Systemic mastocytosis

The case of a 62-year-old man who presented with acute abdominal pain and a widespread tumor involving the retroperitoneum is described. Three weeks after initial presentation, the patient died suddenly of acute cardiac failure with signs of arrhythmia. Autopsy revealed a disseminated tumor with infiltration of the retroperitoneal fat, as well as nodules in the left testis and the right atrium. The tumor cells were reactive for CD45, vimentin, and chloroacetate esterase, but were unreactive with a broad spectrum of antibodies against myelomonocytic and lymphocytic antigens and with antibodies against tryptase and c-kit (CD117), which are characteristic markers for mast cells. However, the bone marrow exhibited the typical picture of mastocytosis, with disseminated clusters of differentiated spindle-shaped cells that stained strongly for tryptase, c-kit, and chloroacetate esterase. No infiltrates of well-differentiated mastocytosis could be detected in any of the extramedullary tissues investigated. A diagnosis of bone marrow mastocytosis with an associated undifferentiated extramedullary tumor of hemopoietic origin was established. By definition, the extramedullary tumor could not be diagnosed as a granulocytic sarcoma or (differentiated) mastocytoma, but the possibility that a mast cell progenitor could be involved in the evolution of both tumors cannot be ruled out.

(Arch Pathol Lab Med. 1997;121:423-426)

Mast cell proliferative disorders (MCPDs) are rare diseases characterized by an increase in mast cell numbers in various tissues. They present with an often complex clinical history that poses considerable diagnostic problems. The histopathologic diagnosis of MCPD is based on the finding of unequivocal evidence of abnormal proliferation of mast cells in certain organs, usually the skin and bone marrow, but also the liver, spleen, and lymph nodes.1-4 However, because the symptoms are mainly due to the abnormal release of mast cell mediators, attempts have also been made to diagnose MCPD purely on the basis of biochemical abnormalities related to the release of increased amounts of mast cell secretory products.5-7

A surprisingly frequent association of the systemic variants of MCPD with a broad spectrum of myeloproliferative and myelodysplastic syndromes has been noted.8 We describe a highly unusual case of MCPD. Although the typical picture of bone marrow mastocytosis was observed in autopsy specimens, the patient initially presented with disseminated tumor masses in the retroperitoneum, left testis, and heart. The tumor cells expressed only a limited range of antigens, namely CD45, chloroacetate esterase, and vimentin. The autopsy findings were summarized in the descriptive diagnosis as "bone marrow mastocytosis associated with a disseminated, undifferentiated extramedullary tumor of hemopoietic origin." The possibility that a mast cell progenitor could have been involved in the evolution of this tumor is discussed.

REPORT OF A CASE

A 62-year-old man presented with acute abdominal pain. Sonography revealed a retroperitoneal mass involving the kidneys and adrenals. Two small tumor nodules were also found in the left testis. There were no skin lesions and no hepatosplenomegaly. The laboratory findings were normal (white blood cells, 7.4 x 10^sup 9^ / L with a normal differential count; red blood cells, 5.31 x 10^sup 12^/L; and platelets, 248 x 10^sup 9^/L). Clinical diagnosis was that of a generalized malignancy of unknown origin, probably malignant lymphoma or metastasizing testicular cancer. Tissue was obtained from the retroperitoneal tumor by percutaneous needle biopsy, but only a very limited number of immunostains could be performed because of the very small size of this specimen, and a definitive diagnosis could not be established. A preliminary diagnosis of lymphoreticular neoplasia was made. There were no clinical signs of systemic release of large amounts of mast cell mediators, such as flushing, diarrhea, or hypotension. About 3 weeks after initial presentation, the patient's condition deteriorated rapidly. After several attacks of severe abdominal pain, he died with clinical signs of cardiac failure due to severe arrhythmia.

MATERIALS AND METHODS

All biopsy and autopsy specimens were fixed in 5% buffered neutral formalin, embedded in paraffin, and cut at 4 (mu)m. Sections were stained with hematoxylin-eosin, Giemsa, periodic acidSchiff (PAS), Gomori's silver impregnation, and the naphthol AS-D chloroacetate esterase reaction.9 Immunostaining with the antibodies shown in Table 1 was performed by the avidin-biotinperoxidase complex method.10

RESULTS

Autopsy Findings

Autopsy revealed large tumor masses (maximum dimension, 14 cm), which were of firm consistency and greyish-white in color, in the retroperitoneal and mesenteric fat, with infiltration of the kidneys, adrenals, and large bowel. An exophytic tumor nodule (maximum diameter, 3 cm) was also found attached to the interatrial septum and partially obstructing the orifice of the superior vena cava. Two tumor nodules (maximum diameter, 2.5 cm) were detected in the left testis. No gross lesions were found in the bone marrow of the spine, right femur, or ribs. The bone marrow exhibited a normal, reddish-brown color. The liver was not enlarged. The spleen weighed 240 g and exhibited no gross abnormalities. There were no macular or maculopapular skin lesions of urticaria pigmentosa. Marked generalized atherosclerosis and hypertrophy of the left ventricle (heart weight, 500 g) were also noted.

