Xun Sun,Bing Dai

1Laizhou Hospital of Traditional Chinese Medicine,Laizhou 261400,China.

Abstract Objective:To summarize the clinical manifestation,diagnosis and treatment of a case of epithelioid hemangioendothelioma of the pancreas(epithelioid hemangioendothelioma,EHE)with liver and right lung involvement.Methods:The clinical,imaging,histomorphological and immunohistochemical features of a patient with pancreatic epithelioid hemangioendothelioma with liver and right lung involvement diagnosed in Laizhou traditional Chinese Medicine Hospital in 2021 were analyzed retrospectively,and the related literatures were reviewed.Results:After 8 cycles of chemotherapy combined with hyperthermia and traditional Chinese medicine treatment,the clinical discomfort symptoms were significantly improved,the quality of life was improved,and the condition was stable,which is still in the process of treatment.Conclusion:Pancreatic EHE is rare in clinic.Imaging plays an important role in the diagnosis of pancreatic EHE,but the final diagnosis should be confirmed by pathological examination.The histological features of this case of EHE should be distinguished from metastatic carcinoma,epithelioid sarcoma,mesothelioma and other common tumors in the abdominal cavity,and its diagnosis is challenging.Surgical resection is the first choice for EHE,but its sensitivity to radiotherapy and chemotherapy is not accurate.The prognosis of EHE needs to collect more case data for in-depth and systematic study and analysis.

Keywords:epithelioid hemangioendothelioma of the pancreas;diagnosis;pathology;treatment;prognosis

Epithelioid hemangioendothelioma,also known as histiocytic hemangioma,is a rare angiogenic tumor,which is between hemangiosarcoma and hemangioma.The clinical manifestations of pancreatic epithelioid hemangioendothelioma are loss of appetite,anorexia,nausea,paroxysmal vomiting,epigastric pain,weight loss,signs can be found hepatosplenomegaly,a small number of patients with jaundice,late patients will be systemic failure.The disease is a multifocal vascular tumor,which usually occurs in the deep soft tissue of the limb,skin,liver,lung,bone and so on.It is often seen in young and middle-aged people.According to the clinical manifestations of multifocal vascular tumors,combined with histopathological examination,the diagnosis can be made[1].However,the clinical manifestations of pancreatic epithelioid hemangioendothelioma are not typical,imaging manifestations are diverse,easy to be misdiagnosed,and need to be diagnosed by pathological examination.The main treatment of epithelioid hemangioendothelioma is surgical resection.According to the needs of the disease,chemotherapy or radiotherapy can be used for comprehensive treatment.

Clinical data

General data:Yang XX,female,59,came to our hospital for"recurrent epigastric pain with nausea and vomiting for half a year".The patient was in good health,the admission NRS score was 7,the KPS score was 40,and the family genetic history and tumor history were denied.Examination outside the hospital:enhanced CT of the upper abdomen showed:1 it was consistent with the CT findings of pancreatic cancer and multiple metastatic tumors of the liver;2.Hepatic cyst,intrahepatic calcification;3 cholecystolithiasis,cholecystitis;4 thickening of left adrenal gland;5 slight thickening of gastric wall in gastric antrum.Chest CT:1.Emphysema;2.Ground glass focus in the basal segment of the lower lobe of the right lung;3.High density foci in the dorsal segment of the lower lobe of the right lung,inflammatory changes(Figure 1)?

Gastroscopy:chronic superficial gastritis.Liver space-occupying biopsy showed epithelioid hemangioendothelioma.The patient was admitted to our hospital from 2021 to March 4,and the liver space occupying biopsy was performed again.The pathological findings were as follows:part of hepatocytes,small strips of necrotic tissue and part of vitreous fibrous tissue were shown in the right lobe of the liver.The infiltration and growth of mild abnormal round and short shaped cells were seen in the focal area.combined with immunohistochemistry and the original history is not excluding epithelioid hemangioendothelioma.Immunohistochemical results:Arg-1(-),CEA(+),CK20(-),CK7(+),CKpan(+),Ki-67(hot spot about 2%),Smur100P(-),Villin(+),Vimentin(+),CD34(+).Sent to Qingdao Jinyu Medical Laboratory Co.Ltd:(liver right lobe puncture biopsy),neoplastic lesions,mucochondral or collagen vitreous degeneration background,tumor cells arranged into a short cord,nest-like or scattered infiltration,part of the cytoplasm red staining, combined with histological morphology and immunohistochemical results, consistent with epithelioid hemangioendothelioma.Immunohistochemical staining showed Hepatocyte(-)and CD31(+)（Figure 2）.Carcinoembryonic antigen(CEA):19.11ng/ml,CA-125:56.30U/ml,CA19-9:55.14 U/ml,AFP:3.01 ng/ml.

