This term was coined to describe three closely related disorders characterized by proliferation of the Langerhans cell, a type of histiocyte. Histiocytosis X was the original term used for this group of diseases. The group comprises three well-known disorders and several rarer ones. Letterer-Siwe disease is a rapidly progressive, fatal condition that is seen mostly in early childhood and infancy. There is widespread involvement of bone, skin, visceral, and reticuloendothelial organs by atypical histiocytes, with accompanying anemia and thrombocytopenia. Bone marrow aspiration or, occasionally, lymph node biopsy is the usual diagnostic procedure. Eosinophilic granuloma is the benign member of the triad. It is seen most often in later childhood and most commonly presents as isolated bone lesions. These usually are single but may be multiple. The lungs are occasionally involved. The lesion is composed of histiocytes with many eosinophils and is diagnosed by direct biopsy. Hand-Sch?ller-Christian disease is somewhat intermediate between the other two in terms of chronicity and histology. Bone lesions, often multiple, are the major abnormalities. Soft tissue and reticuloendothelial organs may be affected. There may be very few systemic symptoms, or there may be anemia, leukopenia, and thrombocytopenia. The lesions are composed of histiocytes containing large amounts of cholesterol in the cytoplasm and accompanied by fibrous tissue and varying numbers of eosinophils. Diagnosis usually is by direct biopsy of a lesion.
Tag: Leukemia
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Immunosuppressive Lymphoproliferative Disorders (ILDs)
These diseases occur predominantly in organ transplant patients and HIV-infected patients, but may appear in patients with congenital immune defects or those having immunosuppressive therapy for other conditions. Some of these lymphoid proliferations are benign, some are malignant, and some are initially benign (using current tests) but later acquire clinical and laboratory evidence of malignancy. Immunosuppressive lymphoproliferative disorder (ILD) develops in about 2% of all organ transplant patients, about 1% (range, 0.6%-15%) of bone marrow transplants, 2% (1%-17%) of kidney transplants, 3% (1%-8.6%) of liver transplants, and about 10% (1.8%-20%) of heart transplants. The lymphocytes in ILD are usually B-cells and are frequently heterogeneous (various B-cell types). Spread to areas outside of lymph nodes is common. Evidence of Epstein-Barr virus infection is extremely common. Four percent to 29% of patients with human immunodeficiency virus (HIV) infection develop ILD, with a very high incidence of non–lymph node sites such as the CNS and GI tract.
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Malignant Lymphomas
The malignant lymphomas include Hodgkin’s disease and non-Hodgkin’s lymphomas; both are derived from lymphoid tissue, predominantly from lymph nodes. Lymph nodes are composed of two parts, germinal centers and lymphoreticular tissue. The germinal centers contain lymphoblasts and reticulum cells; these produce the mature lymphocytes and reticulum cells that form the remainder of the lymphoid tissue. Therefore, three main cell types exist in lymph nodes (and other lymphoid tissue): reticulum cells, lymphoblasts, and lymphocytes. Malignancy may arise from any of these three cell types.
Histologic classification of the non-Hodgkin’s lymphomas (NHL)
Rappaport’s classification. In Rappaport’s classification, the non-Hodgkin’s lymphomas are divided into three types based on whatever cell of origin is suggested by the microscopic appearance: lymphocytic lymphoma, histiocytic lymphoma (originally called reticulum cell sarcoma), and undifferentiated. Lymphocytic lymphoma (originally called lymphosarcoma) may, in turn, be subdivided into well-differentiated and poorly differentiated (lymphoblastic) types, depending on the predominant degree of differentiation of the lymphoid cells (Table 7-3). Besides the degree of differentiation, malignant lymphomas may exist in two architectural patterns, nodular and diffuse. In the nodular type, the lymphomatous tissue is distributed in focal aggregates or nodules. In the diffuse type, the lymphomatous cells diffusely and completely replace the entire lymph node or the nonlymphoid area invaded. However, a significant number of cases have both nodular and diffuse components; there does not appear to be a consensus as to what percentage of the tumor must be nodular in order to designate the tumor as nodular. Hodgkin’s disease, which is discussed later, also exists in a somewhat nodular and diffuse form, although the nodular variety is rare. In the malignant lymphomas as a group, the diffuse pattern is more frequent than the nodular one.
Table 7-3 Histologic classification of non-Hodgkin’s malignant lymphomas (Rappaport modified)
The histiocytic lymphoma category basically includes large cell lymphomas of both lymphocytic and histiocytic origin that may have different nuclear types; but the various possible subclassifications all have roughly the same prognosis. Untreated histiocytic lymphoma has a prognosis comparable with that of acute leukemia. The same is true for the poorly differentiated lymphocytic lymphomas.
