MORPHOLOGY AND BIOLOGY

Acute leukemias—defined as 20% or more blasts in blood or bone marrow under the World Health Organization (WHO) criteria—are classified according to the predominant neoplastic cell line and thus may be designated as lymphoblastic or myeloid. The WHO classification takes into account cytogenetic and molecular findings in addition to morphologic and histochemical criteria (see Tables 15.1 and 15.4 ). About 70% to 80% of cases can be classified on the basis of morphology alone, whereas an additional 10% to 15% of cases require histochemical determinations for specific diagnosis. In approximately 10% of cases, surface marker and cytogenetic studies are necessary for accurate classification, particularly in the “undifferentiated” acute leukemias. Use of monoclonal antibodies has revealed that about 20% of cases of ALL are of T-cell origin; most of the remainder are of B-cell or pre-B cell origin (see Table 15.3 ).

Development of colony assays and new monoclonal antibodies has led to a clearer understanding of normal myeloid ontogeny. The patterns of expression of a variety of antigens during normal myeloid differentiation have been established. Immunophenotyping techniques have demonstrated that some cases of acute “undifferentiated” leukemia, or those considered on the basis of morphology to be ALL, show myeloid markers. Improvement of cytogenetic studies by the use of new banding techniques has revealed that almost all acute leukemias are characterized by chromosomal abnormalities, ranging from hypoploidy to polyploidy. Significant cytogenetic defects that have prognostic importance (e.g., are seen only with certain subgroups) have been identified, involving the ALLs as well as the AMLs. Genetic abnormalities in the acute leukemias can affect genes that encode proteins involved in signal transduction, transcription regulation, cellular differentiation, and apoptosis, as well as tumor suppression (antioncogenes).

In about 10% of adults with ALL, cytogenetic studies will show the presence of the Philadelphia chromosome (t(9;22) (q34;q11)), and the incidence increases with age. These Ph-positive patients tend to be older (median age 46 years vs 35 years) and to have a lower incidence of anemia and a higher incidence of leukocytosis than Ph-negative patients ( ). Ph-positive ALL patients are also likely to have FAB-L2 morphology (see Table 15.1 ), to be common ALL antigen-positive (CALLA-CD10-positive) and CD34-positive, and to have a worse prognosis than Ph-negative ALL cases. In a few patients with ALL and AML who are Ph-negative, molecular studies (e.g., polymerase chain reaction) will reveal the presence of BCR-ABL transcripts diagnostic of the Ph-chromosome abnormality not otherwise detected because of insufficient metaphases ( ).

CLINICAL MANIFESTATIONS

Patients can present with a variety of clinical manifestations, which correlate with the degree of marrow and other organ involvement. Among the more common symptoms are fatigue, bruisability, oral lesions, fever, and infection. Perirectal infections are particularly frequent in AML, and skin and gum infiltrates are seen mainly in AMLs. Joint swelling and bone pain with rheumatic symptoms occur commonly in ALL, which may also present as a meningitis-like syndrome. Diffuse lymphadenopathy and hepatosplenomegaly are more common in ALL (50% of cases) than in AML.

In patients with AML, unusual masses in soft tissues, nodal sites, or other areas may appear, representing collections of extramedullary immature myeloid cells. These lesions may precede overt marrow and peripheral blood invasion (and thus the diagnosis of AML) and may be mistaken for lymphoma or metastatic carcinoma. When they are localized these extramedullary leukemic infiltrates have been called myeloblastomas; the older term, granulocytic sarcoma, is inappropriate. Another term, chloroma, has been used when the tumor appears green, because of the presence in the leukemic cells of enzymes capable of metabolizing heme products; the green color rapidly disappears after oxidation on exposure to air. Myeloblastomas can occur anywhere, but the most common sites are soft tissues, skin, periosteum, bone, and lymph nodes. Diagnosis can be rapidly established on a touch prep stained with Wright-Giemsa and examined for Auer rods or azurophilic granules. The latter are peroxidase- and specific esterase–positive.

ACUTE LYMPHOBLASTIC LEUKEMIA (L1, T-CELL SUBTYPE). ( A ) Low magnification of a bone marrow core biopsy shows a markedly hypercellular marrow (Giemsa stain). ( B ) At high magnification convoluted lymphoblasts can be seen; the small to intermediate-size cells show a characteristic irregular or cerebriform nuclear outline, finely dispersed chromatin, and scant cytoplasm. The nucleolus is typically indistinct (Giemsa stain). ( C ) Lymphoblasts stain positively with H&E. Immunophenotyping showed positivity for CD5 (T1), CD4 (T4), CD8 (T8), and CD2 (T11).

ACUTE LYMPHOBLASTIC LEUKEMIA (L1, T-CELL SUBTYPE). High-power view of a bone marrow aspirate reveals small lymphoblasts with scanty cytoplasm and indistinct nucleoli. The nuclear contours in many of the cells are convoluted or cerebriform.

