunoglobulin (Ig) E. PE can also occur in patients with Kimura disease due to eosinophilia. We herein reported a case of lung cancer-associated PE mimicking Kimura disease.

Case presentation

A 36-year-old Han Chinese male was admitted complaining of repeated cough, hemoptysis, and chest pain, and his recurrent PE with pulmonary artery and bronchial artery were confirmed by chest computed tomographic angiogram (CTA) during both of his two admissions. He had enlarged lymph nodes of bilateral axilla and mediastinum and complained of skin itches, further laboratory examination showed elevated levels of eosinophils and Ig E, which mimicked the syndrome of Kimura disease. In order to clarify the diagnosis, his lymph node biopsy was suggested and performed, however, the pathologic profile of the resected lymph node referred not to Kimura disease, but lung adenocarcinoma. Then, upon definite diagnosis, the patient received standardized anticoagulant and targeted antitumor therapy, he got relief and stayed in stable condition at the time of discharge and during the subsequent 1-month follow-up.

Conclusions

PE, swollen lymph nodes and eosinophilia may occur in both Kimura disease and solid cancer, the differential diagnosis between the two is crucial for the rational management of patients and warranted adequate attention.

Background

Pulmonary embolism (PE) is the most serious form of venous thromboembolism (VTE) [1]. Early detection of this syndrome is of vital importance to initiate the appropriate treatment, as well as accurate identification of its triggers to reduce the risk of recurrence. As described by Virchow in nineteenth century, stasis, endothelial disruption, and hypercoagulability laid the foundation of VTE formation [2]. Cancer, including lung cancer is thought to be one of the risk factors for PE, with high mobidity and mortality, which mainly affected middle aged and elderly people [3]. Kimura disease is a rare and chronic inflammatory disease, primarily characterized by swollen lymph nodes in the head and neck, elevated levels of eosinophils and immunoglobulin (Ig) E, and the pathologic changes of lymph node biopsy can confirm it [4]. PE can occur in patients with Kimura disease due to eosinophilia [5], meanwhile, swollen lymph nodes and eosinophilia can also occur in patients with solid cancer. Hence, Kimura disease is easily misdiagnosed as a solid cancer. Inversely, we herein reported a Chinese young male case of lung cancer-associated PE mimicking Kimura disease, in order to raise the awareness of differential diagnosis between the two.

Case presentation

In March 2024, a 36-year-old Han Chinese male was admitted to our hospital complaining of repeated cough, hemoptysis, and chest pain for 2 months, and his PE with pulmonary artery and bronchial artery were confirmed by chest computed tomographic angiogram (CTA), in addition, several tiny nodules in his upper and middle lobe of both lungs were seen, and also signs of infection. Moreover, his family medical history and psychosocial history were unremarkable, no notable risk factors or concerns identified. Considering his acute PE and infection, he was given piperacillin sodium and tazobactam sodium (2.5 g, bid) for anti-infection, and enoxaparin sodium (4000 IU, bid) for anticoagulation treatment in hospitalization, and Rivaroxaban tablets (20 mg, qd) for hospital discharge. He stopped hemoptysis and got relief after 10 days in hospitalization, and was discharged from hospital.

However, 2 months later, unfortunately, his condition relapsed, and he began to undergo hemoptysis again, manifested as bright red clot sputum with the frequency of 4 to 5 times per day, simultaneously, he felt radiation pain in the right posterior back, especially on deep inspirations. Then he was readmitted to our hospital with the initial diagnosis of PE in May 2024. To confirm and clarify the exact cause of his repeated PE, further imaging and laboratory examination were performed. The CTA examination confirmed his recurrence of PE located in distal branch of lower left pulmonary artery, and in addition, his D-dimer level was significantly elevated with the result of over 21.0 ug/mL FEU, which was in line with his PE diagnosis (Tables 1 and 2).

Table 1.