The nodular pattern comprises about 40% of NHL. Nodular lymphomas are derived from B-lymphocytes. The nodules in most cases are either predominately small cell, predominately large cell, or mixed large and small cell. The cells contain a chromosomal 14-18 translocation associated with the bcl oncogene. Nodular lymphoma originally was called Brill-Symmers disease, or giant follicular lymphoma, and was originally thought to have a better prognosis than the corresponding diffuse pattern. However, evidence exists that prognosis depends to a considerable extent on the cell type as well as the architectural pattern. This would suggest that the poorly differentiated or more primitive cell types do not have a good prognosis even when they appear in a nodular (“follicular”) form.
It is interesting that 20%-30% of non-Hodgkin’s lymphomas of the nodular or the better differentiated type are reported to eventually undergo change to a diffuse pattern or a less favorable nuclear type.
Rappaport’s classification has been criticized by various investigators. Some wish to include more subclassifications, whereas others believe that the terminology does not reflect cell origin correctly. The majority of cases that would be classified as histiocytic by Rappaport’s criteria have been shown by immunologic or genetic techniques to be of lymphoid origin rather than histiocytic. Nevertheless, Rappaport’s classification still is frequently used in the United States and seems to provide a fairly reliable index of prognosis.
Immunologic characterization of malignant lymphomas
Most classifications of hematopoietic malignancies are based on cell morphology and tissue pattern (often including interpretation of cell origin or even cell function as estimated from morphology). Work that characterizes malignancies involving lymphocytes according to phylogenetic origin of the cells (referred to previously in the section on acute leukemia) has been presented. Lymphocytes have two origins: thymus-derived (T) cells, which functionally are responsible for delayed hypersensitivity cell-mediated immune reactions; and bone marrow-derived (B) cells, which are involved with immune reactions characterized by Ig (antibody) production. T-cells in lymph nodes are located in the deep layers of the cortex and in a thin zone surrounding the germinal centers. B-cells are located in germinal centers and in the outer cortex of lymph nodes; they are precursors of plasma cells. In general, most work to date indicates that multiple myeloma, 98% of CLL, Burkitt’s lymphoma, and approximately 75% of lymphocytic lymphomas (especially the better-differentiated varieties) are of B-cell origin. In childhood ALL about 20% of cases are T-cell, about 2% are B-cell, and 75% are pre-pre-B-cell or Pre-B-cell and do not react in E rosette or surface Ig tests. The T-cell subgroup of childhood ALL has many clinical features in common with a subgroup of the non-Hodgkin’s lymphomas (the lymphoblastic lymphoma of Rappaport’s classification or the convoluted lymphocytic lymphoma of the Lukes-Collins classification; the same neoplasm was referred to in the older literature as Sternberg’s sarcoma). These features include presence of a mediastinal tumor mass, onset in later childhood or adolescence, predominance in males, and poor prognosis. Other T-cell malignancies include mycosis fungoides and the Sйzary syndrome, both sometimes referred to as “cutaneous lymphomas.”
Lukes-Collins classification
Lukes and Collins have published a classification of non-Hodgkin’s lymphomas based on results of immunologic testing of lymphomas, the morphologic appearance of the cell nucleus plus cell size, and their concept of lymphoid cell maturation (see box below). This classification has proved attractive to many institutions because it places those lymphomas of Rappaport’s “histiocytic” category that are actually lymphocytic rather than histiocytic into the lymphocytic lymphoma category and emphasizes cell appearance rather than prediction of cell type. The major problem with the Lukes-Collins classification is that it is frequently difficult to decide whether to assign cells with large noncleaved nuclei to the category of large noncleaved follicular center cells or to the category of immunoblastic sarcoma.
Lukes-Collins Classification of Non-Hodgkin’s Lymphomas (Modified 1982)
I. U-cell (undefined cell) type
II. T-cell types
1. Small lymphocytic
2. Cerebriform lymphocytic
3. Convoluted lymphocyte
4. Immunoblastic sarcoma of T cells
5. Lymphoepithelioid lymphocytic
III. B-cell types
1. Small lymphocyte (CLL)
2. Plasmacytoid lymphocyte
3. Follicular center cell (FCC) types (follicular or diffuse, with or without sclerosis)
a. Small cleaved
b. Large cleaved
c. Small noncleaved
Burkitt’s variant
Non-Burkitt’s variant
d. Large noncleaved
4. Immunoblastic sarcoma of B cells
IV. Histiocytic type
V. UnclassifiableNational Cancer Institute lymphoma panel Working Formulation
In 1980, a panel of well-known authorities on histopathology of malignant lymphomas, collectively known as the National Cancer Institute (NCI) Non-Hodgkin’s Lymphoma Pathologic Classification Project, met in Palo Alto, California, and by 1982 developed a new classification of non-Hodgkin’s lymphoma (see box below), which they called the “Working Formulation.” This classification combines some features of Rappaport’s classification (nodular and diffuse patterns, mixed cell pattern) with the basic nuclear morphologic descriptive terms of Lukes and Collins, plus subdivision by degrees of malignancy as found in the British and Kiel (German) classifications. Although the NCI Working Formulation has somewhat improved pathologist agreement in lymphoma classification, even recognized experts in lymphoma pathology do not unanimously agree in about 15% of cases.
