DIAGNOSIS IN ONCOLOGY

Arthur Skarin, MD, Consultant Editor

Challenging and Unusual Cases

CASE 1. SIMULTANEOUS PRESENTATION OF ACUTE MYELOGENOUS LEUKEMIA AND ACUTE MYOCARDIAL INFARCTION

A 54-year-old male presented with a history of generalized myalgia and low back pain for 6 weeks and one episode of epistaxis on the day of admission. Past medical history was signicant for diabetes mellitus type II and alcoholism. He also had a 30-year history of smoking. He denied any shortness of breath, orthopnea, and paroxysmal nocturnal dyspnea. Physical examination revealed normal vital signs and petechiae on the soft palate. Initial laboratory work-up was signicant for a low platelet count of 63,000/UL and hematocrit of 41.4%, and WBC count was 9,400/UL with metamyelocytes (1%), myelocytes (1%), and atypical monocytes (20%). Blood chemistry was normal except for a lactic dehydrogenase level of 3,706 U. Peripheral blood smear revealed metamyelocytes, myelocytes, atypical monocytes, and marked thrombocytopenia. Twenty-four hours after admission, the patient developed excruciating chest pain. His electrocardiograph showed ST segment elevation in inferior leads (II, III, AVF) and lateral leads (V5, V6) consistent with inferolateral myocardial ischemia. His cardiac enzymes became elevated (serum troponin-I was initially 154, later 358 U). Echocardiography showed depressed left ventricular systolic function, ejection fraction of 47%, and hypokinesia of interventricular septum. He was administered oxygen, nitrates, beta-blocker, aspirin, angiotensin-converting enzyme inhibitor, and morphine. Thrombolytic therapy was not administered because of thrombocytopenia and increased risk of hemorrhage. He was evaluated with cardiac catheterization that revealed a thrombus in right coronary artery and inferolateral infarction. Further management was initiated. A bone marrow aspirate and biopsy performed for evaluation of thrombocytopenia and abnormal peripheral smear showed diffuse inltration by sheets of atypical mononuclear cells with nely dispersed chromatin, prominent nucleoli, abundant mitotic gures, and hypercellularity in keeping with acute myelogenous leukemia (AML), subclass acute myelomonocytic leukemia (World Health Organization classication M4; Figs 1 and 2). These myeloid cells stained positive with myeloperoxidase, lysozyme, and CD68 immunohistochemical stains, characteristic for myelomonocytic differentiation. Further management of his acute myocardial infarction (MI) and AML was initiated. 1 AML is the most frequently occurring form of acute leukemia in adults. It is a stem-cell disorder of the hematopoietic system. Displacement of normal hematopoiesis characterized by symptoms of bone marrow insufciency such as anemia, other cytopenias, and circulating leukemic blasts is the result of expansion of the malignant cell clone. Extramedullary organ inltration occasionally 2 occurs in advanced stages. In a majority of patients with AML, the initial symptoms (such as fever, weakness, night sweat, infections, and bleeding) are present only for a short duration before presentation. The new World Health Organization classication 3 divides AML into four different groups. In the rst group are patients with balanced cytogenetic abnormalities such as t8;21, t15;17, inv 16, and 11q23 aberrations. In the second group, patients with no dysplasia and one lineage dysplasia are distinguished from those with two or three lineage dysplasias. The third group includes all cases of secondary AML. All other AMLs are combined into group 3 four. Using this classication in an analysis of 614 patients with de novo AML, Haferlach reported that cytomorphologic features including dysplasia demonstrate only limited prognostic differences in de novo AML. Cytogenetic proles provide a much better

Fig. 1. Bone marrow biopsy (low-power view), showing hypercellularity and diffuse inltration by sheets of atypical mononuclear cells with abundant mitotic gures.

Fig. 2. Bone marrow biopsy (high-power view), revealing atypical large, immature myeloid cells with abundant gray cytoplasm, nely dispersed chroma, increased nuclear-cytoplasmic ratio, and prominent nucleoli.

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Journal of Clinical Oncology, Vol 21, No 7 (April 1), 2003: pp 1416-1421 Downloaded from jco.ascopubs.org on May 17, 2012. For personal use only. No other uses without permission. Copyright 2003 American Society of Clinical Oncology. All rights reserved.

