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Carcinoma Cell Leukemia – an Acute Leukemia−Like

Picture Due to Osteoclast−Like Giant Cell Carcinoma

of the Pancreas

Obraz podobny do ostrej białaczki w przebiegu raka trzustki

podobnego do guza olbrzymiokomórkowego kości

1 _{Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University,}

Poland

2 _{Lower Silesia Center of Tuberculosis and Lung Diseases, Wrocław, Poland}

3 _{Second Department of General and Oncological Surgery, Wroclaw Medical University, Poland} 4 _{Department Gastrointestinal and General Surgery, Wroclaw Medical University, Poland} 5 _{Department of Pathological Anatomy, Wroclaw Medical University, Poland}

Adv Clin Exp Med 2009, 18, 2, 183–188 ISSN 1230−025X

LETTER TO EDITOR

© Copyright by Wroclaw Medical University

Abstract

Carcinocythemia is a rare complication of metastatic carcinoma characterized by the presence of carcinoma cells in the peripheral blood mimicking acute leukemia. Osteoclast−like giant cell tumor is a variant of ductal adenocar− cinoma of the pancreas with an aggressive course. A 33−year−old male was admitted to the Department of Hematology with anemia, thrombocytopenia, and 49% primitive cells in blood and 50% in bone marrow aspirate. Studies of cytochemical and immunologic markers ruled out a hematopoietic origin of the malignant cells. Laparotomy disclosed a pancreatic tumor which histological examination showed to be a pleomorphic giant cell carcinoma. The presented case is the first report of pleomorphic giant cell carcinoma of the pancreas which clini− cally manifested as acute leukemia (Adv Clin Exp Med 2009, 18, 2, 183–188).

Key words:carcinoma cell leukemia, carcinocythemia, osteoclastoma of pancreas, osteoclast−like giant cell tumor of the pancreas.

Streszczenie

Karcynocytemia jest rzadkim powikłaniem złośliwych nowotworów narządowych polegającym na obecności ko− mórek nowotworowych we krwi obwodowej, co przypomina obraz ostrej białaczki. Rak trzustki podobny do gu− za olbrzymiokomórkowego kości jest rzadką odmianą gruczolakoraka przewodowego trzustki o agresywnym przebiegu. 33−letni pacjent został przyjęty do Kliniki Hematologii z powodu niedokrwistości i małopłytkowości. We krwi obwodowej i szpiku stwierdzono obecność odpowiednio: 49 i 50% młodych komórek. Badania cytoche− miczne i immunologiczne wykluczały pochodzenie komórek z układu krwiotwórczego. Podczas laparotomii stwierdzono guz trzustki, który morfologicznie odpowiadał rakowi trzustki podobnemu do guza olbrzymiokomór− kowego kości. Przedstawiony przypadek jest pierwszym opisem raka trzustki podobnego do guza olbrzymioko− mórkowego kości, którego pierwszym objawem były zmiany przypominające ostrą białaczkę (Adv Clin Exp Med 2009, 18, 2, 183–188).

In 1932, Morrison described immature cells in the blood of cancer patients [1]. In 1976, Carey observed a leukemia−like blood picture due to cir− culating cancer cells (CCCs) during metastatic breast carcinoma [2]. This rare complication of carcinoma has been named “carcinocythemia”, or carcinoma−cell leukemia. It is probably caused by widespread infiltration of many bone marrow sites. Carcinocythemia as a result of sinusoidal infiltration of the liver and the release of CCCs from the visceral microcirculation in a patient with indolent breast cancer has also been described [3]. Virtually any tumor can metastasize to the bone marrow. According to the literature, the most com− mon neoplasms associated with circulating cancer cells in the peripheral blood were breast adenocar− cinoma, small−cell lung carcinoma, and rhab− domyosarcoma [4–6]. CCCs usually accounted for 10 to 80% of nucleated blood cells [2, 4]. Patients at the time of carcinocythemia were mostly in the terminal stage of the disease and survived for an average of a few days or weeks [4–6]. Carcinoma cell leukemia as the first manifestation of cancer is very rare. Hayashi et al. described two cases of rhabdomyosarcoma with bone marrow metastases which clinically manifested as acute leukemia at the time of diagnosis [7]. Nevertheless, Bonavina showed that a high percentage (79.1%) of patients with localized esophageal carcinoma had immuno− histochemically positive epithelial cells in the bone marrow at the time of operation [8].