Classification of Non-Hodgkin’s Lymphomas: Non-Hodgkin’s Lymphoma Pathologic Classification Project (“Working Formulation”)
Low gradeSmall (noncleaved) lymphocytic
a.Consistent with CLL
b.PlasmacytoidFollicular* lymphoma, predominantly small cleaved cell
Follicular lymphoma, mixed small cleaved and large cellIntermediate grade
Follicular lymphoma, predominantly large cell
Diffuse small cleaved cell
Diffuse mixed small and large cell
Diffuse large cell (cleaved/noncleaved)High grade
Diffuse large cell of immunoblastic type
Lymphoblastic (convoluted/nonconvoluted)
Small noncleaved cell (Burkitt’s/non-Burkitt’s)Miscellaneous
Composite lymphoma
Histiocytic
Mycosis fungoides
UnclassifiableChromosome studies in lymphoma
A considerable number of lymphoma patients have chromosome abnormalities. Some lymphoma subgroups have a particular abnormality that occurs more often than all others. Currently, no chromosome abnormality has made a major contribution to diagnosis. Perhaps the closest is the translocation often seen in nodular B-cell lymphoma. For additional information.
Burkitt’s lymphoma
Burkitt’s lymphoma is a B-cell variant of malignant lymphoma that was originally reported in African children. It is now known to occur in children elsewhere in the world. In African Burkitt’s lymphoma, about 50%-70% of affected persons have involvement of the jaw, a site rarely affected by other lymphomas. In non-African Burkitt’s lymphoma, the jaw area is involved in only 12%-18% of patients, a tumor mass is frequently located in the abdomen, single peripheral lymph node groups are involved in about 30% of patients, and widespread peripheral lymphadenopathy is rare. Histologically, the cell nuclei are rather uniform in appearance, and sheets of these cells characteristically include scattered single cells exhibiting phagocytosis (“starry sky appearance”). Appearance of individual Burkitt’s cells resembles that of the FAB acute leukemia B-cell category, and occasional Burkitt’s lymphoma patients in the United States have developed ALL. In addition, occasional patients in the United States have been young adults rather than children. There is a strong association with Epstein-Barr virus infection in African Burkitt’s but much less evidence of Epstein-Barr in American Burkitt’s lymphoma.
Other lymphoma subgroups
A number of subgroups have been described that are not part of current standard classification systems. One example is non-Hodgkin’s lymphoma derived from “mucosa-associated lymphoid tissue” (MALT) areas; originally bronchial mucosa and stomach, but later including some lymphomas of other areas such as salivary gland, thyroid, skin, breast, and thymus. These are mostly B-cell tumors thought to be derived from parafollicular (follicular marginal zone) lymphocytes in the outer portions of the lymphoid mantle zone surrounding germinal centers. These cells include small or medium-sized cleaved lymphocytes and plasmacytoid lymphocytes. The lymphoid aggregates tend to infiltrate into epithelial structures; often remain localized for a considerable time; and when spread occurs it tends to involve other mucosal areas. Another subgroup is known as Mediterranean lymphoma (also called alpha heavy chain disease or immunoproliferative small intestine disease), which is a primary small intestine non-Hodgkin’s lymphoma most common in the Middle East and to somewhat lesser extent in other countries bordering the Mediterranean Sea. These tumors also produce chronic disease and are composed predominantly of plasma cells and plasmacytoid lymphocytes. A third example is the Ki-1 large cell non-Hodgkin’s lymphoma diagnosed with antibody against the CD-30 Ki-1 antigen (originally found in Hodgkin’s disease Reed-Sternberg cells). This is an anaplastic large-cell lymphoma most often (but not always) T-cell that tends to affect younger individuals and is found mostly in lymph nodes, the GI tract, and skin. In lymph nodes it tends to involve the sinuses more than the lymphoid parenchyma and often does not affect the entire lymph node. Prognosis ranges from moderate survival length to short survival.
Hodgkin’s disease
Hodgkin’s disease is usually considered a subgroup of the malignant lymphomas. The basic neoplastic cell is the malignant reticulum cell. Some of these malignant reticulum cells take on a binucleated or multinucleated form with distinctive large nucleoli and are called Reed-Sternberg (R-S) cells. These are the diagnostic cells of Hodgkin’s disease.
Other types of cells may accompany the R-S cells. Therefore, Hodgkin’s disease is usually subdivided according to the cell types present (Fig. 7-2). Besides R-S cells there may be various combinations of lymphocytes, histiocytes, eosinophils, neutrophils, plasma cells, and reticulum cells. The main histologic forms of Hodgkin’s disease are shown in Fig. 7-2, using a classification developed by the U.S. Armed Forces Institute of Pathology (AFIP).
Fig. 7-2 Various histologic classifications of Hodgkin’s disease.
