The classification and pathology of the lymphomas and leukemias

The Classification of the Lymphomas Thomas

T

R. Callihan

HE UNDERSTANDING of any disease starts with having a classification scheme through which the disease may be separated from other clinical and pathologic entities. An optimal classification should be easily applied, readily reproducible, clinicopathologically relevant, prognostically informative, and biologically accurate. Ever since Thomas Hodgkin’s paper in 1832, there have been numerous attempts to classify neoplasms of the lymphoreticular system. Historically, classifications have been based on variations in histology, cytology, and patterns of growth. Well known examples of such classifications are those of Rappaport for non-Hodgkin lymphomas49 and Lukes and Butler34 for Hodgkin disease. By applying immunologic techniques developed during the past decade and reviving histochemical and cytochemical techniques, the cells of the lymphoreticular (reticuloendothelial, immune) system have been categorized as B cells, T cells, or histiocytes (monocytes, macrophages). The next logical step, application of these techniques to lymphoreticular neoplasms, revealed that the malignant lymphomas and related neoplasms are actually cancers of the immune system. The cells of lymphoreticular malignancies are neoplastic populations simulating normal cells in various compartments of the organs composing the reticuloendothelial system’ (Fig. 1). In fact, the malignant cells may remarkably mimic, both functionally and morphologically, their normal counterparts. The discovery that many non-Hodgkin lymphomas are derived from T and B cells has led to a plethora of newly proffered and still controversial classifications. The prevailing morphologic classification of Rappaport was proposed and proved to be clinically valuable before modern immunologic methods revealed certain biologic inaccuracies within it. To overcome this deficit, Lukes and Collins proposed a so-called functional classification that correlated the morphology of the neoplastic cells with their presumed immunologic markers.35 Their unique classification is based on the premise that the B or T cell

Seminars

in Roentgenology,

Vol. XV, No. 3 (July), 1990

and Pathology and Leukemias and Costan

W. Berard

nature of the neoplastic cells can be discerned from examination of histologic sections. At present, a modification of the Rappaport classification for non-Hodgkin lymphomas is still the most useful scheme for clinicians and pathologists (Table 1). There are not yet sufficient data to assess the utility of the functional classification of Lukes and Collins. The modified Rappaport classification is based on both the growth pattern (nodular or diffuse) and the cytology of the malignant lymphoma (lymphocytic, undifferentiated, lymphoblastic, or histiocytic).39.44.46

The classification, staging, and treatment of Hodgkin disease are not particularly controversial. However, there is controversy concerning the nature of the malignant cells. The current classification is the Rye modification36 of the Lukes and Butler scheme (Table 2), with four histologic types that correlate well with the clinical stage and aggressiveness of the disease.’ The classification of leukemias has become more important with the advent of increasingly effective chemotherapy, particularly in acute leukemias of childhood. Classification systems of leukemia have been based on (1) morphologic differences, (2) immunologic differences, (3) clinical manifestations and rapidity of onset of these manifestations, and (4) response to therapy and prognosis. The terms acute and chronic are no longer applicable to predicting lifespan but they are still appropriate for describing the rapidity of development of clinical manifestations. While some problems encountered in classification are unique to leukemias, eg, agreeing on From the Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Term. Thomas R. Callihan, M.D.: Assistant Member, Department of Pathology, St. Jude Children’s Research Hospital; Costan W. Berard, M.D.: Chairman, Department of Pathology, St. Jude Children’s Research Hospital. Address reprint requests to Thomas R. Callihan, M.D., Department of Pathology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, Tenn. 38101. 0 1980 by Grune & Straiton. Inc. 0037-I 98X/80/3 5034003%02.00/0

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Mdiiliii Nodular

I

Wolli)

Lymphoma

Fig. 1. Diagram of lymph node illustrating anatomic and functional compartments. Lymphoreticular malignancies are related to the various compartments. F, follicles; PC, paracortex; MC, medullary cords; and S, sinuses. (Reproduced by permission of the American Journal of Pathology.“)

Chronic LymphoqtiiLeukemia WSN DiiLymphocpic Lvmphoma w-s

Msaogkbliiis Hodgkim’s

Dll

methods for distinguishing myeloid from lymphoid cells, other difficulties are the same as those experienced in classifying malignant lymphomas. As with malignant lymphomas, the application of immunologic and cytochemical techniques has revealed important information concerning the nature of leukemic cells. Attempts at classification of leukemias, especially the acute forms, have not always met with widespread acceptance. Because of the wide range of morphologic variation, the same terms are applied in different ways by different observers and different designations are used for the same condition. Two additional findings that Table

1. Modified Non-Hodgkin

Nodular

(Follicular)*

Poorly

differentiated

cytic

Rappaport Malignant

Classification Lymphomas Diffuse

lympho-

Well

(PDL)

Mixed

differentiated

cytic

lymphocytic-histiocytic

(mixed

Ihistiocytic)

Mixed

NON-HODGKIN

differentiated

lymphocytic

(IDL)

differentiated

cytic cell

lympho-

(WDL)

Intermediate

cell)

Poorly Large

of

Nodular

IPDLI

(histiocytic)

(DLCL)

Undifferentiated,

Burkitt

Undifferentiated,

non-Burkitt

(pleomorphic) Lymphoblastic

lymphocytic pattern.

examples have

of been

lymphoma

nodular

well

reported. may

exhibit

differentiated Intermediate a vaguely

(Follicular)

(TABLE

I)

Lymphomas

2.

