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Multiple esophageal variceal ruptures with massive ascites due to myelofibrosis-induced portal hypertension

Koichi Tokai, Hiroyuki Miyatani, Yukio Yoshida, Shigeki Yamada

Koichi Tokai, Hiroyuki Miyatani, Yukio Yoshida, Department of Digestive Organs, Jichi Medical University, Saitama Medical Center, Saitama 330-8503, Japan Shigeki Yamada, Department of Pathology, Jichi Medical Uni-versity, Saitama Medical Center, Saitama 330-8503, Japan Author contributions: Tokai K, Miyatani H, and Yoshida Y designed the research; Tokai K performed the research, analyzed the data, and wrote the paper; Yamada S supervised research pathologically. Correspondence to: Koichi Tokai, MD, Department of Diges-tive Organs, Jichi Medical University, Saitama Medical Center, 1-847 Amanuma, Omiya, Saitama-shi, Saitama 330-8503, Japan. [email protected] Telephone: +81-48-6472111 Fax: +81-48-6485188 Received: February 20, 2012 Revised: April 18, 2012Accepted: April 22, 2012 Published online: July 28, 2012

AbstractA 75-year old man had been diagnosed at 42 years of age as having polycythemia vera and had been moni-tored at another hospital. Progression of anemia had been recognized at about age 70 years, and the patient was thus referred to our center in 2008 where second-ary myelofibrosis was diagnosed based on bone mar-row biopsy findings. Hematemesis due to rupture of esophageal varices occurred in January and February of 2011. The bleeding was stopped by endoscopic vari-ceal ligation. Furthermore, in March of the same year, hematemesis recurred and the patient was transported to our center. He was in irreversible hemorrhagic shock and died. The autopsy showed severe bone marrow fibrosis with mainly argyrophilic fibers, an observation consistent with myelofibrosis. The liver weighed 1856 g the spleen 1572 g, indicating marked hepatospleno-megaly. The liver and spleen both showed extramedul-lary hemopoiesis. Myelofibrosis is often complicated by portal hypertension and is occasionally associated with gastrointestinal hemorrhage due to esophageal varices. A patient diagnosed as having myelofibrosis needs to

be screened for esophageal/gastric varices. Myelofibro-sis has a poor prognosis. Therefore, it is necessary to carefully decide the therapeutic strategy in consider-ation of the patient’s concomitant conditions, treatment invasiveness and quality of life.

© 2012 Baishideng. All rights reserved.

Key words: Myelofibrosis; Portal hypertension; Rupture of esophageal varices

Peer reviewer: Dr. Xiaoyun Liao, Department of Medical On-cology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Room JF-208E, Boston, MA 02215, United States

Tokai K, Miyatani H, Yoshida Y, Yamada S. Multiple esopha-geal variceal ruptures with massive ascites due to myelofibrosis-induced portal hypertension. World J Gastroenterol 2012; 18(28): 3770-3774 Available from: URL: http://www.wjgnet.com/1007-9327/full/v18/i28/3770.htm DOI: http://dx.doi.org/10.3748/wjg.v18.i28.3770

INTRODUCTIONMyelofibrosis is a disease resulting in extensive diffuse fi-brosis involving the bone marrow and is characterized by hepatosplenomegaly, leukoerythroblastosis and so on.

Portal hypertension reportedly occurs as a complica-tion in 10%-17% of patients[1] and may be accompanied by gastroesophageal variceal hemorrhage[2]. Herein, we present a patient diagnosed with myelofibrosis who died 3 years later due to repeated ruptures of esophageal vari-ces, associated with massive ascites. Autopsy findings of this case are described with a discussion of the relevant literature.

CASE REPORTThe patient was a 75-year-old man. Increases in 2 blood

CASE REPORT

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World J Gastroenterol 2012 July 28; 18(28): 3770-3774 ISSN 1007-9327 (print) ISSN 2219-2840 (online)

© 2012 Baishideng. All rights reserved.

cell lines, white and red blood cells, had been detected by medical examination at age 42 years, and polycythemia vera was diagnosed at another hospital. Blood hemoglo-bin (Hb) at this time was approximately 19 g/dL. There-after, the patient had been monitored without treatment, but blood Hb gradually decreased from 2005 onward. Thus, the patient was referred to the Department of He-matology of our center in October 2009.

The white blood cell count was 29 700/μL, the red blood cell count 641 × 106/μL, showing an increase in 2 blood cell lines, and juvenile cells were noted (Table 1).

Abdominal computed tomography scan revealed a large quantity of ascites in the peritoneal cavity, and marked spleen enlargement and dilatation of the splenic vein were seen (Figure 1). There were no abnormalities of the liver or other organs. No obvious blood clot for-mation was seen in the main blood vessels.

Bone marrow aspiration was attempted to evaluate the disease state but the tap was dry. Therefore, bone marrow biopsy was conducted from the ilium (Figure 2). Adipocytes were completely absent and hematopoietic cells markedly decreased. Thus, secondary myelofibrosis was diagnosed. There were no findings of progression to leukemia, and the patient was thus monitored by our hematology department.