The most widely accepted pathologic classification today is the one developed by Lukes and co-workers at the Rye Conference in 1965(see Fig. 7-2). This classification combines certain histologic tissue patterns having similar prognosis, resulting in four groups instead of six. Of the groups, lymphocytic predominance comprises about 12% (range, 5%-17%) of patients with Hodgkin’s disease, nodular sclerosing about 45% (27%-73%), mixed cellularity about 30% (16%-37%), and lymphocytic depletion about 10% (3%-23%). Prognosis is relatively good for untreated lymphocytic predominance (9-15 years’ average survival after onset). Lymphocytic depletion behaves like histiocytic lymphoma or acute leukemia, with an average survival of 1 year or less. Mixed cellularity has an intermediate prognosis (average, 2-4 years’ survival). The nodular sclerosing category as a group has a prognosis between that of lymphocytic predominance and mixed cellularity with much individual variation; a considerable number of patients achieve the survival time of patients with lymphocytic predominance Hodgkin’s disease. Life expectancy in Hodgkin’s disease is quite variable, even without treatment, and some patients live for many years with the lymphocytic predominance, nodular sclerosing, and even the mixed cellularity forms.
Also of great importance, especially for therapy, is the degree of spread when the patient is first seen (Table 7-4). Localized Hodgson’s disease has an encouraging possibility of cure by adequate radiotherapy. There is considerable correlation between the tissue histologic patterns and the clinical stage (degree of localization) of disease when first seen.
Clinical findings in malignant lymphoma
Clinically, malignant lymphoma is more common in males. The peak incidence for Hodgkin’s disease is age 20-40, and age 40-60 for other malignant lymphomas. Lymph node enlargement is found in the great majority of cases but may not become manifest until later. Fever is present at some time in at least one half of patients. Staging laparotomy has shown that splenic Hodgkin’s disease occurs in 35%-40% of cases; if this occurs, paraaortic nodes are usually involved. Liver metastasis is found in 5%-10% of cases; if the liver is involved, the spleen is always invaded. In non-Hodgkin’s lymphoma, laparotomy discloses splenic involvement in 30%-40% and hepatic metastasis in 10%-20% of cases, with rather wide variation according to histologic classification. Splenomegaly is not reliable as a criterion for presence of splenic tumor. Bone marrow metastasis is present at the time of diagnosis in 10%-60% of cases of non-Hodgkin’s lymphoma and 5%-30% of cases of Hodgkin’s disease. Lymphocytic lymphoma has a greater tendency to reach bone marrow, liver, or spleen than histiocytic lymphoma, and the nodular form is more likely to metastasize to these organs than the diffuse type.
Laboratory findings in malignant lymphoma
Anemia is found in 33%-50% of cases and is most common in Hodgkin’s disease and least common in histiocytic lymphoma. Occasionally, this anemia becomes overtly hemolytic. The platelet count is usually normal unless the bone marrow is extensively infiltrated. The WBC count is usually normal in non-Hodgkin’s lymphoma until late in the disease; in Hodgkin’s disease, it is more often mildly increased but may be normal or decreased. WBC differential counts are usually normal in malignant lymphoma unless malignant cells disseminate into the peripheral blood or, more commonly, if some other condition is superimposed, such as infection. In Hodgkin’s disease, eosinophilia may occur; in late stages, leukopenia and lymphopenia may be present. Bone marrow needle biopsy in both Hodgkin’s and non-Hodgkin’s lymphoma demonstrates bone marrow involvement more frequently than clot sections or smears. A second biopsy increases the yield by 10%-20%.
Diagnosis of malignant lymphoma
Diagnosis of the malignant lymphomas is established by tissue biopsy, usually lymph node biopsy. The particular node selected is important. The inguinal nodes should be avoided, if possible, because they often contain changes due to chronic inflammation that tend to obscure the tissue pattern of a lymphoma. If several nodes are enlarged, the largest one should be selected; when it is excised, the entire node should be taken out intact. This helps to preserve the architectural pattern and permits better evaluation of possible invasion outside the node capsule, one of the histologic criteria for malignancy.
In difficult cases it is possible (as discussed earlier) to employ immunologic stains on tissue slides or flow cytometry methods to demonstrate B-cell or T-cell lineage; a monoclonal lymphocyte phenotype would be evidence for malignancy. It is also possible to employ nucleic acid probes for Ig rearrangement (B-cells) or TCR rearrangement (T-cells). Some medical centers routinely obtain this information and also attempt to determine the stage of maturation of the cell type for therapeutic and prognostic information.
