PRACTICAL GASTROENTEROLOGY • NOVEMBER 200332

INTRODUCTION

M yelofibrosis also known as agnogenic myeloidmetaplasia is a disorder of multipotenthematopoieitic stem cell of unknown etiology

characterized by bone marrow fibrosis, splenomegaly,

extramedullary hematopoeisis, and myeloid metapla-sia with a leukoerythroblastic blood smear. Mostpatients are asymptomatic in the early phases of thedisease and are diagnosed after further evaluation forincidentally detected splenomegaly on physical exam.Some patients may present with the hematologicalmanifestations of the disease, or with abdominalsymptoms related to the mass effect of an enlargedspleen (1), or with symptoms of a hypercatabolic statesuch as weight loss, fatigue, night sweats and lowgrade fever (2).

Others with myelofibrosis may present with ascitesand esophageal varices attributed to be secondary to por-tal hypertension (1). Rarely myelofibrosis may presentas ascites secondary to seeding of the peritoneum bymyelometaplastic cells.

New Onset Ascites Secondary toExtramedullary Hematopoiesis as an Initial Manifestation ofMyelofibrosis: A Case Report

A CASE TO REMEMBER

Sherif Saadeh, M.D. and Kevin Mullen, M.D., Depart-ments of Gastroenterology, Internal Medicine at theCleveland Clinic Foundation, Cleveland, Ohio, Divi-sion of Gastroenterology at MetroHealth Medical Cen-ter, Case Western Reserve University, Cleveland,Ohio. Rony Abou Jawde, M.D., Gabriel Bou Merhi,M.D., Tarun Mullick, M.D., Tarek Mekhail, M.D., TerryGramlich, M.D., Amjad El Mahameed, M.D., WilliamCarey, M.D., Departments of Gastroenterology, Inter-nal Medicine at the Cleveland Clinic Foundation,Cleveland, Ohio.

A 57-year old male presented with new onset ascites, lower extremity edema andsplenomegaly. Cytological analysis of the ascitic fluid revealed multinucleated giantcells consistent with megakaryocytes suggestive of extramedullary hematopoeisis. Liverbiopsy confirmed the presence of extramedullary hematopoiesis. Bone marrow biopsyrevealed myelofibrosis. The patient was treated conservatively for symptom relief.Ascites in myelofibrosis is most often attributed to portal hypertension and is consid-ered a late presentation of the disease. After careful workup, the ascites in this case wasattributed to be secondary to peritoneal implants of hematopoietic stem cells andextramedullary hematopoeisis secondary to myelofibrosis. As such extramedullaryhematopoeisis should be considered under the differential diagnosis of ascites.

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by Sherif Saadeh, Kevin Mullen, Rony Abou Jawde, Gabriel Bou Merhi, Tarun Mullick,Tarek Mekhail, Terry Gramlich, Amjad El Mahameed, William Carey

PRACTICAL GASTROENTEROLOGY • NOVEMBER 200334

CASE REPORTA 57-year-old male was admitted to theCleveland Clinic Foundation in March2001 with new onset ascites. He was in hisusual state of health until December 2000when he started complaining of increasedabdominal girth, lower extremity edema,and generalized weakness. He denied anyhistory of fever, night sweats, nausea,vomiting, melena or rectal bleeding. Hehad no prior history of blood transfusion,alcohol intake, or exposure to tuberculardisease. He stopped smoking twenty yearsago. He reported no family history of can-c e r, hematological, or liver diseases.

On physical exam, he had stable vitalsigns and was afebrile. He had non-ictericsclera. Heart and lung exam were unre-markable. His abdomen was tensely dis-tended with positive fluid shift, with superficial venouscollaterals, but no spider angiomata. He had evidence ofsplenomegaly at 15 cm below left subcostal margin, buthe had no palpable liver. Neurological exam was grosslyn o n - f o c a l .

Blood chemistry revealed the following: Whiteblood cell count 10.39 K/uL with 12% metamyelo-cytes, 3% blasts, 5% nucleated red blood cells. Hemo-globin 9.2gm/dL, platelet count 113k/uL. Blood smearshowed neutrophilic leukocytosis with left shift,leukoerythroblastic changes, thrombocytopenia. Hisbasic metabolic profile and liver function test werewithin normal limits. He had negative viral serology.

An abdominal paracentesis was done and six litersof ascitic fluid were drained. Analysis of the asciticfluid revealed the following: • Red blood cells: 3900, white blood cells: 900 (neu-

trophils 15%, lymphocytes: 35%, monocytes: 42%,reactive 5%, rare megakaryocytes, reactive lympho-cytes).