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basis for distinguishing prognostic groups in AML. The malignant cells in most patients with AML have clonal chromosomal abnormalities that are acquired and not random. In some cases, specic cytogenetic abnormalities are closely, and sometimes uniquely, associated with morphologically and clinically distinct subsets of the disease. In addition to establishing the type of AML, specic cytogenetic abnormalities have diagnostic, prognostic, and therapeutic importance. Complete remission is the target of chemotherapy in acute leukemia. Anthracycline-induced cardiotoxicity has been reported in patients receiving standard doses of 4,5 anthracyclines to treat AML. 1 MI as an initial presentation of acute leukemia has been reported only rarely. Many pathologic causes of acute MI without atherosclerosis have been described. In connection with acute leukemia, the following trigger mechanisms for MI and various electrocardiographic changes have been reported: leukemic inltration into the myocardium or pericardium, effects of the antileukemic therapy such as chemotherapy or radiation therapy, occlusion of a major coronary artery by leukemic thrombus, secondary disorders of coagulation caused by leukemic process, with embolization in a hypercoagulable state or hemorrhages in the myocardium or intima of a coronary artery, disseminated intravascular coagulation, thrombocytopenia, hyperbrinolysis, and deciency of coagulation factors. Atherosclerosis is generally asymptomatic until plaque stenosis exceeds 70% or 80%, which can produce a critical reduction in ow to the myocardium. These large lesions can produce typical symptoms of angina pectoris. However, clinical studies indicate that acute coronary and cerebrovascular syndromes are caused by rupture of atherosclerotic plaques with less than 50% stenosis. It has been postulated that coronary vasospasm plays a role in occlusive coronary thrombosis, contributing to the occurrence of an acute coronary syndrome. Vasospasm may be provoked by vasoactive substances, such as serotonin or histamine, which are released from activated platelets or by inammatory cells, including mast cells, which accumulate in coronary plaques at the site of rupture. In a patient with an acute promyelocytic leukemia presenting as acute MI, a brin platelet 6 thrombus was demonstrated postmortem in the anterior descending branch of left coronary artery. In another case report, a 42-year-old man presented with an anterior AMI and revealed an AML-M2 (World Health Organization classication M2) on 1 peripheral smear and bone marrow examination. The patient described in this report has an unusual acute simultaneous presentation of MI and AML. Hassan Pervez, Anil Potti, and Syed A. Mehdi Department of Internal Medicine, University of North Dakota School of Medicine and Health Sciences, Fargo, ND Copyright 2003 American Society of Clinical Oncology
REFERENCES
1. Jachmann-Jahn U, Cornely O, Laufs U, et al: Acute anterior myocardial infarction as rst manifestation of acute myeloid leukemia. Ann Hematol 80:677-681, 2001 2. Scheinberg DA, Golde DW: The leukemias, in Harrisons Principles of Internal Medicine. New York, NY, McGraw Hill, 1994, pp 1764-1774 3. Haferlach: The new WHO Classication. Ann Hematol 80:9, 2001 (suppl 2) 4. Federman DG, Henry G: Chemotherapy induced myocardial necrosis in a patient with chronic lymphocytic leukemia. Respir Med 91:565-567, 1997 5. Shan K, Lincoff M, Young JB: Anthracycline induced cardiotoxicity. Ann Intern Med 105:67-81, 1996 6. Solomons HD, Stanley A, King PC, et al: Acute promyelocytic leukemia associated with acute myocardial infarction. S Afr Med J 70:117118, 1986