Differential diagnosis of malignant lymphoma
Several diseases enter into the differential diagnosis of malignant lymphoma. Tuberculosis, sarcoidosis, and infectious mononucleosis all produce fever, lymphadenopathy, and, frequently, splenomegaly. The atypical lymphocytes of infectious mononucleosis (Chapter 17) may stimulate lymphocytic lymphoma cells, since both are abnormal lymphocytic forms. Usually lymphoma cells in the peripheral blood are either more immature or more distorted than the average infectious mononucleosis (virocyte) cell. Nevertheless, since infectious mononucleosis patients are usually younger persons, the finding of lymphadenopathy and a peripheral blood picture similar to infectious mononucleosis in a patient over age 40 would suggest lymphosarcoma (if some other viral illness is not present). Suspicion is intensified if results of the Paul-Bunnell (heterophil) test (Chapter 17) are less than 1:28 or are 1:28-1:112 with a normal differential absorption pattern (two different determinations normal, done 2 weeks apart to detect any rising titer). Occasionally, rheumatoid-collagen diseases create a clinical picture suggestive of either an occult malignant lymphoma or its early stages. Phenytoin (Dilantin), smallpox vaccination, and certain skin diseases may produce a lymphadenopathy, which creates difficulty for both the clinician and the pathologist. Malignant lymphoma often enters into the differential diagnosis of splenomegaly, especially if no other disease is found to account for the splenomegaly.
The same immunologic methods used for lymphoma diagnosis can also be applied to differential diagnosis.
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Polycythemia
Polycythemia is an increase in the total blood RBCs over the upper limit of the reference range. This usually entails a concurrent increase in hemoglobin and hematocrit values. Since various studies disagree somewhat on the values that should be considered the upper limits of normal, partially arbitrary criteria are used to define polycythemia. A hemoglobin level more than 18 gm/100 ml (180 g/L) for men and 16 gm/100 ml (160 g/L) for women, with a hematocrit of more than 55% for men and 50% for women are generally considered consistent with polycythemia.
Polycythemia may be divided into three groups: primary (polycythemia vera), secondary, and relative.
Polycythemia vera has sometimes been included with CML and AMM as a myeloproliferative disease. Polycythemia vera is most frequent in persons between ages 40 and 70 years. Splenomegaly occurs in 60%-90% of patients and is more common in those with leukocytosis. Hepatomegaly is less frequent but still common (40%-50%). Polycythemia vera is reported to progress to myelofibrosis with myeloid metaplasia in about 20%-25% (range, 15%-30%) of cases, usually in 5-15 years. Five percent to 6% of polycythemia vera cases terminate in acute leukemia; this is more frequent after therapy with radioactive phosphorus (average, 10%-20% of cases) or after chlorambucil chemotherapy. The incidence of acute leukemia after phlebotomy therapy is not known with certainty but is believed to be considerably less than that associated with radioactive phosphorus. Clinically, there is an increased incidence of peptic ulcer and gout and a definite tendency toward the development of venous thrombosis.
Laboratory picture.— In classic cases, peripheral blood WBC counts and platelets are also increased with the RBC counts; however, this is not always found. The peripheral blood WBC count is more than 10,000/mm3 (10 x 109/L) in 50%-70% of the cases. About 20%-30% of patients have leukocytosis of more than 15,000/mm3 with relatively mature forms; about 10% have leukocytosis of more than 15,000/mm3 with a moderate degree of neutrophil immaturity (myelocytes and metamyelocytes present). Platelets are elevated in about 25% of cases. There may be small numbers of polychromatophilic RBCs in the peripheral blood, but these are not usually prominent. Bone marrow aspirates usually show marrow hyperplasia with an increase in all three blood element precursors—WBCs, RBCs, and megakaryocytes and with absent marrow iron. A marrow section is much more valuable than marrow smears to demonstrate this. The serum uric acid level is elevated in up to 40% of cases due to the increased RBC turnover.
The classic triad of greatly increased RBC mass (hemoglobin and hematocrit levels), leukocytosis with thrombocytosis, and splenomegaly makes the diagnosis obvious. However, the hemoglobin and hematocrit values are often only moderately elevated, and one or both of the other features may be lacking. The problem then is to differentiate between polycythemia vera and the other causes of polycythemia.
True polycythemia refers to an increase in the total RBC mass (quantity). Relative polycythemia is a term used to describe a normal total RBC mass that falsely appears increased due to a decrease in plasma volume. Dehydration is the most common cause of relative polycythemia; in most cases, the hematocrit value is high-normal or only mildly increased, but occasionally it may be substantially elevated. In simple dehydration, the values of other blood constituents, such as the WBCs, electrolytes, and blood urea nitrogen, also tend to be (falsely) elevated. The most definitive test is a blood volume study (Chapter 10), which will demonstrate that the RBC mass is normal. Stress polycythemia (Gaisbьck’s syndrome) also is a relative polycythemia due to diminished plasma volume. Most persons affected are middle-aged men; there is a strong tendency toward mild degrees of hypertension, arteriosclerosis, and obesity.