Patient’s timeline of events and progression

Time point	Clinical event
T = 0 (First hospitalization)
Clinical symptoms	Repeated cough, hemoptysis, and chest pain for 2 months
Clinical diagnosis	PE and infection
Clinical treatment	Anticoagulation (enoxaparin sodium, 4000 IU bid) and anti-infection (piperacillin sodium and tazobactam sodium, 2.5 g bid) therapy
T = 2 months (Second hospitalization)
Clinical symptoms	Hemoptysis, radiation pain in the right posterior back, enlarged lymph nodes of bilateral axilla and mediastinum, skin itches, elevated levels of eosinophils and Ig E
Clinical diagnosis	Low differentiated adenocarcinoma of lung (stage IV, bone metastases), accompanied with recurrent PE
Clinical treatment	Targeted antitumor (Alectinib, 600 mg bid) and standardized anticoagulant (enoxaparin sodium, 4000 IU bid) therapy
T = 3 months (Follow-up after discharge)	Continued the targeted antitumor (Alectinib, 600 mg bid) and preventive anticoagulation (Rivaroxaban tablets, 20 mg qd), the patient stayed in stable condition with steady decline in the levels of tumor markers (CEA, NSE and SCC), and no recurrence of PE

PE Pulmonary embolism, Ig Immunoglobulin, CEA carcino- embryonic antigen, NSE neuron-specific enolase, SCC, squamous cell carcinoma antigen

Table 2.

Patient’s laboratory examination results during hospitalizations and follow-up after discharge

Parameters	Results	Reference interval
T = 0 (First hospitalization)
WBC, × 109/L	9.17	3.5–9.5
Eo#, × 109/L	0.17	0.02–0.52
HGB, g/L	127	130–175
PLT, × 109/L	199	125–350
D-dimer, ug/mL FEU	> 21.0	< 0.5
T = 2 months (Second hospitalization)
WBC, × 109/L	10.53	3.5–9.5
Eo#, × 109/L	1.15	0.02–0.52
HGB, g/L	125	130–175
PLT, × 109/L	165	125–350
D-dimer, ug/mL FEU	> 21.0	< 0.5
PC activity, %	85	70–142
PS activity, %	94	77–143
AT, %	103	80–120
IgE, IU/mL	237.9	< 100
Lupus anticoagulant (dRVVT ratio)	1.14	< 1.20
Lupus anticoagulant (SCT ratio)	0.88	< 1.21
IgA/IgG/IgM aCL	Negative	Negative
IgA/IgG/IgM anti-β2GPI	Negative	Negative
ANA	Nuclear granular type, 1:320	Negative
HCY, umol/L	18.8	6–16
CEA, ng/mL	2.57	≤ 5.0
NSE, ug/L	50.77	< 16.30
SCC, ng/mL	8.1	≤ 1.5
T = 3 months (Follow-up after discharge)
D-dimer, ug/mL FEU	2.15	< 0.5
CEA, ng/mL	2.06	≤ 5.0
NSE, ug/L	29.60	< 16.30
SCC, ng/mL	1.2	≤ 1.5

WBC white blood cell, Eo Eosinophil, HGB hemoglobin, PLT blood platelet count, PC protein C, PS protein S, AT antithrombin, Ig Immunoglobulin, DRVVT Dilute Russell's viper venom time, SCT silica clotting time, aCL anticardiolipin antibodies, aβ2GPI anti-β2-glycoprotein I antibodies, ANA anti-nucleic antibody, HCY homocysteine, CEA carcino-embryonic antigen, NSE neuron-specific enolase, SCC squamous cell carcinoma antigen

So far, for this patient, his recurrent PE was a major concern, in order to identify the risk factors for thrombophilia, we measured the serum levels of protein C (PC), protein S (PS), and antithrombin III (AT), which were the major thrombolic factors among Chinese population, however, all these anticoagulant proteins were within normal ranges. In addition, we also measured other common thrombophilia risk factors, such as lupus anticoagulant (LA), anticardiolipin antibodies (aCL) and anti-β2-glycoprotein I antibodies (aβ2GPI), homocysteine (HCY), and so on, but there were no obvious positive findings observed. His comprehensive laboratory examinations were listed in Table 2. Furthermore, we noticed that his blood routine test revealed significantly elevated level of eosinophils with an absolute count of 1.15 × 10⁹/l and percentile of 10.9%, which was thought to be a thrombophilia risk factor and mainly seen in parasitic infections [6]. However, his full screening for parasites showed no positive findings. Considering his swollen lymph nodes in the head and neck (only be sensed by finger palpation), intermittent pruritus, and elevated level of IgE, Kimura disease was highly suspected, which often offended Asian young males, and could also be complicated with PE [5]. Then we suggested to perform a lymph node biopsy for him with the purpose of making a definite diagnosis to confirm or rule out Kimura disease.