DOI: 10.1200/JCO.2003.06.168

CASE 2. CONCURRENT GASTROINTESTINAL STROMAL TUMOR AND BURKITTS LYMPHOMA

A 76-year-old human immunodeciency virusnegative Chinese woman presented with intestinal obstruction. Laparotomy showed a 10 8 cm eshy tumor encasing multiple small intestinal segments (Fig 1A), with no retroperitoneal lymphadenopathy. A gastrojejunal bypass and biopsy was performed, revealing a gastrointestinal stromal tumor (GIST). The cells expressed CD34, CD117 (c-kit), c-myc (Fig 1B), and frequently Ki67, but were negative for Epstein Barr virus encoded RNA and other lineage markers. One month after surgery, she developed an 8-cm rapid growing jaw mass (Fig 1C), with elevated lactate dehydrogenase level (1,100 U/L). A biopsy showed Burkitts lymphoma (BL), positive for c-myc (Fig 1D), Ki67, CD10, CD20, and surface immunoglobulin, but negative for EBER, c-kit, CD34, and terminal deoxynucleotidyl transferase. She was treated with cyclophosphamide, vincristine, methotrexate, and prednisolone (COMP) chemotherapy with complete disappearance of the jaw mass after the rst dose. A lumbar puncture and marrow biopsy were normal. She was treated with six once-monthly cycles of COMP with intrathecal methotrexate. Reassessment computerized tomography scan showed no evidence of GIST or BL at 6 months. 1 Sporadic Burkitts lymphoma is uncommon in Chinese, and 73% of cases are Epstein-Barr virus (EBV)-negative. The markers 2 c-myc and Ki67 occur in 47% of GIST cases and are associated with aggressive disseminated disease. Our novel patient case with near-concomitant aggressive c-mycrelated GIST and BL in an immunocompetent patient raise several interesting points. First, the clustering of two short-latency malignancies is unlikely to be a chance occurrence. Both tumors were EBV-negative, in contrast to 3 opportunistic human immunodeciency virusrelated GIST and BL in immunocompromised hosts. Although lymphoma with c-kit 4 mutation has been reported, c-kit was not expressed by our BL case. In the absence of apparent tumor-prone phenotype and common 5 etiology, an immune trigger (eg, major abdominal surgery) is a plausible link. The presence of unknown BL trigger factors is 6 evidenced from the time and place clustering of African BL cases. We have previously reported aggressive natural killer lymphoma
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Fig. 1. (A) Computer tomography scan of intestinal tumor; (B) c-myc expression in malignant gastrointestinal stromal tumor cells; (C) coronal section of rapid enlarging facial mass; (D) uniform expression of c-myc in Bukitt lymphoma cells.

triggered by resection of colonic carcinoma. Second, in all patients with known primary malignancy, secondary tumor masses withunusual location, growth, and treatment responses should always undergo biopsy for concurrent second malignancies. Finally, complete response of GIST to combination chemotherapy is rare, and the optimal regimen is undened. Recently, the novel tyrosine kinase inhibitor imatinib mesylate (Gleevec [Novartis, Basel, Switzerland], STI-571) have shown promising results in patients with 8 advanced GIST. However, complete response was rare, and early resistance is not uncommon. Our experience indicated that in c-myc expressing GIST, a cyclophosphamide/methotrexate-based regimen may be an additional option. W.Y. Au, W.M. Wong, U.S. Khoo, and R. Liang Departments of Medicine and Pathology, Queen Mary Hospital, Hong Kong Copyright 2003 American Society of Clinical Oncology
REFERENCES
1. Chan JK, Tsang WY, Ng CS, et al: A study of the association of Epstein-Barr virus with Burkitts lymphoma occurring in a Chinese population. Histopathology 26:239-245, 1995 2. Panizo-Santos A, Sola I, Vega F, et al: Predicting metastatic risk of gastrointestinal stromal tumors: Role of cell proliferation and cell cycle regulatory proteins. Int J Surg Pathol 8:133-144, 2000 3. Kubben FJ, Kroon FP, Hogendoorn PC, et al: Absence of Epstein-Barr virus (EBV) in a gastrointestinal stromal cell tumour (GIST) in an adult human immunodeciency virus-seropositive patient with past EBV infection. Eur J Gastroenterol Hepatol 9:721-724, 1997 4. Kuwahara Y, Hirata A, Miwa H, et al: Epstein-Barr virus associated B-cell lymphoma of brain developing in myelodysplastic syndrome with c-kit mutation (Try-557 - stop). Am J Hematol 65:234-238, 2000 5. Au WY, Yeung CK, Chan HH, et al: Cutaneous CD30-positive T cell lymphoma with concurrent solid tumor. Br J Dermatol 146:10911095, 2002 6. van den Bosch C, Hills M, Kazembe P, et al: Time-space case clusters of Burkitts lymphoma in Malawi. Leukemia 7:1875-1878, 1993 7. Chim CS, Au WY, Shek TW, et al: Primary CD56 positive lymphomas of the gastrointestinal tract. Cancer 91:525-533, 2001 8. Demetri GD, von Mehren M, Blanke CD, et al: Efcacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472-480, 2002

DOI: 10.1200/JCO.2003.05.181

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CASE 3. PERITONEAL CYSTIC MESOTHELIOMA