ACUTE LYMPHOBLASTIC LEUKEMIA (L3 SUBTYPE). Bone marrow core biopsy of a markedly hypercellular marrow containing small to intermediate-size cells with one or more distinct nucleoli. Multiple mitotic figures are seen (Giemsa stain).

ACUTE LYMPHOBLASTIC LEUKEMIA (L3, BURKITT LEUKEMIA/LYMPHOMA). This Q-banded karyotype shows 46; X,Y, t(8;14) (q24;q23).

(Courtesy of Ramana Tantravahi, PhD, Dana-Farber Cancer Institute, Boston, MA.)

ACUTE MYELOBLASTIC LEUKEMIA (MO SUBTYPE). ( A ) Hypercellular bone marrow biopsy composed of myeloblasts with minimal differentiation. The blasts were negative for Auer rods and histochemical markers of AML, but were positive for myeloid differentiation markers (CD13, CD33) by flow-cytometric examination (Giemsa stain). ( B ) Bone marrow aspiration smear from same case showing blasts with prominent nucleoli and basophilic cytoplasm without any granules (×1000; Wright-Giemsa stain).

ACUTE MYELOBLASTIC LEUKEMIA (M1 SUBTYPE). ( A ) Acute leukemia is marked by replacement of the normal bone marrow by blasts. In this instance the cellularity is 99%, whereas normal cellularity is about 50%, with fat representing the remaining 50%. Rare cases of “hypocellular” AML have been described in which the background fat is normal or increased. ( B , C ) At higher magnification, characteristic myeloblasts can be seen showing predominantly round nuclear outlines, distinct nucleoli (often centrally located), and a moderate amount of cytoplasm. Distinct red-pink cytoplasmic granules are occasionally noted (Giemsa stain).

ACUTE MYELOBLASTIC LEUKEMIA (M1 SUBTYPE). Peroxidase staining (Kaplan method) of a bone marrow aspirate shows many Auer rods and early azurophilic granules (golden color) in myeloblasts.

ACUTE PROMYELOCYTIC LEUKEMIA (M3 SUBTYPE). A partial karyotype of G-banded chromosomes 15 and 17 is shown ( above ). The translocated chromosomes are on the right in each pair. The corresponding diagrams ( below ) represent a systematized description of the structural aberration that fuses the PML gene on chromosome 15 with the retinoic acid receptor-α on chromosome 17, resulting in a fusion protein involved in leukemogenesis.

(Courtesy of Dr. L.M. Secker-Walker.)

ACUTE MYELOMONOCYTIC LEUKEMIA (M4 SUBTYPE). High magnification of a bone marrow core biopsy shows many blasts with irregular, folded nuclear outlines and some with pink-red cytoplasmic granules. Histochemical staining is necessary for definitive diagnosis.

CUTANEOUS MANIFESTATIONS. A 35-year-old woman with previous AML developed extensive skin lesions on the anterior chest as the first evidence of relapse. Biopsy showed infiltration of the dermis by monoblasts. Leukemic skin infiltrates can occur in any type of AML but are especially common in the M4 and M5 subtypes. They may be flat or raised, solitary or multiple.

CUTANEOUS MANIFESTATIONS. A 23-year-old woman with AML developed skin lesions on ( A ) the right shoulder and ( B ) the lower back. The lesions regressed after 2 weeks’ chemotherapy.

( A ) Histologic section (low power) from a patient with leukemia cutis, showing diffuse infiltration of the dermis and subcutaneous tissue. ( B ) High-power view shows immature myeloid cells, including numerous blast forms (H&E).

(Courtesy of Dr. S. Granter.)

INTRAORAL MANIFESTATIONS. Gingival hypertrophy most often occurs when there is a monoblastic element in AML. It is not seen in edentulous patients. This patient had AML.

MYELOBLASTOMA PRESENTING IN A LYMPH NODE. In this 30-year-old man who presented with cervical lymphadenopathy, nodal architecture was effaced by homogeneous myeloblasts with large, round nuclei with prominent central nucleoli. The differential diagnosis includes non-Hodgkin lymphoma, large cell, immunoblastic type. The infiltrate was reactive for myeloperoxidase and chloracetate esterase, confirming a diagnosis of extramedullary acute myeloblastic leukemia.

MYELOBLASTOMA (GRANULOCYTIC SARCOMA). A 37-year-old man underwent orchidectomy for a testicular mass believed to represent primary testicular carcinoma. ( A ) Histologic examination, however, reveals AML, as evidenced by the dense leukemic infiltrate enveloping the intact seminiferous tubules. ( B ) High magnification shows that the tumor is composed of cells with predominantly round nuclear outlines and distinct nucleoli. ( C ) Immunoperoxidase staining for lysozyme is strongly reactive.

ACUTE FEBRILE NEUTROPHILIC DERMATOSIS (SWEET’s SYNDROME). ( A , B ) These patients with AML developed fever and multiple cutaneous, tender, red plaquelike lesions on the face, arms, and hands. Skin biopsy showed a dense nodular and patchy dermal infiltrate composed primarily of mature neutrophils. There was marked edema of the papillary dermis, but the epidermis was essentially normal. There was eventual total resolution of the lesions following corticosteroid treatment. Sweet’s syndrome occurs in association with AML and may predate the diagnosis of acute leukemia. It is also associated with chronic myeloproliferative disorders and miscellaneous malignancies, or it may be idiopathic. The differential diagnosis includes pyoderma. The lesions may involve the mucous membranes or cause pulmonary infiltrates; systemic symptoms may also occur. The etiology remains obscure.