Secondary polycythemia is a true polycythemia, but, as the name implies, there is a specific underlying cause for the increase in RBC mass. The most common cause is either hypoxia (due to chronic lung disease but sometimes to congenital heart disease or life at high altitudes) or heavy cigarette smoking (“smoker’s polycythemia,” due to carboxyhemoglobin formation). In some cases associated with heavy smoking the RBC mass is within reference limits but the plasma volume is reduced, placing this group into the category of relative polycythemia. Cushing’s syndrome is frequently associated with mild, sometimes moderate, polycythemia. A much less common cause is tumor, most frequently renal carcinoma (hypernephroma) and hepatic carcinoma (hepatoma). The incidence of polycythemia is 1%-5% in renal carcinoma and 3%-12% in hepatoma. The rare tumor cerebellar hemangioblastoma is associated with polycythemia in 15%-20% of cases. There are several other causes, such as marked obesity (Pickwickian syndrome), but these are rare.
Laboratory tests useful to differentiate secondary and relative polycythemia from polycythemia vera
1. Blood volume measurements (RBC mass plus total blood volume) can rule out relative polycythemia. In relative polycythemia there is a decreased total blood volume (or plasma volume) and a normal RBC mass.
2. Arterial blood oxygen saturation studies frequently help to rule out hypoxic (secondary) polycythemia. Arterial oxygen saturation should be normal in polycythemia vera and decreased in hypoxic (secondary) polycythemia. Caution is indicated, however, since patients with polycythemia vera may have some degree of lowered PO2 or oxygen saturation from a variety of conditions superimposed on the hematologic disease. In smoker’s polycythemia, arterial blood oxygen saturation measured directly by a special instrument is reduced, but oxygen saturation estimated in the usual way from blood gas data obtained by ordinary blood gas analysis equipment is normal. In heavy smokers with polycythemia, a blood carboxyhemoglobin assay may be useful if arterial oxygen saturation values are within reference limits. A carboxyhemoglobin level more than 4% is compatible with smoker’s polycythemia (although not absolute proof of the diagnosis).
3. Leukocyte alkaline phosphatase is elevated in approximately 90% of patients with polycythemia vera; the elevation occurs regardless of the WBC count. Elevated LAP is unlikely in other causes of polycythemia unless infection or inflammation is also present.
4. Bone marrow aspiration or biopsy is often useful, as stated earlier. If aspiration is performed, a marrow section (from clotted marrow left in the syringe and fixed in formalin or Bouin-type fixatives, then processed like tissue biopsy material) is much better than marrow smears for this purpose. However, even bone marrow sections are not always diagnostic. In one study, about 5% of patients had normal or slightly increased overall marrow cellularity in conjunction with normal or only slightly increased numbers of megakaryocytes.
5. Erythropoietin hormone assay may be needed in a few equivocal cases (in most instances this would not be necessary). In polycythemia vera, erythropoietin levels are decreased, whereas in relative or secondary polycythemia, erythropoietin levels are normal or increased.
6. An elevated serum uric acid level without other cause favors the diagnosis of polycythemia vera, since secondary polycythemia is associated with normal uric acid values. However, since uric acid is normal in many cases of polycythemia vera, a normal value is not helpful. -
Leukemoid Reaction
Leukemoid reaction is an abnormally marked granulocytic response to some bone marrow stimulus, most commonly infection. Leukemoid reaction is basically the same process as an ordinary leukocytosis except in the degree of response. The expected peripheral blood WBC count response is even more marked than usual and may reach the 50,000-100,000/mm3 (50-100 x 109/L) range in some cases. Instead of the mild degree of immaturity expected, which would center in the band neutrophil stage, the immature tendency (“shift to the left”; see Chapter 6) may be extended to earlier cells, such as the myelocyte. The bone marrow may show considerable myeloid hyperplasia with unusual immaturity. However, the number of early forms in either the peripheral blood or bone marrow is not usually as great as in classic CML. There is no basophilia, although the increased granulation often seen in neutrophils during severe infection (“toxic granulation”) is sometimes mistaken for basophilia. The bone marrow in leukemoid reaction is moderately hyperplastic and may show mild immaturity but, again, is not quite as immature as in CML. Splenomegaly and lymphadenopathy may be present in a leukemoid reaction due to the underlying infection, but the spleen is usually not as large as in classic CML.
One other phenomenon that could be confused with CML is the so-called leukoerythroblastic marrow response (Chapter 6) seen with moderate frequency in widespread involvement of the bone marrow by metastatic cancer and occasionally in diseases such as severe hemolytic anemia, severe hemorrhage, and septicemia. Anemia is present, and both immature WBCs and nucleated RBCs appear in the peripheral blood.