Histologic Findings

The biopsy specimen and autoptic tumor tissue from all sites (retroperitoneum, heart, and testis) consisted of dense sheets of small to medium-sized cells with round to ovoid nuclei, inconspicuous nucleoli, and a narrow rim of cytoplasm (Fig 1). A small proportion of the tumor cells were spindle-shaped and possessed fairly abundant pale cytoplasm. Scattered mitoses were seen. The tumor cells were surrounded by a dense network of reticulin fibers. Even after meticulous evaluation of Giemsa-stained sections, metachromatic granules could not be found in any of the tumor cells, but there was always a small proportion that exhibited a positive chloroacetate esterase reaction (Fig 2). Tumor cells from the various sites involved all exhibited the same phenotype. Out of the large panel of antibodies applied, they reacted only with anti-CD45 and antivimentin and showed no immunoreactivity for lymphocytic or myelomonocytic markers, such as lysozyme, myeloperoxidase, tryptase, or c-kit (CD117).

Bone marrow histology revealed completely intact hematopoiesis, with normal distribution of fat cells in most areas. However, disseminated, usually perivascular or peritrabecular clusters of spindle-shaped cells were seen. Most of these cells contained metachromatic granules and were strongly chloroacetate esterase positive (Fig 3). They also stained intensely for tryptase and c-kit (CD117). The nuclei were round or ovoid with a normal nucleocytoplasmic ratio. Lobated nuclei were not detected. Plasma cells, eosinophilic granulocytes, fibroblasts, and many lymphocytes were seen in the proximity of mast cell aggregates. Altogether, clusters of metachromatic cells occupied about 5% of the bone marrow spaces. No extramedullary infiltrates of mature mast cells, such as those seen in the bone marrow, were detected.

A diagnosis of disseminated bone marrow mastocytosis associated with an undifferentiated, extramedullary tumor of hemopoietic origin involving the retroperitoneum, heart, and testis was rendered. The cause of death was determined to be cardiac failure due to severe arrhythmia.

COMMENT

This report describes a unique case of MCPD in a 62-year-old man who presented with abdominal pain and a retroperitoneal tumor mass consisting of undifferentiated hemopoietic cells expressing CD45 and chloroacetate esterase. The patient died 3 weeks after initial presentation with signs of cardiac failure due to severe arrhythmia. Autopsy revealed extensive tumor masses in the retroperitoneum and tumor nodules in the heart and left testis. Bone marrow histology revealed the typical picture of differentiated mastocytosis with multifocal lesions.1 A diagnosis of bone marrow mastocytosis associated with an undifferentiated extramedullary tumor of hemopoietic origin was established.

Mast cells have a unique phenotype and can be discriminated from all other types of hemopoietic cells. In the case described, the mast cells in the bone marrow had the typical phenotype of differentiated (mature) mast cells in that they exhibited strong metachromasia and expressed tryptase, c-kit (CD117), and chloroacetate esterase, but not myeloperoxidase. By contrast, the cells of the extramedullary tumor did not contain metachromatic granules and did not express tryptase or c-kit, although a small proportion reacted positively for chloroacetate esterase. Since antibodies against tryptase and chymase have a very high sensitivity, expression of these mast cell antigens at low levels in the more malignant-appearing tumor cell population seems unlikely. Moreover, it is also unlikely that the lack of staining of tumor cells with the c-kit antibody applied is due to mutations in the c-kit proto-oncogene because functionally relevant mutations of c-kit have been detected in the kinase domain but not in the antibodybinding sites.11 The extramedullary tumor cells expressed no other hemopoietic markers, with the exception of CD45 (Table 1). These findings suggest this tumor was a very immature hemopoietic neoplasm, probably of myeloid origin, but the cell lineage involved could not be established with certainty.

In fact, it seems likely that there is some sort of relationship between the two tumors, particularly when one considers the well-recognized fact that there is a high incidence of other hemopoietic malignancies in systemic MCPD.8 It has been shown that patients with certain types of systemic MCPD, in particular malignant or aggressive mastocytosis (without cutaneous involvement), have a relatively high risk of developing hemopoietic malignancies, including acute and chronic myeloid leukemia, as well as myelodysplastic and myeloproliferative syndromes.7,8,12-14 Thus, it could be speculated that the extramedullary tumor may have represented a secondary process resulting from transformation and deregulation of a long-standing MCPD involving a mast cell progenitor. A second possibility is that the bone marrow mastocytosis might be a reactive process or an epiphenomenon related to the widespread extramedullary neoplasm. This possibility seems unlikely because the bone marrow exhibited the typical histologic picture of MCPD and, moreover, no mast cell infiltrates were found in the immediate vicinity of the undifferentiated neoplasm or at any other extramedullary site. However, it cannot be ruled out that the coexistence of the two hemopoietic tumors occurred purely by chance.