Three days later, his lymph node biopsy results came back, and cancer cells were found under the microscope (Fig. 1A, B), not indicating the diagnosis of Kimura disease. Then, in order to identify the origin of these cancer cells and detect distant metastases, lung biopsy and pathological examination, and whole-body PET/CT imaging were performed, and confirmed his low differentiated adenocarcinoma of lung (stage IV, bone metastases) (Fig. 1C, D), with immunohistochemical results of CK8/18( +), CK7( +), TTF-1( +), NapsinA( +), and P40(-). Upon definite diagnosis, following the recommendations stated in relevant clinical guidelines [7, 8], the patient received standardized anticoagulant (enoxaparin sodium, 4000 IU bid) and targeted antitumor (Alectinib, 600 mg bid) therapy, he got relief and stayed in stable condition after 9 days in hospitalization, and was discharged from hospital.

Fig. 1.

Pathological findings of the patient’s cervical lymph node and lung tissue. A, B Cancer cell were seen from exfoliated cells punctured in left cervical lymph nodes (A) and left lung (B). C, D Pathological examinations of left cervical lymph nodes (C) and lung tissue (D), diagnosis of poorly differentiated lung adenocarcinoma

After being discharged from the hospital, he continued the targeted antitumor (Alectinib, 600 mg bid) and preventive anticoagulation (Rivaroxaban tablets, 20 mg qd) treatment as prescribed by the doctor. Subsequent 1-month follow-up revealed a steady decline in the levels of his tumor markers, with no recurrence of PE. The patient’s timeline of events and progression, and the laboratory examination results during hospitalizations and follow-up after discharge were detailed in Tables 1 and 2.

Discussion

Collectively, we reported a Chinese young man with PE as his first symptom, characterized by peripheral eosinophilia and elevated level of IgE, intermittent pruritus and painless subcutaneous mass lesions on the head and neck, which highly mimicked Kimura disease [4]. However, his pathologic profile of the resected lymph node confirmed pulmonary adenocarcinoma, not Kimura disease. Notably, the diagnosis of this case was challenged by significant overlaps between lung cancer-associated PE and Kimura disease, as well as their rare coexistence, leading to initial diagnostic confusion before pathological confirmation.

Kimura disease is a rare, chronic inflammatory disease of unknown etiology [4]. It is generally assumed that any triggers, such as infections, allergic reactions, and autoimmune disease with an aberrant immune reaction, that causing an abnormal T cell stimulation to the state of hypersensitivity could lead to the occurrence of Kimura disease [4]. Kimura disease tends to affect young Asian men in his third decade of lifetime, and the prevalence rate for male and female is approximately 4:1 [4, 5]. The final definitive diagnosis depends on the histopathological examination of enlarged lymph nodes, characterized as eosinophil infiltration, follicular hyperplasia, and reactive germinal center in the interfollicular area [4]. It is worth noting that the patient we reported had positive result of anti-nucleic antibody (ANA), which may indicate autoimmune-related diseases. As we have discussed above, autoimmune-related diseases are one of the important triggering factors for Kimura disease [4]. To determine whether the patient had any underlying autoimmune disease, we conducted a comprehensive screening for autoantibodies, however, except for ANA, all the other tests were negative. Lung cancer could also be associated with positive ANA, which was thought to be due to the antigen substances released by tumor cells stimulating the body's immune system, triggering an immune response, and eventually resulting in the production of autoantibodies [9].

Kimura disease is considered to be a benign disease with favorite prognosis, but easy to recurrence with the rate up to more than 50% reported previously [4, 10]. Regarding for the treatment, surgical resection and additional medical therapy, such as regional or systemic steroid therapy, cytotoxic therapy, and radiation have been recommended [4, 10]. Primarily due to peripheral eosinophilia, Kimura disease could also be associated with PE, which was reported by Ye and his (or her) colleagues [5], though being with relatively low incidence. In view of this situation, treatment of the primary disease is fundamental, and meanwhile, timely and effective anticoagulant therapy may be equally important.

