—  SHORT COURSE #39  —

Neoplastic Disorders Of The Spleen

Section 6 - Myeloid Neoplasms and Related Disorders

Attilio Orazi
Dennis P. O'Malley


Acute Myeloid Leukemias (AML)
Acute myeloid leukemia (AML) is a heterogeneous group of disorders which includes several morphologic and cytogenetically defined subtypes [1, 2]. The distinction between the different morphologic subtypes of AML is difficult on examination of the spleen alone and rarely required. Although touch imprints supplemented by cytochemical stains may be helpful, immunophenotypic analysis by flow cytometry and/or immunohistology is usually required for an adequate characterization. Splenic involvement with AML may precede or occur concurrently with systemic evidence of leukemia, or be a manifestation of relapse. It may also occur as a part of the blast transformation process of a chronic myeloproliferative disorder (MPD) or myelodysplastic syndrome. The existence of an underlying MPD may be suggested by the concomitant presence of a background of differentiated myeloid cells and/or the presence of trilinear extramedullary hematopoiesis. Histologically, all the various subtypes of myeloid leukemias involve the spleen in a similar topographic manner i.e. infiltration of red pulp cord and sinuses. In rare cases, erythroleukemia in particular, the leukemic infiltrate is largely intrasinusoidal [3]. In some cases, a localized proliferation of blasts may result in the formation of an identifiable tumor-like mass usually referred to as myeloid sarcoma.

Chronic Myeloproliferative Disorders
The chronic myeloproliferative disorders are a group of interrelated clonal hematopoietic stem cell disorders [1, 2]. These disorders include chronic myelogenous leukemia, polycythemia vera, chronic idiopathic myelofibrosis, and essential thrombocythemia. A variable degree of splenomegaly occurs in all these disorders. Although each has its own somewhat distinctive characteristics, a precise diagnostic subtyping cannot be made on morphologic examination of the spleen alone in the absence of relevant clinical and laboratory data as well as the examination of bone marrow and peripheral blood.

Chronic Myelogenous Leukemia (CML)
CML is frequently associated with massive splenomegaly [3]. The cut surface of the spleen is deep red without visible white pulp because CML, in most cases, obliterates completely the lymphoid follicles. Infarcts are common, and fibrosis of the cords may be prominent. Histologic examination reveals a polymorphous cellular infiltrate in the red pulp, which includes granulocytic cells at all stages of maturation [3]. The identification of promyelocytes and other immature myeloid cells can be facilitated by using immunohistologic stains for myeloperoxidase, lysozyme, or the enzymatic chloracetate esterase reaction (Leder stain). Rare localized collections of ceroid-containing histiocytes (pseudo-Gaucher cells) similar to those seen in the bone marrow may also be observed in spleen from CML patients. The majority of CML cases terminate with the development of an accelerated/blastic phase that resembles a "de novo" acute leukemia. Approximately one-third of the cases of blast crisis arise in an extramedullary site, the most common of which is the spleen [4]. Several studies have indicated that the myeloid cells in the spleen may develop additional cytogenetic abnormalities before those in the bone marrow [5]. In blastic phase CML, gross examination may reveal a homogeneous or a multinodular appearance [3]. Most often the blasts are myeloblasts, although, in approximately 25% of cases, these cells are lymphoblasts and, in rare cases, megakaryoblasts or erythroblasts. Immunohistochemistry with a panel of antibodies which includes myeloperoxidase, CD34, CD117, TdT, CD79a, CD10, CD3, and CD42b may be helpful in confirming the presence of blasts and in identifying their lineage derivation. Therapy with colony-stimulating factors, G-CSF, in particular, may simulate splenic involvement with CML or a myelodysplastic/myeloproliferative disorder. Occasionally, it may mimic acute myeloid leukemia and even be associated with splenic ruptures [6].

Polycythemia Vera (PV)
Splenomegaly occurs in the majority of patients who have PV and is one of the major criteria for diagnosis [7, 8]. The degree of splenomegaly in the erythrocytotic phase of PV usually is mild or moderate; the size of the spleen roughly correlating with the duration of the disease [9]. In approximately 15% of cases, however, polycythemia vera evolves to a spent phase, also called postpolycythemic myeloid metaplasia (PPMM), which is indistinguishable from chronic idiopathic myelofibrosis [9, 10]. Spleens that have been obtained in the erythrocytotic phase show intense congestion of the cords of Billroth and the sinuses of the red pulp, accompanied by a reactive proliferation of cordal macrophages without significant myeloid metaplasia. In contrast, spleens obtained from patients whose disease has evolved to PPMM, show the presence of prominent myeloid metaplasia [11].