A 50-year-old man presented with diffuse abdominal discomfort and increasing distension. He had undergone umbilical herniorrhaphy 18 months previously and was found to have ascites. Subsequent laparoscopy revealed multiple cystic lesions that were biopsied, and histopathologic diagnosis of peritoneal cystic mesothelioma was conrmed by immunocytochemistry. Computed tomography scan of the abdomen showed massive accumulation of multiloculated ascitic uid with compartmentalization of the small bowel (Fig 1). At surgical exploration, there was a conglomeration of cystic structures contained within the greater omentum ranging in size from 1 mm to 10 cm in diameter, lling the abdomen and pelvis. The greater omentum was most extensively involved (Fig 2). The parietal peritoneal surfaces contained small nodules that could be debrided away. The surface of the liver, gallbladder, and spleen were free of tumor. There was no evidence of soft tissue invasion. A greater and lesser omentectomy, partial stripping of the right hemidiaphragm (to remove the tumor from the right retrohepatic space), pelvic peritonectomy, and left colectomy with primary anastomosis were performed with heated intraoperative intraperitoneal chemotherapy (doxorubicin and cis-platinum). A tumor specimen weighing approximately 18 lb was resected. Histopathologic analysis revealed variably sized coalescent cysts with brocollagenous walls lined by cuboidal mesothelial cells with mild atypia. No solid or tubulopapillary components were noted (Fig 3). Immunohistochemistry tests conrmed that the cyst lining cells were positive for vimentin, cytokeratins (monoclonal antibodies to lowmolecular-weight keratins CAM 5.2 and AE1/AE3) and stained strongly for calretinin and cytokeratin 5/6, consistent with a mesothelial origin. The primary differential diagnosis was lymphangioma; however, all endothelial markers were negative (factor 8, CD31, CD34). The patient required a second surgery at 24 hours postoperatively for a bile leak from the liver edge, which was sutured. The patient remains free of disease after 5 years and has no sign of recurrence clinically or on recent CT scan. Peritoneal cystic mesothelioma is a rare tumor for which pathophysiology remains equivocal and controversial. It occurs predominantly in young to middle-aged women; only 17% of these tumors occur in men. It is frequently associated with a positive history of previous abdominal surgery, pelvic inammatory disease, and leiomyoma of the uterus. No racial, genetic, or environmental (such as asbestos exposure) inuence has been reported. It is difcult to make a rm preoperative diagnosis of cystic mesothelioma. Computed tomography scan typically shows a well-dened, noncalcied, multiloculated mass. The cyst contents have a Hounseld density similar to that of water. The cyst walls are thin and enhance with contrast. 1 Weiss and Tavassoli reviewed 37 patient cases from the Armed Forces Institute of Pathology, Washington, DC, accumulated between the years 1972 and 1987. Although the cytopathology was bland and the inammatory changes marked, they suggested that

Fig. 1. Computed tomography scan of the abdomen, showing the pathognomic apearance of cystic peritoneal mesothelioma. A conglomerate of multiple thinwalled cysts occupies the abdomino-pelvic space.

Fig. 2. Intraoperative photograph, showing characteristic thin-walled cysts in the pelvis.

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Fig. 3. Histology showing variably sized coalescent cysts with bro-collagenous walls and attened cuboidal mesothelial cells.

this entity be regarded as a neoplastic rather than a reactive process. They noted recurrences and occasional transition to conventional 1 2 malignant mesothelioma. Ross et al reported 12 of 25 patients who developed a recurrence. Sometimes the lesions showed changes 2 suggestive of malignant mesothelioma. Lack of follow-up prevented a prognostic assessment. Immunohistochemical studies allow 3 the separation of reactive and neoplastic lesions. Cystic mesotheliomas are thought to be benign because they do not metastasize; however, they have a high propensity for local 4,5 6,7 recurrence. Recurrence may occur in 27% to 75% of the patients within 3 months to 22 years of the initial resection. The concept 8 of peritoneal stripping for these patients was introduced by Datta and Paty. Combined modality treatment with cytoreductive surgery plus heated intraoperative intraperitoneal chemotherapy may minimize the high risk of recurrence. The use of heated intraoperative intraperitoneal chemotherapy (procedure is in trials) may eradicate free tumor cells that implant and then progress over an extended 9 time. This strategy has been successful in the treatment of pseudomyxoma peritonei and may lead to prolonged disease-free survival for patients with cystic mesothelioma. Faheez Mohamed, Kaiumarz Sethna, Dominique Elias, and Paul H. Sugarbaker The Washington Cancer Institute, Washington Hospital Center, Washington, DC; and the Department of Surgical Oncology, Institut Gustave Roussy, Villejuif, France Copyright 2003 American Society of Clinical Oncology
REFERENCES
1. Weiss SW, Tavassoli FA: Multicystic mesothelioma: An analysis of pathological ndings and biologic behavior in 37 cases. Am J Surg Pathol 12:737-746, 1988 2. Ross MJ, Welch WR, Scully RE: Multilocular peritoneal inclusion cysts (so-called cystic mesotheliomas). Cancer 64:1336-1346, 1989 3. Cusatelli P, Altavilla G, Marchetti M: Benign cystic mesothelioma of peritoneum: A case report. Eur J Gynaecol Oncol 18:124-126, 1997 4. ONeill JD, Ros PR, Storm BL, et al: Cystic mesothelioma of the peritoneum. Radiology 170:333-337, 1989 5. Schneider JA, Zelnick EJ: Benign cystic peritoneal mesothelioma. J Clin Ultrasound 13:190-192, 1985 6. Katsube Y, Mukai K, Silverberg S: Cystic mesothelioma of the peritoneum: A report of 5 cases and review of literature. Cancer 50:16151622, 1982 7. Miles JM, Hart WR, McMahon JT: Cystic mesothelioma of the peritoneumReport of a case with multiple recurrences and review of the literature. Cleve Clin Q 53:109-114, 1986 8. Datta RV, Paty PB: Cystic mesothelioma of the peritoneum. Eur J Surg Oncol 23:461-462, 1997 9. Sugarbaker PH, Ronnett BM, Archer A, et al: Pseudomyxoma peritonei syndrome. Adv Surg 30:233-280, 1996