The patient was urgently transported to our center due to hematemesis in January 2011. Urgent endoscopy was conducted, and esophageal varices of Lm, F2, and


Tokai K et al . Variceal rupture with myelofibrosis-induced portal hypertension

Table 1 Laboratory data

Hematology Blood chemistry Coagulation

WBC 29 700/μL Na 142 mEq/L PT 0.98BAND 35.4% K 4.5 mEq/L APTT 32.9 sSEG 45% Cl 103 mEq/L LYMP 2.6% BUN 24 mg/dLMONO 1.4% Cr 0.8 mg/dL Serology EOSI 2.8% AST 26 IU/L HBsAg (-) BASO 4.2% ALT 25 IU/L HBsAb (-) PRO + ALP 599 IU/L MYELO 7.4% LDH 578 IU/LMETA 0.8% γ-GTP 65 IU/LBLAST 0.2% T-Bil 1.4 mg/dL RBC 641 × 1/μL Amy 28 IU/L Hb 14.2 g/dL CK 39 IU/L Ht 47.3% TP 6.3 g/dL MCV 73.8 fl Alb 4.1 g/dL MCH 22.2 pg CRP 1.36 mg/dLMCHC 30 g/dL Plt 156 × 1/μL

WBC: White blood cell; BAND: Blood band cell; SEG: Blood segmented neutrophil; LYMP: Lymphocyte; MONO: Monocyte; EOSI: Eosinocyte; BASO: Basocyte; PRO: Promyelocyte; MYELO: Myelocyte; BLAST: Blast cell; RBC: Red blood cell; Hb: Hemoglobin; Ht: Hematocrit; MCV: Mean corpuscular volume; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular hemoglobin concentration; Plt: Platelet; BUN: Blood urea ni-trogen; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; LDH: Lactate dehydrogenase; γ-GTP: Gamma-glutamyl transpeptidase; T-Bil: Total bilirubin; CK: Creatine kinase; TP: To-tal protein; Alb: Albumin; CRP: C-reactive protein; PT: Prothrombin time; APTT: Activated partial thromboplastin time; HBsAg: Hepatitis B surface antigen; HBsAb: Hepatitis B surface antibody; META: Metamyelocyte.

Figure 1 Spleen enlargement and dilatation of the splenic vein on ab-dominal computed tomography.

Figure 2 Microscopic findings on autopsy on bone marrow biopsy. A: He-matoxylin and eosion, × 20; B: Hematoxylin and eosion, × 40; C: Silver, × 40. Adipocyte disappearance and markedly decreased hematopoietic cells.

100 μm

C

B

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Cb and the red color sign (hematocystic spot) in the

lower esophagus were found (Figure 3). Therefore, en-doscopic variceal ligation (EVL) was conducted. A large quantity of poorly controlled ascites was observed, and the patient’s activities of daily living (ADL) were poor. Thus, no additional treatment such as endoscopic in-jection sclerotherapy was conducted, and the patient was discharged from the hospital. He had hematemesis in February of the same year, and bleeding was again stopped with EVL. However, no additional treatment was conducted for similar reasons. Furthermore, the patient had hematemesis again in March of the same year and was emergently transported to our center. Urgent endos-copy was conducted; however, because there was a large quantity of fresh blood in the stomach and esophagus, it was difficult to identify bleeding points. Blood pressure became unstable during the examination. Therefore, we abandoned EVL and inserted a Sengstaken-Blakemore tube. The patient was hospitalized at this time. However, the hemorrhagic shock was irreversible and he died 20 h after emergency transport. With informed consent from his family, autopsy was conducted the same day.

Autopsy findings The enlarged liver weighed 1856 g but there were no ob-vious abnormalities on histopathological observation of the portal area or in hepatocytes. Extramedullary hemo-poiesis was seen mainly in sinusoids. The spleen weighed 1572 g, indicating marked splenomegaly, and obscura-tion of white matter and the presence of bone marrow cells with splenic red pulp were the main features noted (Figures 4 and 5). In addition to these findings, small


B

A

Figure 3 Endoscopic image in the lower esophagus. A: Showing a hema-tocystic spot by the white arrow; B: Endoscopic variceal ligation was thus con-ducted.

Figure 4 Macroscopic findings on autopsy. A: The liver weighed 1856 g; B: The spleen 1572 g indicating hepatosplenomegaly.

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Figure 5 Microscopic findings on autopsy stained with hematoxylin and eosion. A: Liver; B: Spleen. Both the liver and the spleen showed extramedul-lary hemopoiesis.



myelodysplastic syndrome or myelofibrosis, hemorrhage, and so on[3,4].

The present case was diagnosed as having polycythe-mia vera, and then showed a disease shift to secondary myelofibrosis approximately 30 years later. The histology of both biopsy and autopsy osseous samples showed increased cells in the 3-lineage differentiations. Since there was no morphological abnormality in them and limited proliferation of immature cells, it was considered that malignant lymphoma and leukemia could be ruled out.