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Chronic Myelogenous (granulocytic) Leukemia (CML)
CML is most common between the ages of 20 and 50 and is rare in childhood. It comprises about 20% of all leukemias. There is an increased (total) peripheral WBC count in more than 95% of patients, with about 70% more than 50,000/mm3 (50 Ч 109/L) and about 45% more than 100,000/mm3. There is usually a predominance of myeloid cells having intermediate degrees of maturity, such as the myelocyte and early metamyelocyte. In fact, the peripheral blood smear often looks like a bone marrow aspirate. Anemia is usually present, although initially it is often slight. Later, anemia becomes moderate. There may be mild reticulocytosis with polychromatophilia, and occasionally there are a few nucleated RBCs in the peripheral blood. Platelets are normal in about 75% of patients and increased in the remainder, with about 8% having thrombocytosis more than 1,000,000/ mm3. Average patient survival is 2-4 years after onset. Terminally, 70%-80% of patients develop a picture of acute leukemia (the blast crisis); about 70% of these are AML and about 30% are ALL or rarely some other type.
Bone marrow aspiration in CML shows a markedly hypercellular marrow due to the granulocytes, with intermediate degrees of immaturity. In this respect it resembles the peripheral blood picture. Some patients develop varying degrees of marrow fibrosis and can therefore simulate myelofibrosis (myeloid metaplasia, discussed later).
On physical examination there are varying degrees of adenopathy and organomegaly. The spleen is often greatly enlarged, and the liver may be moderately enlarged. Lymph nodes are often easily palpable but generally are only slightly to moderately increased in size.
Many patients with CML have an increased number of basophils in the peripheral blood. The reason for the basophilia is not known.
An interesting aspect of CML is the presence of a specific chromosome abnormality called the Philadelphia chromosome in the leukemic cells of most patients. No other neoplasm thus far has such a consistent cytogenetic abnormality. The abnormality involves the breaking off of a portion of the long arm of chromosome number 22 (formerly thought to be number 21) of the 21-22 group in the Denver classification (G group by letter classification); the broken-off chromosome segment is usually translocated to chromosome number 9. The abnormal chromosome 22 (Philadelphia chromosome) using standard cytogenetic methods is found in approximately 85%-90% of patients with CML (reported range, 60%-95%). Those not having it seem as a group to have a worse prognosis. Interestingly, the Philadelphia chromosome has also been reported in about 25% of patients with adult-onset ALL and in some patients with the ALL variant of CML blast crisis.
Philadelphia chromosome detection usually involves cytogenetic chromosome analysis, that is, separating the chromosomes from several body cells and visually inspecting each chromosome for abnormality. It is now possible to use the nucleic acid probe (see “DNA Probe,” Chapter 14) technique for the same purpose. There is a gene area called bcr (breakpoint cluster region) in chromosome 22 that develops a crack or fissure to which a genetic area called c-abl (located at one end of the long arm of chromosome 9) becomes attached and fused. The restructured chromosome 22 with the grafted DNA material from chromosome 9 now has a hybrid gene bcr-abl at the fusion area. There is some evidence that this abnormal hybrid gene may have a role in the events that lead to the development of CML (therefore it acts as an oncogene). A DNA probe has been constructed to detect the new hybrid gene; this has been called by some “bcr gene rearrangement assay.” The DNA probe method has certain advantages over the cytogenetic method. The DNA probe can be used on peripheral blood specimens, does not require bone marrow, does not need dividing cells, and analyzes thousands of cells—versus less than 20 by cytogenetic analysis. In addition, the DNA probe is claimed to be 5%-10% more sensitive than cytogenetic analysis. At present, the bcr rearrangement assay is mostly available in reference laboratories or university medical centers.
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Chronic Lymphocytic Leukemia (CLL)
CLL comprises about 30% of all leukemias. It is uncommon in Asians. The lymphocytes of CLL are B-lymphocytes, although there are about 2%-3% (range, 2%-5%) of cases that consist of T-lymphocytes. The disease is usually found after the age of 50. It is twice as common in men than in women. Average survival is 3-7 years after diagnosis, with an appreciable number of patients alive at 8-10 years. Various chromosome abnormalities are reported in about 50% of patients. Total WBC counts are usually elevated; in one study about 10% were normal; about 45% were between 10,000 and 50,000/mm3 (10-50 Ч 109/L), about 15% were between 50,000 and 100,000/mm3, and about 35% were more than 100,000/mm3. The majority (frequently, the great majority) of the WBCs are lymphocytes; of these, most (often nearly all) are mature types. In some patients there may be a considerable number of prolymphocytes and even some blasts, but this is not common. There is mild to moderate normocytic-normochromic anemia, usually without reticulocytosis. Platelets are decreased in approximately 40% of cases, but this may not occur until late in the disease. The bone marrow contains at least 20% lymphocytes and usually more than 50%. There is splenomegaly in 65%-75% of cases, usually to at least moderate degree, and moderate adenopathy in 65%-85% of cases. Hepatomegaly is found in approximately 50% of patients. Occasionally the splenomegaly and adenopathy are marked. There is a considerable tendency to infection, and this is often the cause of death. A Coombs’-positive autoimmune hemolytic anemia is reported in about 10% (5%-20%) of cases; a Coombs’-negative hemolytic anemia, often without a reticulocytosis, eventually develops in 15%-25% of cases. About 50% (40%-77%) of patients eventually develop some degree of hypogammaglobulinemia, with any or all of the major immunoglobulins (IgG, IgA, and IgM) being involved. There is some disagreement as to which of the three is most frequently decreased. Up to 5% of CLL patients develop a serum monoclonal protein like those produced in myeloma.