Because a minor fraction of the tumor cells expressed chloroacetate esterase, which is a reliable but not specific marker for tissue mast cells,9 the possibility that this was a true mast cell sarcoma must be considered, even though such tumors are extremely rare. To our knowledge, only one proven case of primary mast cell sarcoma in a human, which arose in the larynx, has been reported.15 We feel that undifferentiated hemopoietic sarcoma (possibly mast cell sarcoma) is probably the most appropriate diagnosis for the extramedullary tumor described in this case.

Another unusual aspect of this case is the fact that the patient exhibited some clinical features that are usually associated with indolent or benign MCPD (bone marrow histology with disseminated small clusters of mast cells and otherwise completely normal hematopoiesis; mature phenotype of strongly metachromatic mast cells with expression of tryptase, CD45, and CD117; normal blood picture; and absence of hepatosplenomegaly and lymphadenopathy), as well as others that are generally indicative of malignant or aggressive MCPD (lack of skin involvement, coexistence of a malignant hemopoietic tumor). To the best of our knowledge, no similar cases have ever been described. According to the currently used classification systems of human mastocytosis (Tables 2 and 3) this unique case could be categorized either as "mastocytosis with an associated hematologic disorder" (Table 2) or as the rare "systemic mastocytosis with a malignant hematologic disorder" (Table 3).

The authors thank H. Ableiter and A. Mall for excellent technical assistance and M. Ruck, MD, for help in preparation of the manuscript.

References

1. Horny H-P, Parwaresch MR, Lennert K. Bone marrow findings in systemic mastocytosis. Hum Pathol. 1985;16:808-814.

2. Horny H-P, Kaiserling E, Campbell M, Parwaresch MR, Lennert K. Liver findings in generalized mastocytosis: a clinicopathologic study. Cancer 1989;63: 532-538.

3. Horny H-P, Ruck MT, Kaiserling E. Spleen findings in generalized mastocytosis: a clinicopathologic study. Cancer.1992;70:459-468. 4. Horny H-P, Kaiserling E, Parwaresch MR, Lennert K. Lymph node findings in generalized mastocytosis. Histopathology 1992;21:439-446.

5. Longley J. Is mastocytosis a mast cell neoplasia or a reactive hyperplasia? Clues from the study of mast cell growth factor. Ann Med. 1994;26:115-116. 6. Metcalfe DD. Classification and diagnosis of mastocytosis: current status.J Invest Dermatol. 1991;96:255.

7. Travis WD, Li C-Y, Bergstralh El, Yam LT, Swee RG. Systemic mast cell disease; analysis of 58 cases and literature review. Medicine. 1988;67:345-368. 8. Horny H-P, Ruck M, Wehrmann M, Kaiserling E. Blood findings in generalized mastocytosis: evidence of frequent simultaneous occurrence of myeloproliferative disorders. Br J Haematol. 1990;76:186-193.

9. Leder L-D. Uber die se(ektive fermentcytochemische Darstellung von neutrophilen myeloischen Zellen und Gewebsmastzellen im Paraffinschnitt. Klin Wochenschr.1963;42:553.

10. Hsu S, Raine L, Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem.1981;29:577-580.

11. Nagata H, Worobec AS, Oh CK, et al. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci USA. 1995;10560-10564.

12. Lawrence JB, Friedman BS, Travis WD, Chinchill VM, Metcalfe DD. Hematologic manifestations of systemic mast cell disease: a prospective study of laboratory and morphologic features and their relation to prognosis. Am J Med. 1991;91:612-624.

13. Travis WD, Li C-Y, Yam LT, Bergstralh El, Swee RG. Significance of systemic mast cell disease with associated hematologic disorders. Cancer.1988;62:965972.

14. Valent P, Spanbl6chl E, Bankl H-C, et al. Kit ligand/mast cell growth factorindependent differentiation of mast cells in myelodysplasia and chronic myeloid leukemia blast crisis. Blood. 1994;84:43224332.

15. Horny H-P, Parwaresch MR, Kaiserling E, et al. Mast cell sarcoma of the larynx. J Clin Pathol.1986;39:596-602.

Accepted for publication September 26, 1996. From the Institute of Pathology, University of Tibingen, Germany (Drs Horny and Kaiserling), and the Department of Internal Medicine I, Division of Hematology, University of Vienna, Austria (Drs Sillaber, Walchshofer, and Valent).

Reprint requests to Institut fr Pathologie, Universitat Tubingen, Liebermeisterstr 8, D-72076 Tubingen, Germany (Dr Horny).

Copyright College of American Pathologists Apr 1997
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