REFRACTORY ANEMIA (MDS TYPE I). Peripheral blood film shows marked anisocytosis and poikilocytosis.

MYELODYSPLASTIC SYNDROMES

The myelodysplastic syndromes (MDSs) are a group of disorders that primarily occur in the elderly, who present with an anemia that proves refractory to treatment, with progressive neutropenia and thrombocytopenia, or with various combinations of these. In the past these syndromes, particularly those with normal numbers of blasts (<5%) in the marrow, have been referred to as “preleukemia.” To varying degrees there is a tendency to progression to acute leukemia, ranging from progression in approximately 10% of cases of refractory anemia and refractory anemia with ringed sideroblasts to progression in more than 40% of cases of refractory anemia with excess blasts.

Classification and Cytogenetics

Given the variable presentation and prognosis of these disorders, various classification schemes have been devised to better divide and define these disorders. According to the French-American-British (FAB) classification scheme, the MDSs have been classified into five subgroups, which have been modified by the WHO into seven subgroups (see Fig. 15.54 ). The blood film abnormalities in each subgroup are highly variable, although general features include macrocytic red cells, qualitative granulocytic and monocytic changes, and giant platelets. Whereas patients with refractory anemia may show no gross changes in blood morphology, patients with refractory anemia with ringed sideroblasts frequently show a dimorphic red cell population. Leukoerythroblastic changes are common in patients with refractory anemia with excess blasts. “Chronic myelomonocytic leukemia,” a diagnostic entity included with the MDSs by the FAB classification scheme, is marked by abnormal myelomonocytic cells and monocytosis of more than 1.0 × 10 ⁹ cells/L, with or without splenomegaly, and is considered separately by the WHO classification. A former category, RAEB-T, is no longer an entity under the WHO classification and is considered a progression to AML.

WHO classification of the myelodysplastic syndromes with peripheral blood and bone marrow findings.

The bone marrow in the MDSs is typically hypercellular and shows morphologic abnormalities, often in all three series of hematopoietic cells. Cytogenetic abnormalities are common, particularly in secondary MDS (related to prior radiation therapy or therapy with alkylating agents) ( Table 15.5 ). They include –5 or –5q, –7 or –7q, –20 or –20q, +8 and –9q. Patients with complex cytogenetic abnormalities (the most common chromosomal abnormality observed) or –7 or –7q typically have an aggressive clinical course. There is usually evidence of dyserythropoiesis with nuclear atypia, some megaloblastosis, and ringed sideroblasts. In some cases reticulin is increased, whereas occasional cases are hypocellular. Granulocytic abnormalities include hypogranular or agranular myelocytes, metamyelocytes and neutrophils, pseudo-Pelger-Huët cells, and hypersegmented or polypoid neutrophils. Megakaryocyte abnormalities include small mononuclear or binuclear forms or large megakaryocytes with multiple, round nuclei and large granules in the cytoplasm. In the more advanced MDSs the blast cell population is also increased, but by definition these cells constitute less than 20% of the marrow cell total. When the level of blast cells exceeds this figure, it is assumed that a transformation to AML has occurred.

Table 15.5

Common Cytogenic Abnormalities in Myelodysplastic Syndrome

Adapted from Greenberg P, Cox C, LeBeau MM, et al: International Scoring System for evaluating prognosis in myelodysplastic syndromes, Blood 89:2079–2088, 1997.

Abnormality	Incidence (%)
Loss of all or part of chromosome 5	13
Loss of all or part of chromosome 7	5
Trisomy 8	5
del 17p	<1
del 20q	2
Loss of X or Y chromosome	2

 

Clinical Manifestations and Prognosis

Clinically, patients present with symptoms related to bone marrow failure, with frequent episodes of infection and with bleeding abnormalities. These complications of severe neutropenia or thrombocytopenia result in death in many patients, but in others the disease progresses to frank AML. Typically, the liver, spleen, and lymph nodes are not enlarged. Gum hypertrophy and skin deposits do not usually occur. The prognosis is variable, and prognostic schemes have been devised. The most widely accepted and adopted has identified cytogenetics, the number of cell lines affected, and the number of blasts in the bone marrow to be important predictors of prognosis (see Table 15.6 ).

Table 15.6

International Prognostic Scoring System for Myelodysplastic Syndrome

Adapted from Greenberg P, Cox C, LeBeau MM, et al: International Scoring System for evaluating prognosis in myelodysplastic syndromes, Blood 89:2079–2088, 1997.

Overall Score *	Median Survival (Years)
Low (0)	5.7
Intermediate
1 (0.5 or 1.0)	3.5
2 (1.5 or 2.0)	1.2
High (≥2.5)	0.4

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