In the majority of patients with CLL the disease is relatively benign and only slowly progressive over a period of several years. In approximately 20% the disease is more aggressive. Whether this represents a distinct subset of CLL or simply diagnosis relatively late in the course of the disease is still being debated. Patients with CLL have an increased chance of developing a second malignancy, most often a carcinoma. This tendency is disputed by some but has been reported to be as high as 34%. One well-recognized condition is called Richter’s syndrome, in which approximately 5% (literature range, 3%-15%) of CLL cases evolve into or develop non-Hodgkin’s lymphoma, most commonly the large cell type (histiocytic lymphoma in the Rappaport classification). About 1.5% (0%-6.9%) of CLL cases terminate in a “blast crisis.” The majority are ALL, but acute myeloblastic leukemia (AML) and others have been reported. Finally, a few patients with CLL develop transformation to prolymphocytic leukemia, which is more aggressive. Prolymphocytic leukemia can also exist without known previous CLL but is very uncommon.
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Hairy Cell Leukemia
This disease has now been classified as a B-lymphocyte disorder. A few variant patients, such as rare patients with T-cell characteristics, have been reported. A few cases have been reported in association with retrovirus HTLV-II infection. Hairy cell leukemia was originally called leukemic reticuloendotheliosis. It affects primarily men (male/female ratio 4:1) between ages 40 and 60 (range, 24-80) years. The clinical course if untreated is usually described as chronic but progressive (mean 4 years, range <1 to >20 years). The most common cause of death is infection (55%-65% of patients). There is splenomegaly in 80%-90% of cases; about 20% have spleens with enlargement to palpation of less than 5 cm, whereas about 15% are more than 15 cm. In the typical patient there is splenomegaly without lymphadenopathy; lymphadenopathy actually does occur in approximately 30% of cases but is usually not prominent. Mild hepatomegaly is found in approximately 20%.
Laboratory picture.— Cytopenia in one or more peripheral blood elements is present in 87%-100% of patients. Normocytic-normochromic anemia is found in 80%-84%; thrombocytopenia in 60%-70% (range, 50%-87%); leukopenia in 50%-60% (range, 48%-66%); normal WBC count in 20% (range, 15%-24%); leukocytosis in 10%-15%; and pancytopenia in about 60% (range, 35%-90%). A relative lymphocytosis is frequently present. Serum alkaline phosphatase levels are elevated in about 20% of cases. Hairy cells are present in the peripheral blood in approximately 90% of patients, although the number of such cells varies considerably. In most cases there are relatively few hairy cells; in 10% of cases more than one half of all leukocytes are hairy cells. Hairy cells are present in the bone marrow and spleen as well as the peripheral blood. The hairy cell is similar to a lymphocyte in appearance but the cytoplasm appears frayed or has irregular, narrow, hairlike projections. The hairy cytoplasm appearance is not specific; it may occasionally be seen in a few persons with other conditions or as an artifact (usually only a few cells are affected).
Bone marrow aspiration is diagnostic in 70%-80% of cases in which marrow is obtained; no marrow can be aspirated in 30%-50% of patients, and a bone biopsy is then necessary. Some investigators believe that bone marrow is nearly always diagnostic if the correct specimen in sufficient quantity is obtained and adequate testing is done. Clot sections as well as smears should be prepared if marrow is aspirated, and slide imprints should be made if a bone biopsy is performed. The bone marrow is usually hypercellular but occasionally may be normocellular or even hypocellular. Some patients develop varying degrees of marrow fibrosis, which could lead to a misdiagnosis of myeloid metaplasia. Marrow infiltration by hairy cells begins in small patches that eventually become confluent and finally become generalized. Spleen sections typically show involvement of the red pulp rather than the malpighian corpuscles, and spleen sections may contain diagnostic pseudosinuses lined by hairy cells.
Acid phosphatase stain.— Hairy cells typically demonstrate a positive cytoplasmic acid phosphatase cytochemical reaction, which is resistant to tartrate. This reaction was originally thought to be specific for hairy cells but has since been found (more often with weak reactivity) in some patients with B-cell or T-cell CLL, prolymphocytic leukemia, adult T-cell leukemia, Sйzary syndrome, and occasionally in acute myeloblastic leukemia and acute monoblastic leukemia. On the other hand, the number of hairy cells that exhibit a positive tartrate-resistant acid phosphatase reaction is variable (5%-95% of the hairy cells), and in about 5% (range, 5%-10%) of patients all peripheral blood and bone marrow cells may be normal. A few patients become diagnostic problems, and electron microscopy (ribosomallamellar complex in 60%) or testing for certain antigens (e.g., HLA-DR) may be helpful.