• Proteins: 2.8 g/dL, Glucose 160 mg/dL, LDH: 454u/L, albumin: 1.2, Serum albumin ascitic gradient(SAAG) = 1.7.

• Cytology: Negative for malignant cells, howeverthere was evidence of multinucleated giant cells con-sistent with megakaryocytes (Figure 1); findings sug-gestive of extramedullary hematopoeisis.

• Cultures (including bacterial, fungal and mycobacte-rial) were negative.

Echocardiogram was within normal limits. Ultra-sound of the abdomen showed patent hepatic vascula-ture, large volume ascites, and a normal liver textureand size. The spleen was enlarged with sagittal dimen-sions estimated at 26–27 cm. Computerized tomogra-phy scan of the abdomen (Figure 2) revealed ascites,splenomegaly, and evidence of mesenteric strandingand peritoneal nodularity consistent with peritonealcarcinomatosis Trans-jugular liver biopsy with pres-sure measurements showed the following results: rightatrium pressure: 12 mmHg, IVC: 14 mmHg, righthepatic venous pressure; 12 mmHg, wedge hepaticvenous pressure; 20 mmHg, corrected wedge/gradient;8 mmHg; findings not consistent with portal hyperten-sion. The right hepatic vein was widely patent. Liverbiopsy revealed normal hepatic parenchyma withoutevidence of fibrosis and clusters of cells infiltrating thesinusoids compatible with extramedullaryhematopoeisis (Figure 3) . Peripheral smear, bone mar-row aspirate and biopsy were diagnostic of myelofi-brosis (Figure 4).

The patient was managed conservatively withdiuretic therapy and large volume paracentesis. Afterdiscussing various palliative measures, he elected not

A CASE TO REMEMBER

New Onset Ascites Secondary to Extramedullary Hematopoiesis

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Figure 1. Ascitic fluid cytology showing multinucleated giant cells consistentwith megakaryocytes.

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PRACTICAL GASTROENTEROLOGY • NOVEMBER 2003 37

A CASE TO REMEMBER

New Onset Ascites Secondary to Extramedullary Hematopoiesis

to have radiation therapy or any other therapy at thispoint of time.

DISCUSSIONAround 10% of patients with myelofibrosis may presentwith ascites, and a similar percentage of patients maypresent with portal hypertension and evidence ofesophageal varices as a complication of their disease (3).

Symptomatic ascites as the initial presentation ofmyelofibrosis is rare (1). Multiple theories have beenproposed to explain ascites in the setting of myelofi-brosis. Portal hypertension as an etiology was consid-ered. One of the contributing factors for the portalhypertension can be the increased blood flow throughthe portal system, so called "forward hypertension"(1). The increased blood flow may be due tosplenomegaly, where flow in the splenic vein mayincrease to 3000 mL/minute from a normal value of100 mL/minute as the size of the spleen increases (4).However this alone cannot entirely account for theascites especially that ascites occurs even in splenec-tomized patients with myelofibrosis (5). On the otherhand, portal pressure measurements before and aftersplenectomy suggested a major role of enlarged spleenand hence increased blood flow as a factor in thedevelopment of portal hypertension (6,7).

Another theory is portal hypertension secondary toportal vein thrombosis or Budd Chiari syndromewhich may occur more frequently in patients withmyelofibrosis given their increased clotting tendency,hence increasing resistance to splanchnic blood flow(8). However several case reports of patients withascites and myelofibrosis including our case did notshow evidence of venous thrombosis (9).

A third theory for portal hypertension has beenproposed suggesting that extensive portal zone infiltra-tion by primitive hematopoeitic cells might causeintrahepatic perisinusoidal obstruction and secondaryhypertension (10). However in those cases described,the wedge hepatic venous pressure was normal butintrasplenic pressure was increased.

More rarely, widespread thrombotic occlusionscan cause obliterative portal venopathy secondary tosmaller portal vein radical involvement, eventuallyleading to a nodular regenerative hyperplasia onpathology, causing increased portal outflow resistanceand sinusoidal hypertension (11).

Myelofibrosis is characterized by extramedullaryhematopoeisis mostly of the reticuloendothelial organssuch as spleen, liver and lymph nodes causing thehepatosplenomegaly (12). However organs such ask i d n e y, pancreas, adrenals, heart retroperitoneum,stomach, epididymus, gall bladder, ovaries, skin as

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Figure 3. H&E stain of liver biopsy revealing normal hepaticparenchyma and cluster of cells infiltrating the sinusoidscompatible with extramedullary hematopoiesis.