Classification

Modification”

lymphocytic differentiated nodular

In the United States, nodular lymphomas comprise approximately 40-45% of all adult non-Hodgkin lymphomas. As pointed out by Jones et a1,29these neoplasmsdisplay distinctive clinical features, namely, prevalence in older Table

(LBL)

Unclassified *Rare

LYMPHOMAS

lympho-

lymphocytic-histiocytic

(Ml Large cell

lymphoma

have complicated the classification of leukemias are (1) the presence of cells with typical lymphoid morphology in what are otherwise typical myeloid leukemias4 and (2) the overlap between certain leukemias and lymphomas (eg, acute lymphoblastic leukemia and lymphoblastic lymphoma, chronic lymphocytic leukemia, and well differentiated lymphocytic lymphoma). A group of French, American, and British hematologists recently published proposals for the classification and nomenclature of acute 1eukemiasP Their classification is based on morphological appearances of bone marrow and peripheral blood in Romanowsky-stained smears supplemented by selected cytochemical reactions. A useful morphologic classification of leukemias is given in Table 3. In the ensuing pageseach of the major types of lymphomas and leukemias will be discussed.

growth

of Hodgkin of Luke+Butler

Lymphocytic Mixed

predominance

cellularity

Lymphocytic Nodular

Disease Classification) (LP)

(MC) depletion

sclerosis

(NS)

(LD)

(HD)

(Rye

CLASSIFICATION

AND

Table

205

PATHOLOGY

3.

Classification

of Leukemias

Lymphoid Acute

lymphoblastic

Chronic

lymphocytic

S&ry

syndrome

Myeloid Acute

myeloblastic

and

(promyelocytic, myelomonoblastic, Chronic

its variants

monoblastic, and

erythroleukemia)

myelocytic

Granulocytic Leukemic

sarcoma

conversion

of lymphomas

Others Hairy

cell leukemia

(leukemic

reticuloendotheliosisl Plasma Mast

cell cell

Congenital Dysmyelopoletic

leukemia

leukemia leukemia syndromes

patients (fifth through seventh decades), rarity in children and adolescents, equal sex incidence, and usually disseminated disease at presentation. Historically, one of the major types of lymphoma is the so-called giant follicular lymphoma. Gall and Rappaport” introduced the term nodular to replace follicular since at the time there was no proof that follicular lymphomas actually originated from or were associated with normal follicles or germinal centers. Lennert32 felt that nodular lymphomas resulted from malignant transformation of normal follicular cells, and he provided cytochemical and electron microscopic evidence to support this contention. Lukes also supported a follicular origin, since cytologically the malignant cells of nodular lymphoma resembled some of the nonneoplastic cells of normal germinal centers. Subsequently, Jaffe et a126 presented immunologic proof that nodular lymphoma originates from follicular B lymphocytes. In nodular lymphoma, even the large cells originally designated as “histiocytes” by Rappaport are in fact transformed B lymphocytes. The most striking histologic feature of these neoplasms is the nodular pattern of growth. The normal architecture of the lymph node is effaced by nodular aggregates of neoplastic cells that compress the surrounding parenchyma (Fig. 2). These nodules contain, in contrast to the polymorphous cellular composition of reactive germi-

Fig. 2. Nodular uniform shape and E. x 8).

size

lymphoma. efface the

Nodules of relatively nodal architecture (H &

nal centers, a monomorphic or bimorphic population of cells. The three cytologic types of nodular lymphomas (Table 1) represent three cytologic variants of a single disease entity. The term poorly diflerentiated lymphocytic (PDL) designates the most commonly encountered nodular (follicular) lymphoma, with nodules composed predominantly of small lymphocytes with scant cytoplasm, coarse chromatin, and irregular,

Fig. 3. Nodular poorly differentiated lymphoma. The nuclei are irregular coarse chromatin (H 81 E. x 860).