Figure 1 pre-treatment CT imaging examination,pancreatic,liver and right lung tumors

Treatment and follow-up:From March 2021 to July 2021,gemcitabine 1.4g d1.8+cisplatin 20mg D1-5 regimen was given for 6 cycles,supplemented with deep thermotherapy twice a week,and traditional Chinese medicine(Ganshu,Pishu,Yishu scraping,pricking and cupping,combined with acupuncture,Xuefu Zhuyu decoction combined with Chaihu Shugan Powder and Wumei pills).After 2 cycles of chemotherapy,the symptoms of clinical discomfort were significantly improved,no abdominal distension,abdominal pain,cough,sputum,nausea and vomiting,NRS score 0-1,KPS score 80,diet,sleep and defecation were significantly improved.Re-examination of tumor markers:carcinoembryonic antigen(CEA):23.13ng/ml,CA-125:58.50U/ml,CA19-9:31.33 U/ml,AFP:3.12 ng/ml。Re-examination of CT:chest+whole abdominal enhanced CT:1.high-density lesions of the right lower lobe,except for space-occupying lesions,please combine with C-guided biopsy when clinically necessary; 2.emphysema, bilateral pulmonary bronchiectasis and infection;3.ground glass foci in the basal segment of the right lower lobe,similar to before,further examination or reexamination is recommended.4.abnormal density focus of pancreatic body and dilatation of main pancreatic duct,which is similar to that before,MRI is recommended for further examination;5.considering multiple metastatic tumors in the liver,similar to before;6.hepatic cyst;complex cyst of right kidney;7.cholecystolithiasis with cholecystitis;8.left adrenal gland is plump,similar to before,it is recommended to follow up;9.a small amount of fluid in abdominal and pelvic cavity（Figure 3）.

Figure 2 pathological examination

Figure 3 CT imaging findings after treatment,pancreatic,liver and right lung tumors

In October 2021,the tumor markers were reexamined,and carcinoembryonic antigen(CEA)：42.34ng/ml,CA-125:47.60U/ml,CA19-9:40.71U/ml.The imaging and clinical symptoms did not change much.The patients were treated with albumin paclitaxel+gemcitabine regimen for 2 cycles,and the patient's condition was stable.Since then,the patient has been treated with oral traditional Chinese medicine until now,due to family economic factors and has been treated with traditional Chinese medicine until now,and the condition is stable.

Discussion

Epithelioid hemangioendothelioma (epithelioid hemangioendothelioma,EHE)is a malignant angiogenic tumor between traditional hemangioendothelioma and hemangiosarcoma(ICD-O code 9133).In the past 10 years,it has been found that more than 90%of EHE have WWTR1-CAMTA1 fusion[2,3],and a few EHE have YAP1-TFE3 fusion[4].Both WWTR1 and YAP1 are downstream factors of Hippo pathway(tumor suppressor pathway).Studies[2,3]found that the fusion products of WWTR1-CAMTA1 and YAP1-TFE3 can lead to tumor inhibition dysfunction of Hippo pathway and cause tumorigenesis.

Clinical features

The incidence of pancreatic EHE is less than 1/1,000,000[5],which is found accidentally by physical examination.Some patients may be accompanied by pain,weight loss,jaundice,ascites and other manifestations[6].A few patients may have slight increase of CA19-9,CEA or CA125[7,8].More than 75% of the liver EHE showed multiple lesions in the liver,and a few patients were solitary lesions[6].In some patients with EHE,liver,lung,bone and brain were involved at the same time,and about 18% of EHE involved both liver and lung[9].Pancreatic EHE with liver and lung involvement is very rare.This case was diagnosed as pancreatic EHE with liver and right lung metastasis.Chest CT showed high density focus in the lower lobe of the right lung,except for space-occupying lesions,and ground glass focus in the basal segment of the lower lobe of the right lung.Although the imaging consideration of the ground glass focus and high density focus in the lower lobe of the right lung,the involvement of EHE in the right lung could not be completely ruled out.In the later stage of treatment,attention should be paid to the reexamination of chest CT.The author believes that in the process of diagnosis and treatment,we should also pay attention to the development of pulmonary lesions.