Pancreatic adenocarcinoma is one of the most aggressive human malignancies. Because of its late clinical manifestation and rapid growth, it has been called a “silent killer”. Osteoclast−like giant cell carcinoma is a variant of ductal adenocarcino− ma of the pancreas. It comprises less than 1% of pancreatic cancers. The clinical course is extreme− ly aggressive, with most patients dying within one year. A patient with pleomorphic giant cell carci− noma of the pancreas which clinically manifested as acute leukemia is presented here. The authors are unaware of any similar case.

Case Report

A 31−year−old male patient with a history of nephrolithiasis was admitted to the Department of Hematology, Wroclaw Medical University, in October 2004 with anemia (Hb 7.4 g%), thrombo− cytopenia (PLT 56 109_{/l), and leukocytosis (WBC}

15.6 109_{/l) with a presence of immature white and}

red blood cells in the peripheral blood smear. The patient presented weakness and sweats, without weight loss or fever. A large tumor in the mid abdomen measuring 12 cm in diameter and with

smooth borders was examined; there were also an enlarged liver and spleen. In a peripheral blood smear, up to 49% atypical immature cells were found (Fig. 1A) and in hypercellular bone marrow 50% immature osteoclast−like giant cells with polymorphous nuclei, pleomorphic cells, and oval and spindle−shaped mononuclear cells, immuno− phenotypically CD45– _{(Fig. 1B). Immunohisto−}

chemical study of the bone marrow and peripheral blood revealed neoplastic cells that were CD2–_,

CD3–_{, CD5}–_{, HLADR}–_{, CD19}–_{, CD15}–_{, CD20}–_,

and CD23–_{, which excluded a hematological ori−}

gin. Furthermore, the cells were strongly immuno− reactive for vimentin and EMA (epithelial mem− brane antigen) but negative for LCA. The labora− tory data showed ALAT 153 U/l, LDH 3878 U/l, and increased bilirubin (1.29 mg%); the serum

Fig. 1. (A) Peripheral blood smear: atypical immature pleomorphic cells with navy blue cytoplasm and osteoclast−like multinuclear giant cells (May− Gruenwald−Giemsa stain), (B)Bone marrow smear: osteoclast−like multinuclear giant cell and spindle mononuclear cells (May−Gruenwald−Giemsa stain)

Ryc. 1. (A) Rozmaz krwi obwodowej: atypowe, nie− dojrzałe, pleomorficzne komórki z granatową cytopla− zmą i podobne do osteoklastów wielojądrowe komórki olbrzymie (barwienie May−Gruenwald−Giemsa),

(B)Rozmaz szpiku: podobne do osteoklastów wieloją− drowe olbrzymie komórki i jednojądrowe komórki wrzecionowate

A

concentrations of carcinoembryonic antigen (CEA), alpha−fetoprotein (AFP), carbohydrate antigen (CA 19−9), and prostate−specific antigen (PSA) were within the normal limits. Cytogenetic analysis was normal.

Ultrasonography (US) showed a large hypoe− choic tumorous mass in the region of the pancreas head and duodenal loop, 12 ×8 ×10 cm in size, extending to the mesenteric lymph nodes, a hepat− ic metastatic lesion measuring 3 × 1.5 cm, and hepatosplenomegaly. Low−flow color Doppler ultrasonography (CDUS) detected rich tumor vas− cularity. Moreover, magnetic resonance imaging (MRI) of the abdominal cavity demonstrated an irregular tumor adjacent in front to the rectus abdominal muscle, from behind to the anterior arm of Gerot’s fascia, and from above to the lower margin of the right liver lobe. The tumor was also adjoined to the abdominal aorta and vena cava inferior, but without their infiltration (Fig. 2). On gastroscopy, the tumor modeled from outside the pylorus and pressed against the duodenum bulb, without signs of high gastrointestinal tract occlu− sion.