Chronic Idiopathic Myelofibrosis (CIMF)
(Slide #7) The degree of splenomegaly seen in CIMF is often the most striking among the myeloproliferative disorders. In CIMF, splenomegaly is associated with reticulin or collagen fibrosis in the bone marrow, and leukoerythroblastosis and dacrocytosis in the peripheral blood [12]. Symptoms related to massive enlargement of the organ may be the presenting feature of this disorder. The degree of splenomegaly has been shown to correlate with the duration of disease [9, 12]. Increasing splenomegaly may be arrested transiently by splenic irradiation or chemotherapy. Splenomegaly in CIMF results from the presence of myeloid metaplasia (MM) also known as extramedullary hematopoiesis, in the red pulp [8, 9]. On gross examination, the spleen is uniformly enlarged, purple-red, with indistinct white pulp markings. Infarcts are common. In some cases, however, grossly recognizable nodules may be noted. Microscopic examination reveals multifocal MM throughout the splenic cords and within the splenic sinuses. MM may be accompanied by variable degrees of fibrosis and microinfarcts, often resembling Gamna-Gandi bodies seen in sickle cell anemia. Although the hematopoiesis present is always trilinear, one cell line may predominate in a given case; the latter instance may produce the distinct nodules previously mentioned. Histologically, erythroid precursors form easily recognizable clusters, frequently in the sinuses. Megakaryocytes show the same dysplastic features as those in the bone marrow with clusters of large, bizarre forms. Although granulocytic precursors may be difficult to distinguish from cordal macrophages in routinely stained sections, they can be easily identified in touch imprints or in tissue sections by using immunostains for myeloperoxidase or lysozyme. The trilinear nature of the hematopoiesis seen in CIMF as well as the presence of the characteristically giant megakaryocytes with plump nuclear lobulation (similar to those present in the bone marrow) aids in the distinction of this disorder from CML in which the myeloid proliferation is usually monolineage, i.e. granulocytic, and the megakaryocytes small. As in CML, blastic transformation may be heralded by an increase in immature cells; their identification can be facilitated by the use of immunostains such as CD34, CD117, and MPO. In addition to CML, the differential diagnosis of myeloid metaplasia in the spleen includes myelodysplastic syndromes [13] and myelodysplastic/myeloproliferative disorders such as chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia [14]. These cases need usually to be evaluated extensively, and often require correlation with cytogenetic findings (e.g. to exclude the presence of BCR-ABL rearrangement). MM seen in reactive conditions (e.g. severe hemolytic anemia) can also be easily distinguished from CIMF-associated MM since the former is mostly characterized by erythropoiesis only [Table 6-1].

Essential Thrombocythemia (ET)
ET is characterized by a marked megakaryocytic hyperplasia in the bone marrow associated with thrombocytosis [15, 16]. The degree of splenomegaly in ET is usually less marked than that seen in the other chronic myeloproliferative disorders and hypersplenism is not a common clinical manifestation. In the rare spleen examined, the most common finding is enlargement of the red pulp, which may appear hypocellular at low power because of the presence of large masses of platelets both in the cords and sinuses. Touch preparations of the spleen may be useful for demonstrating the sequestration of platelets. In advanced cases, the spleen may become atrophic and nonfunctional, with atrophy resulting from multiple infarctions. No significant myeloid metaplasia is seen in ET with the exception of rare cases evolving to myelofibrosis.

Mast Cell Disease (MCD)
The spleen usually is involved in cases of systemic mastocytosis, although the degree of splenomegaly is frequently only mild to moderate [3, 17]. The pattern of involvement of the spleen in MCD is variable [18, 19, 20]. Early involvement may show a preferential localization to paratrabecular areas and/or to the marginal zones of the white pulp. A characteristic fibroblastic reaction, resulting in a concentric rimming of the lymphoid follicles may be observed. Other cases show a diffuse infiltration of the red pulp with extensive fibrosis, and/or nodular perivascular infiltrates [20]. Mast cells typically appear cuboidal, with pale nuclei and grayish cytoplasm. Spindle-shaped forms also may be seen. Mast cell granules can be demonstrated with the chloracetate esterase stain and are metachromatic with toluidine blue and Giemsa stains, although neoplastic mast cells are often degranulated. Tryptase and CD117 positivity may be helpful in confirming splenic involvement particularly in cases associated with a marked degree of fibroblastic reaction and relatively rare mast cells. Systemic mast cell disease may be associated with other hematologic disorders, most notably acute leukemia and chronic myeloproliferative disorders [3, 21], which may also be present concurrently in the spleen.

Table 6-1: Evaluation of Myeloid Metaplasia in Spleen
Etiology Hematopoiesis
Benign Hypersplenism due to non-neoplastic etiologies. Typically trilineage hematopoiesis.
Hemolytic anemias and other anemias Predominantly erythroid with occasional megakaryocytes
Cytokine-induced (e.g. G-CSF) Predominantly myeloid - may simulate acute myeloid leukemia (AML-M2 or M3 in particular)
Lymphoma/other malignancies (carcinoma, sarcoma) Variable degrees of trilineage hematopoiesis without atypia.
Clonal MPD Usually trilineage - occasionally one lineage predominant. Atypia seen in megakaryocytes. May represent initial site of blast transformation.
MDS/MPD Findings overlap with both MPD and MDS.
MDS Usually trilineage, occasionally with increased monocytes/macrophages. Dysplasia seen in megakaryocytes. Increased immature myeloid/blasts may herald blast transformation.

References
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