Three years thereafter, the patient repeatedly suffered rupture of esophageal varices and ultimately died of this complication. Non-cirrhotic portal hypertension has vari-ous causes. Myeloproliferative tumors are often accompa-nied by marked splenomegaly and can cause portal hyper-tension due to increased portal vein flow[5,6]. Furthermore, Shaldon et al[7] reported that pre-sinusoidal blood flow resistance increases, in association with extramedullary hemopoiesis in hepatic sinusoids. Even if the increase in blood flow is mild, impaired blood flow can be regarded as the cause of increased pressure. Other than this, portal vein thrombosis within and outside of the liver and ve-nous thrombosis can be causes in some cases. Liver histol-ogy in the present case showed mild fibrosis in the portal area and extramedullary hemopoiesis in hepatic sinusoids but no inflammatory cell infiltrate or reconstruction of hepatic lobules.

At autopsy, extramedullary hemopoiesis was not con-sidered to be severe enough to have resulted in impaired blood flow. In addition, no obvious portal vein thrombo-sis or venous thrombosis was seen, while spleen weight was markedly increased as compared with that of the liver. These findings and splenic vein enlargement were consistent with portal hypertension. Thus, portal hyper-tension may have been caused by the increased blood flow associated with splenomegaly in our present case.

Myelofibrosis is often associated with splenomegaly, and we advocate paying close attention to myelofibrosis that may be accompanied by portal hypertension clini-cally. Patients with concomitant gastroesophageal varices can reportedly be treated effectively with splenectomy, splenic embolization, and transjugular intrahepatic portal-hepatic venous shunting[2,8].

The massive ascites in our present case was consid-ered to have been caused by pre-sinusoidal lymphatic blockade due to extramedullary hemopoiesis; however, ascites was refractory to treatments such as the adminis-tration of diuretics. Therefore, we considered the possi-bility that transjugular intrahepatic portal-hepatic venous shunting would be effective.

The ADL of the present case were poor, and ascites was poorly controlled at the time of the initial hospital-ization. Treatments for portal hypertension were thus considered to be too invasive and difficult; thus, they were not administered. When a patient is diagnosed as having myelofibrosis, screening endoscopy for esophageal and gastric varices should be conducted regularly, keeping in mind that portal hypertension may develop. When risk of

numbers of foci of extramedullary hematopoiesis were detected in the lungs, kidneys and lymph nodes around the pancreas. In bone marrow, adipocytes had completely disappeared, and 3-line cellular growth was seen. Severe fibrosis with mainly argyrophilic fibers was revealed by silver staining, and this finding was consistent with my-elofibrosis (Figure 6).

DISCUSSIONPolycythemia vera is a myeloproliferative tumors result-ing in absolute increases in the red blood cell count and circulating blood volume due to an acquired genetic abnormality of hematopoietic stem cells. Survival with-out treatment averages 18 mo, and the leading causes of death are reportedly thrombosis, progression to leukemia,

B

A

C

Figure 6 Microscopic findings on autopsy (bone marrow). A: Hematoxylin and eosion (HE), × 10; B: HE, × 40; C: Silver, × 10. Adipocyte disappearance and 3-lineage differentiation were seen. Silver staining showed severe fibrosis with mainly argyrophilic fibers.



rupture is considered, prophylactic endoscopic therapy or endovascular treatment should be considered while the patient’s general condition is good. However, the average survival period for myelofibrosis patients ranges from 3 to 7 years, and no more than 20% can expect a median survival of 10 years as this disease has a poor prognosis[2]. Therapy should be carefully selected in full consideration of invasiveness, as it impacts quality of life and prognosis.

REFERENCES1 Ward HP, Block MH. The natural history of agnogenic

myeloid metaplasia (AMM) and a critical evaluation of its relationship with the myeloproliferative syndrome. Medicine (Baltimore) 1971; 50: 357-420

2 Sullivan A, Rheinlander H, Weintraub LR. Esophageal vari-ces in agnogenic myeloid metaplasia: disappearance after

splenectomy. A case report. Gastroenterology 1974; 66: 429-432 3 Campbell PJ, Green AR. Management of polycythemia vera

and essential thrombocythemia. Hematology Am Soc Hematol Educ Program 2005; 201-208

4 Polycythemia vera: the natural history of 1213 patients fol-lowed for 20 years. Gruppo Italiano Studio Policitemia. Ann Intern Med 1995; 123: 656-664

5 Oishi N, Swisher SN, Stormont JM, Schwartz SI. Portal hy-pertension in myeloid metaplasia. Report of a case without apparent portal obstruction. Arch Surg 1960; 81: 80-86

6 Blendis LM, Banks DC, Ramboer C, Williams R. Spleen blood flow and splanchnic haemodynamics in blood dyscra-sia and other splenomegalies. Clin Sci 1970; 38: 73-84

7 Shaldon S, Sherlock S. Portal hypertension in the myelopro-liferative syndrome and the reticuloses. Am J Med 1962; 32: 758-764

8 Lukie BE, Card RT. Portal hypertension complicating my-elofibrosis: reversal following splenectomy. Can Med Assoc J 1977; 117: 771-772

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