In our reported case, recurrent PE was his most initial and prominent clinical manifestation. PE, which is a special, but serious type of VTE, is an acute and fatal clinical syndrome [1]. Dyspnea, chest pain and hemoptysis are regarded as the typical triad of PE, but clinically, these occur in less than 30% of the patients [1]. Any risk factors for VTE can lead to PE [1]. In our reported case, eosinophilia was found in his routine blood test, and it was regarded as a risk factor for VTE (including PE) as described by previous studies [5, 11]. The mechanisms behind the eosinophilia and VTE (or PE) were not fully elucidated yet. Several potential explanations were presented as below [5, 11]. First, eosinophils can provide a procoagulant phospholipid surface and express tissue factor (TF), which may support and induce the autonomous TF-dependent generation of thrombin. Second, major basic protein-induced direct toxic by eosinophils and eosinophil itself would cause damage to microvascular endothelial cells and eventually lead to microthrombi. Third, activated eosinophils release various substances, such as cytokines, chemokines, cytotoxic granule proteins, and lipid mediators, which can initiate and facilitate local inflammatory response when they accumulate in circulating blood. It is clarified that inflammation is closely related to initiation and progression of thrombosis [12]. All of three above could contribute to the hypercoagulable state in patients with eosinophilia, and account for the potential explanations of VTE or PE among them.

Except for eosinophilia, cancer, especially lung cancer, was an another risk factor for VTE or PE in this case. It was reported that about 4 ~ 20% cancer patients were associated with VTE, and lung cancer accounted for 21% of VTE in all tumor patients [3, 13]. The mechanisms behind the lung cancer patients with PE are often more complicated and multi-factors, which include lung cancer-related, patient- related, and treatment-related risk factors [3, 13]. Of particular note is that all these three risk factors keep to the principle of Virchow’s Triad, namely stasis, endothelial disruption, and hypercoagulability [2]. It is worth highlighting that tissue factors and procoagulant proteins secreted by lung tumor cells are important factors that cause blood hypercoagulability, which will eventually lead to VTE [3, 13]. Furthermore, the histological type and stage of lung cancer are closely related to the occurrence of PE [13]. Non-small cell lung cancer (NSCLC), especially adenocarcinoma, more tends to develop PE [13], which is in line with our reported case. In addition, advanced stage of lung cancer, such as stage Ⅳ in NSCLC was regarded as an independent risk factor for PE [13]. The young man we reported was confirmed to have low differentiated adenocarcinoma of lung (stage Ⅳ), a type of NSCLC with high malignant degree and poor prognosis, which may also contribute to his PE occurrence [3, 13].

Conclusion

We reported a Chinese young male with recurrent pulmonary embolism as his initial symptom, characterized by swollen lymph nodes in the head and neck, and elevated levels of eosinophils and Ig E, which highly mimicked Kimura disease. Ultimately, lung cancer with the type of adenocarcinoma was confirmed through the pathological examination of lymph node biopsy. Kimura disease was easily misdiagnosed as a solid cancer, inversely, lung cancer-associated pulmonary embolism mimicking Kimura disease was rarely reported previously, and thus more attention should be paid to raise the awareness of differential diagnosis between the two.

Abbreviations

PE

Pulmonary embolism

VTE

Venous thromboembolism

Ig

Immunoglobulin

CTA

Computed Tomographic Angiogram

PC

Protein C

PS

Protein S

AT

Antithrombin III

LA

Lupus anticoagulant

aCL

Anticardiolipin antibodies

aβ2GPI

Anti-β2-glycoprotein I antibodies

HCY

Homocysteine

ANA

Anti-nucleic antibody

TF

Tissue factor

NSCLC

Non-small cell lung cancer

CEA

Carcino-embryonic antigen

NSE

Neuron-specific enolase

SCC

Squmaous cell carcinoma antigen

Author contributions

H.B contributed to the study design, analyzed the data, and drafted the manuscript. C.W, W.S, and S.E contributed to perform the literature review and collected the data. N.T contributed to the study design, analyzed the data, and revised the manuscript. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved the submission.

Funding

None.

Data availability

Data is available upon reasonable request from the corresponding author.

Declarations

Ethics approval and consent to participate

This study was approved by the ethical committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors report no conflict of interest.