Neoplastic Disorders Of The Spleen
Section 6 -
Myeloid Neoplasms and Related Disorders
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
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 . 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
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 . 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 . 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 . Several studies have indicated that the
myeloid cells in the spleen may develop additional cytogenetic abnormalities before those in the bone
In blastic phase CML, gross examination may reveal a homogeneous or a multinodular appearance .
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 .
Polycythemia Vera (PV)
Splenomegaly occurs in the majority of patients who have PV and is one of the major criteria for
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 . 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
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 .
Chronic Idiopathic Myelofibrosis (CIMF)
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 . 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
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
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
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  and myelodysplastic/myeloproliferative disorders such as chronic
myelomonocytic leukemia and juvenile myelomonocytic leukemia . 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
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
The pattern of involvement of the spleen in MCD is variable
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 . 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
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.|
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