Figure 2. CT abdomen revealing splenomegaly, ascites,mesenteric stranding and peritoneal nodularity. Liverappears normal in texture.

PRACTICAL GASTROENTEROLOGY • NOVEMBER 200338

well as pleura and omentum can also be involved (13).Hence extramedullary hematopoiesis and ectopicimplants in the peritoneum can explain ascites forma-tion. The occurrence of such condition is rare andmore rarely is the occurrence of ascites fromextramedullary hematopoisis as the initial presentationof myelofibrosis (1,14).

Some reports suggested the peritoneal involvementcould be as a result of minute spontaneous splenic rup-tures (5). Silverman, et al described ectopic multi-cen-tric myeloid metaplasia of the omentum in patients withintact splenic capsule (12). Others described these focias "metastatic lesions"(1), causing ascites by obstruc-tion of lymphatic ducts by extra medullary foci, or byincreased permeability of the capillaries (1). However,in order to explain the characteristic and diagnosticcytological findings of ascites secondary toextramedullary hematopoiesis, Silverman, et al alsosuggested that the most likely mechanism of ascitesformation is desquamation or exfoliation of themyeloid and megakaryocyte cells into the peritoneum.

Megakaryocytes in the peritoneum and the asciticfluid are rarely found, and are highly suggestive ofperitoneal extramedullary hematopoeisis (5). As

described previously, in almost 5000 peritoneal andpleural fluid samples, only 5 had megakaryocytesamong which 3 had myelofibrosis, 1 had lymphoma,and 1 had chronic myelogenous leukemia (5). As such,cytological analysis should be performed in all casesof ascites and myelofibrosis.

Based on the above-proposed mechanisms, it isevidently very important to determine the factors con-tributing to the ascites in myelofibrosis because differ-ent etiologies are usually treated differently.

Several treatment options were used to treat themyelofibrosis and its complications, but usually mostof the treatment for myelofibrosis is only supportiveand palliative. Splenectomy, in good surgical candi-dates, was used for refractory anemia, symptom con-trol, and the relief from symptomatic splenomegalyand portal hypertension, yet this modality was not verye ffective (15). Some, however, contributed theincreased aggressiveness of myelofibrosis to splenec-tomy (2). Alkylating agents such as hydroxyurea orbusulfan were used for hematologic control of diseaseas well as symptom control and ascites formation, yetnone was really effective (1,16).

A CASE TO REMEMBER

New Onset Ascites Secondary to Extramedullary Hematopoiesis

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Figure 4. A+B: Peripheralsmear showing megakary-ocyte, tear drop RBC's, reac-tive lymphocytes. C+D+E:Bone marrow biopsy H&E/trichome stain showing marrow spaces extensivelyreplaced by fibrous tissuewith associated osteosclero-sis and panhypoplasia con-sistent with myelofibrosis.A C

D E

B

PRACTICAL GASTROENTEROLOGY • NOVEMBER 200340

Hematopoietic tissues, whether in bone marrow orat extramedullary sites, are highly sensitive to radiationt h e r a p y. Radiation therapy may be very useful in treat-ing symptomatic non-hepatosplenic extramedullaryhematopoiesis, such as patients with spinal cord com-pression, or even with pleural or peritoneal involve-ment (2,5,16–18).

In one study, 23 patients with myelofibrosis andmyeloid metaplasia, splenic irradiation resulted in tran-sient reduction in size of spleen in more than 90% ofpatients, for a mean duration of six months, yet 26%had severe myelosuppression (2). They reported that62% of patients treated with radiotherapy for sympto-matic hepatomegaly, with or without ascites, becamecytopenic and 2 patients died as a consequence. Theobjective response was not always present although themajority of patients had subjective relief; these symp-toms were short lived, for a median of 3 months with-out affecting survival favorably (2). On the other hand,this study did not evaluate the role of radiotherapy inearlier stages of myelofibrosis with peritoneal implantsand secondary ascites. One reported case of intractableascites in myelofibrosis was successfully treated with aLeveen shunt (19). Others reported a case of ascitessecondary to extramudullary hematopoiesis of the peri-toneum with rapid symptomatic relief after treatmentwith intraperitoneal Ara-C (14). Lukie, et al describedresolution of ascites and gastroesophageal varices in apatient with myelofibrosis and myeloid metaplasia withintractable ascites following splenectomy (20).