The patient underwent laparotomy, but the tumor was unresectable due to massive infiltration

of adjacent organs, i.e. the stomach, duodenum hilus, gallbladder, pancreas, transverse colon, and mesentery (Fig. 3). A tumor segment was taken for histopathological examination. Moreover, side−to− side gastrojejunal anastomosis, side−to−side ileo− transversal anastomosis, and jejunojejunal anasto− mosis applying Braun’s method were performed.

The patient died due to cardiac arrest three days after surgery and three weeks after admis− sion. The resected specimen was a solid tumor with a cyst with bloody content. Pathological find− ings showed the tumor comprised osteoclast−like multinucleated giant cells with central nucleoli, pleomorphic cells, and oval and spindle−shaped mononuclear cells. The giant cells were positive for vimentin but negative for EMA and keratin. The tumor was diagnosed as a pleomorphic giant cell tumor of the pancreas (Fig. 4).

Discussion

Giant cell tumors resembling osteoclastomas of the bone have been reported to occur in certain extra−osseous sites, including the thyroid, liver, and pancreas [9–14]. Osteoclast−like cell carcino− mas of the pancreas are composed of malignant mononuclear, undifferentiated, round or spindle−

Fig. 2.MRI scan of the abdominal cavity: irregular tumor of the pancreas adjacent in front to the rectus abdominal muscle, from behind to the anterior arm of Gerot’s fascia, from above to the lower margin of the right liver lobe, and adjoined to the abdominal aorta and vena cava inferior, without their infiltration

Ryc. 2. MRI jamy brzusznej: nieregularny guz wywo− dzący się z trzustki przylegający od przodu do mięśnia prostego brzucha, od tyłu do przedniego ramienia po− więzi Gerota, od góry do dolnej granicy prawego płata wątroby i przylegający do aorty brzusznej i żyły czczej dolnej bez ich naciekania

Fig. 3.Unresectable tumor, massive infiltration to the stomach, duodenum hilus, gallbladder, pancreas, trans− verse colon, and mesentery

shaped cells associated with osteoclast−like giant cells. They have been classified as osteoclast−like giant cell tumors (OGCTs), which consist of osteo− clast−like multinucleated cells within mononuclear epithelial cells, or as pleomorphic giant cell carci− nomas (PGCCs), composed of atypical mononu− clear and multinuclear giant cells [15, 16]. According to Tschang and Trepeta, cytologically malignant giant cells form pleomorphic carcinoma and cytologically benign ones generate giant cell tumors (osteoclastoma) of the pancreas [11, 17]. Both types of pancreatic giant cell cancers have their origin in the pancreatic ductal or acinar epithelium [11].

The histogeneses of these two types of giant cell tumors and the distinction between OGCT and PGCC remains unclear. OGCT usually has a better prognosis than PGCC [15, 16]. The mononuclear cells have demonstrated epithelial characteristics in both electron−optic and immunocytochemical studies [18]. The epithelial nature of the neoplastic component is supported by their reactivity with epithelial markers, whereas they were negative for histiocytic markers (CD−68, lysozyme). In con− trast, osteoclast−like giant cells rarely stain posi− tive for epithelial markers. Their immunohisto− chemical profile supports a non−epithelial origin and suggests a derivation similar to that of giant cell tumor of the bone [19, 20]. Findings by Wueling on the nature of giant cell tumor of the bone indicated that the malignant mononuclear cells secrete differentiation factors (MCP1 – mono− cyte chemoattractant−1, and M−CSF – macrophage colony−stimulating factor) which are monocyte chemoattractants essential for osteoclast differen−

tiation and which stimulate blood monocyte migration into the tumor mass and enhance their fusion into osteoclast−like multinucleated giant cells [21]. Sun and Shiozawa suggested that circu− lating monocytic stem cells may be stimulated by local factors to proliferate and differentiate into osteoclast−like cells [22, 23].