DOI: 10.1200/JCO.2003.06.167

CASE 4. MALIGNANT MESOTHELIOMA PRESENTING AS AN ANTERIOR MEDIASTINAL MASS

A 51-year-old nonsmoker was investigated for an abnormal preoperative chest x-ray. Symptoms were of intermittent right-sided chest pain, a dry cough, and hoarseness. The patient had no known exposure to asbestos. Chest x-ray revealed a mediastinal mass (Fig 1). A computed tompgraphy scan conrmed the presence of a large anterior mediastinal mass (Fig 2). A core biopsy showed a malignant epithelioid tumor with glandular and papillary differentiation (Fig 3A). Immunohistochemistry revealed positive staining for mesothelial markers including calretinin (Fig 3B), thrombomodulin, cytokeratin 5/6, Hector Battifora mesothelial epitope 1 (HBME-1; Dako [Sydney, Australia], dilution 1 in 5,000), and epithelial membrane antigen (membranous staining). Immunomarkers of adenocarcinomatous differentiation including carcinoembryonic antigen, Ber-EP4, CD15 (leuM1), and B72.3 were all negative. Electron microscopy conrmed the presence of mesothelial differentiation, and a diagnosis of malignant 1,2 mesothelioma (epithelioid type) was made. The patient was treated with external beam radiotherapy. Follow-up computed tomography imaging documented a good partial response with a reduction in tumor size from 8 7 7 cm to 3 4 5.5 cm.
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Fig 1.

Chest x-ray.

Fig 3. (A) Core biopsy showing glands lined by cytologically malignant epithelioid cells (hematoxylin and eosin; original magnication, 400 ). (B) Calretinin immunohistochemical stain showing nuclear and cytoplasmic positivity of the tumor cells (immunohistochemical section; original magnication, 400 ).

Fig 2.

Computed tomagraphy, chest.

Malignant mesothelioma typically presents with diffuse pleural thickening and recurrent pleural effusions. Rare cases of mesothelioma presenting as a localized pedunculated pleural-based lesion or sessile mass with broad-based pleural attachment have been described 4 5 previously; however, mesothelioma has never to our knowledge presented as a mediastinal mass. The relationship of localized mesothelioma to its more common diffuse counterpart and clinical behavior remain unknown. C. Featherstone, R. Scolyer, G. Hruby, M. Tin, E.J. Wills, and P.N. Hendel Royal Prince Alfred Hospital and Concord Repatriation General Hospital, Sydney, Australia Copyright 2003 American Society of Clinical Oncology
REFERENCES
1. Leong AS-Y, Stevens MW, Mukherjee TM: Malignant mesothelioma: Cytological diagnosis with histologic, immunohistochemical and ultrastructural correlation. Semin Diagn Pathol 9:141-150, 1992 2. Okamura H, Kamei T, Mitsuno A, et al: Localized malignant mesothelioma of the pleura. Pathol Int 51:654-660, 2001 3. Kawashima A, Libshitz HI: Malignant pleural mesothelioma: CT manifestations in 50 cases. Am J Roetgenol 155:965-969, 1990 4. Crotty TB, Myers JL, Katzenstein AA, et al: Localized malignant Mesothelioma: A clinicopathologic and ow cytometric study. Am J Surg Pathol 18:357-363, 1994 5. Mullen B, Richardson JD: Primary anterior mediastinal tumors in children and adults. Ann Thorac Surg 42:338, 1986

DOI: 10.1200/JCO.2003.03.115

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