Untill now, no specific and effective treatment hasbeen shown to have a sustained response and favorableeffect on survival for patients with ascites secondary tomyelofibrosis.

CONCLUSIONOur patient presented with new onset ascites, which isan unusual initial manifestation of myelofibrosis.There was no evidence of liver, heart or kidney dis-ease. Cytological analysis of the ascitic fluid suggestedextramedullary hematopoeisis. Liver biopsy confirmedthe presence of extramedullary hematopoiesis. Bonemarrow biopsy revealed myelofibrosis. The patientwas treated conservatively for symptom relief. Thisdemonstrates the need to include extramedullary

hematopoeisis under the differential diagnosis ofpatients presenting with ascites, although it is rare inthis context. ■

References1 . Szu-Chun H, Ming-Lih H, Shian-Min L, et al. Massive Ascites

Caused by Peritoneal Extramedullary Hematopoiesis as the InitialManifestation of Myelofibrosis. Am J Med Sci, 1999; 318(3): 198-2 0 0 .

2 . Tefferi A, Jimenez T, Gray LA, et al. Radiation Therapy for Symp-tomatic Hepatomegaly in Myelofibrosis with Myeloid Metaplasia.Eur J Haematol, 2 0 0 1 : 6 6 : 3 7 - 4 2 .

3 . Ward HP, Block MH. The Natural History of Agnogenic MyeloidMetaplasia (AMM) and a Critical Evaluation of its Relationshipwith the Myeloproliferative Syndrome. M e d i c i n e , 1971; 50:73-84.

4 . Dudley F, Cebon J, Ireton H. A 70 Year Old Man With PortalHypertension. Aust NZ J Med, 1985; 15:461-467

5 . Ilana O, Adriana G, Nuhad H, et al. Ascites and Pleural EffusionSecondary to Extramedullary Hematopoiesis. Am J Med Sci, 1 9 9 9 ;318(4): 286-288.

6 . Sullivan AS, Rheinlander H, Weintraus LR. Esophageal Varices inAgnogenic Myeloid Metaplasia: Disappearing after Splenectomy.Gastroenterology, 1974; 66: 429.

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10. Shaldon S, Sherlock S. Portal Hypertension in MyeloproliferativeSyndrome and the Reticuloses. Am J Med, 1962; 32:758-764.

11. Wanless IR, Godwin TA, Allen F, et al. Nodular RegenerativeHyperplaisa of the Liver in Hematologic Disorder; a PossibleResponse to Obliterative Portal Venopathy. A MorphometricStudy of Nine Cases with an Hypothesis on the Pathogenesis.Medicine, 1980; 50:367-379.

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1 3 . Pitcock JA, Renhard EH, Justin BW, et al. A Clinical and Patholo-logical Study of Seventy Cases of Myelofibrosis. Ann Intern Med,1962; 57:73-84.

1 4 . Stahl RL, Hoppstein L, Davidson TG. Intraperitoneal Chemother-apy with Cytosine Arabinoside in Agnogenic Myelofibrosis withMyeloid Metaplasia and Ascites due to PeritonealExtramedullary Hematopoiesis. Am J of Hematology, 1993; 43(2): 156-157.

15. Glew R, Haese W, Mcintyre P. Myeloid Metaplasia withMyelofibrosis. The clinical Spectrum of ExtramedullaryHematopoiesis and Tumor Formati o n . Johns Hopkins MedicalJournal, 1973; 132 (5): 253-270.

1 6 . Patel N, Kurtides S. Ascites in Agnogenic Myeloid Metaplasia.Association with Peritoneal Implant of Myeloid Tissue and Ther-apy. Cancer. 1982; 50:1189-1190.

1 7 . Crawford DC, Nightingale S, Bates D, et al. Spinal Cord Com-pression by Extramedullary Hematopoiesis in Myelofibrosis. P o s t -grad Med J, 1984; 60:62-63.

1 8 . Jacobs P, Wood L, Robson S. Refractory Ascites in the ChronicMyeloproliferative Syndrome: A Case Report. Am J of Hematol -o g y , 1991; 37:128-129.

1 9 . Kiat H, Van Der Weyden M, Jakobovits A, et al. IntractableAscites in Idiopathic Myelofibrosis. Med J Aust, 1983; 2: 144-145.

2 0 . Lukie B, Card R. Portal Hypertension Complicating Myelofibrosis:Reversal Following Splenectomy. CMAJ, 1977; 117(7): 771-772.

A CASE TO REMEMBER

New Onset Ascites Secondary to Extramedullary Hematopoiesis

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