According to Gocke, pancreatic giant cell tumors, whether of the pleomorphic or osteoclas− toma type, carry mutations in their KRAS onco− gens, similarly to duct adenocarcinoma [24]. The absence of KRAS mutations in each of the malig− nant fibrous histiocytomas may provide assistance in the differential diagnosis of pleomorphic pan− creatic tumors [25].

The presented case is the first pleomorphic giant cell carcinoma of the pancreas which devel− oped a large number of circulating carcinoma cells detectable in the peripheral blood and bone mar− row at diagnosis. On admission, bone marrow aspirate revealed extensive infiltration by 50% atypical blast−like cells, which was interpreted as acute leukemia. However, synchronous occur− rence of carcinoma (due to the presence of the abdominal tumor) and acute leukemia was also taken into consideration. A case with simultaneous metastatic epidermoid carcinoma and chronic myelogenous leukemia has been described [26]. Mishra et al. presented a case of breast carcinoma which was followed by acute leukemia within one month of diagnosis of the former [27]. In the patient of the present study, the cytochemical and immunological marker studies ruled out a hema− topoietic origin of the malignant cells and con− firmed a diagnosis of carcinocythemia of epithelial cells. Intraoperative management was complicated by the tense structure of the tumor, filling the upper abdomen. En bloc resection was unfeasible because of the risk of tumor spill.

Pathological evaluation revealed a very unu− sual osteoclastic−like giant cell carcinoma of the pancreas, with the subform of pleomorphic giant cell carcinoma. In the presented patient the giant cells were morphologically malignant and, as in Fischer’s data, positive for vimentin but negative for EMA and keratin [28]. The histological picture of the tumor justified the diagnosis of pleomorphic giant cell carcinoma.

Since 1966, osteoclast−like giant tumor cells of the pancreas have been extremely rare and, in a review prepared by Shiozawa et al. in 2002, only 32 previously reported cases were mentioned [22]. Osaka in 2004 and Beaufort in 2005 described two successive patients with osteoclastic giant cell tumor of the pancreas [29, 30]. Of 17 men and 17 women aged 40–72 years (mean: 59 years) pre− sented in previous papers, most presented late and

Fig. 4.Multiple histological section from representa− tive areas of the tumor comprised osteoclast−like giant cells, pleomorphic cells, and oval and spindle−shaped mononuclear cells (hematoxylin−eosin stain)

advanced stages of disease. The leading symptoms at presentation were abdominal pain, a palpable tumor, weight loss, anorexia, and jaundice. Tumor diameters ranged from 4 to 24 cm. Lung, liver, and lymph nodes metastases were common. Only a few patients had hematological symptoms such as anemia and leukocytosis, with a maximum leukocyte count of 18.5 mm3_{, but none had car−}

cinocythemia. Twenty−two of all patients present− ed in the literature underwent surgery and 13 were alive at the time of their case reports. Mean sur−

vival was 20.4 months after surgery. Ten of 12 inoperable patients died. The patient of the pre− sent study was younger and without any gastroin− testinal disturbances; however, symptoms of leukemia were strongly presented. The tumor was inoperable at the time of diagnosis.

The rapid fatal outcome observed in this patient was in accordance with the very poor prog− nosis encountered in this rare carcinoma which develops this rare phenomenon of carcinoma cell leukemia.

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Address for correspondence:

Lidia Usnarska−Zubkiewicz Department of Hematology Wroclaw Medical University Pasteura 4

50−367 Wrocław Poland

Tel.: +48 71 784 01 12 E−mail: [email protected]

Conflict of interest: None declared