Imaging features

Recent studies have shown that the characteristic CT or MRI imaging findings of pancreatic EHE include:(1)capsular retraction sign,which can be distinguished from localized capsule bulging in liver metastatic tumors,and(2)the"core pattern"of round high signal intensity in the center of EHE lesions can be distinguished from the irregular central necrosis of metastatic tumors.(3)the"lollipop sign"in which the veins extend the edge of the focus or penetrate the focus can be distinguished from the"fast-in and fast-out"characteristics of hepatocellular carcinoma during dynamic contrast-enhanced scanning[8].EHE was not considered in the original imaging diagnosis of this case,but reviewing the abdominal enhanced CT,we can see the characteristic changes of"lollipop sign"and"core mode"of EHE.Therefore,attention should be paid to the differential diagnosis of these rare diseases in clinical work.

Immunohistochemical staining characteristics

EHE tumor cells express vascular endothelial cell markers such as CD31,CD34,ERG and FLi-1,as well as D2-40.CAMTA1 or TFE3 is a specific marker to distinguish EHE from other angiogenic tumors.The immunohistochemical staining of this patient was Hepatocyte(-),CD31(+)and CD34(+).It is consistent with epithelioid hemangioendothelioma.

treatment and prognosis

Surgical resection is the first choice for the treatment of pancreas,liver and other parts of EHE.Liver transplantation is also available when the liver is widely involved.The 5-year survival rate of liver EHE patients after partial hepatectomy was about 55%[10];the 5-and 10-year survival rates after liver transplantation were 83% and 74%,respectively,and the recurrence rates were 18% and 36%[10],respectively.It is reported that there are few cases of liver EHE treated by liver transplantation in China,and 1 case has no recurrence after follow-up for 2 years[11].EHE is not sensitive to radiotherapy and chemotherapy[12],so this patient is given deep hyperthermia(thermotherapy and chemotherapeutic drugs have an organic complementary effect to increase the sensitivity of the patient to chemotherapy.It can kill malignant tumor cells more effectively,improve the quality of life of patients,prolong their lives,and at the same time reduce the side effects of chemotherapy)and reduce the toxicity and efficiency of traditional Chinese medicine.The drugs that can be selected for chemotherapy include cisplatin,vincristine,cyclophosphamide,etoposide and so on.In recent years,there are reports on the use of targeted drugs in the treatment of EHE,mostly using anti-tumor angiogenic drugs such as bevacizumab[9,11].The overall mortality rate of EHE is 7.1%-65%[13,14].A study followed up for at least 4 years[15]showed that the fatality rates of lung,liver and soft tissue EHE were 65%,35% and 13%,respectively.Distant metastasis may occur in 20% to 30% of liver EHE[6].The overall poor prognostic factors included multiple organ involvement[25],obvious clinical symptoms or signs[9,12],tumor diameter＞3 cm and so on[13,14].

To sum up,pancreatic EHE is rarely seen clinically,especially with liver and lung involvement.Imaging plays an important role in the diagnosis of EHE,and the final diagnosis should be combined with histological morphology.Immunohistochemical staining includes comprehensive analysis of CAMTA1 or TFE3 and positive vascular endothelial cell markers.Surgical resection is the first choice for EHE,and it is not sensitive to radiotherapy or chemotherapy.During the current treatment of this patient,the preliminary evaluation of clinical symptoms and related hematological examination have been improved in varying degrees,and the imaging is more stable.The author believes that the treatment of traditional Chinese medicine may play an important role in the treatment,but the mechanism remains to be further studied.In the process of follow-up treatment,we need further follow-up and summarize the experiences and lessons of this kind of disease,so as to provide clinical data support and data for the follow-up in-depth study of this kind of disease.