and

lymphocytic cleaved with

206

indented, and cleaved nuclei (Fig. 3). The term large cell (histiocytic) is applied to the infrequent nodular lymphoma composed predominantly of large cells (2-3 times the diameter of normal lymphocytes) with a moderate amount of cytoplasm, vesicular nuclei, and l-3 nucleoli. Finally, the nodules may be composed of an approximately equal admixture of small cleaved lymphocytes and large lymphoid cells (histiocytes). Such lymphomas are designated as mixed lymphocytic-histiocytic. In contrast to Lukes, it has been our experience that mixed lymphocytichistiocytic lymphomas are composed of large noncleaved and small cleaved cells rather than large cleaved and small cleaved cells. This type of lymphoma (nodular mixed) is very difficult to distinguish from benign reactive follicular hyperplasia. As previously mentioned, a classification should provide both prognostication and relevant clinical correlations. The Rappaport classification meets these objectives in its subcategorization of nodular lymphomas. Since the large cell (histiocyte) has the most marked proliferative activity, one would expect nodular lymphomas with the greatest number of large cells to have, for a given stage, the most aggressive clinical course and worst prognosis. This expectation is substantiated in reality with the median survivals of nodular lymphoma in one series being PDL-78 mo, mixed-55 mo, and histiocytic29 mo.23 Stanford University data are similar, with median survivals of 7.5 yr, 7 yr, and 2.9 yr for nodular PDL, mixed, and histiocytic, respectively.2’ Although patients with nodular PDL lymphoma usually present with disseminated disease (frequently with bone marrow and hepatic involvement), they have a relatively favorable prognosis. In contrast to patients with nodular PDL lymphoma, patients with the nodular histiocytic form more often present with localized disease. Even so, their survival is the poorest of all nodular lymphomas. Another important feature of nodular lymphomas is their tendency to progress from a relatively favorable cytology, eg, PDL, to a more aggressive histiocytic lymphoma. There is also commonly a change in growth pattern from nodular to diffuse. Patients with both nodular and diffuse patterns of histiocytic lymphoma are believed to have a poorer prognosis than those with a purely nodular pattern. In contradistinc-

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tion, a combination of nodular and diffuse patterns with either PDL or mixed lymphoma did not impart a poorer prognosis.62 Garvin et alz3 reviewed 515 cases of nonHodgkin lymphomas and evaluated all histologic changes in biopsies 3 mo or more following the initial diagnostic biopsy. Of the 118 patients rebiopsied, 44 (37%) showed histologic changes. In 35 of these, the changes consisted of progression from a nodular to a diffuse pattern, progression to less favorable cytology, or both. The progression in histology was accompanied by a significant shortening of median survival.” Diffuse

Lymphomas

From both clinical and morphological viewpoints, this group of tumors is diverse. It contains someof the most indolent malignancies known to affect humans as well as some of the most aggressive. Well Diferentiated Lymphocytic Lymphoma, Waldenstrijm Macroglobulinemia, and Chronic Lymphocytic Leukemia Pangalis et a1,48in a review of 108 patients with well differentiated lymphocytic malignancies, found three distinct groups. The first consistedof 41 patients without peripheral blood lymphocytosis or monoclonal gammopathy. Even though 59% of these patients had bone marrow involvement, only 4 developed lymphocytosis during the course of the disease. The second was composedof 20 patients with monoclonal gammopathy. Half of them had bone marrow involvement, but none developed leukemia. In the third group were 47 patients with peripheral lymphocytosis but no monoclonal gammopathy. These three groups were considered to be diffuse well differentiated lymphocytic lymphoma (WDL) (small lymphocytic type of Lukes), Waldenstrom macroglobulinemia (WM) (plasmacytoid lymphocyte of Lukes), and chronic lymphocytic leukemia (CLL), respectively. These three forms of presentation, which represent about 5% of non-Hodgkin lymphomas, occur in older (sixth or seventh decade) patients. There is usually a paucity of symptoms despite generalized disease.Diffuse WDL presents with adenopathy, CLL with peripheral blood and bone marrow involvement, and WM with adenopathy and hepatosplenomegaly. All have a

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PATHOLOGY

protracted course. Histologically these diseases are quite similar. Lymph nodes involved with diffuse WDL or CLL show replacement of the normal population by a proliferation of small round lymphocytes. Scattered either individually or in clusters among the small lymphocytes are large lymphoid cells with vesicular nuclei and prominent nucleoli. Even though these clusters, which are called pseudofollicular growth centers, may contain mitotic figures, they are not a prognostically unfavorable finding.*’ In WM, the neoplastic cells secrete monoclonal IgM into the serum, detectable as a spike on electrophoresis. The histologic picture of WM is variable. In about 80% of cases the lymph nodes contain small lymphocytes admixed with plasmacytoid forms and large lymphoid cells. The lymph nodes from another 10% are identical to those seen in CLL or diffuse WDL lymphoma, while the histologic findings in the final 10% are typical of multiple myeloma, ie, they show proliferation of mature and immature plasma cells. Non-neoplastic well differentiated B lymphocytes of the medullary cords of lymph nodes and bone marrow are the counterparts of diffuse WDL, WM, and CLL. Since some normal medullary cord lymphocytes differentiate into plasma cells and secrete immunoglobulin, the diverse histologic changes seen in WM are not surprising. The cells have undergone neoplastic transformation at an early secretory stage and are merely performing their normal function of IgM secretion. In addition, medullary cord lymphocytes are normally mobile and in free exchange with peripheral blood. Hence these patients may develop circulating neoplastic cells (ie, CLL). Occasionally any well differentiated lymphocytic neoplasm may undergo progression to a large cell (histiocytic) malignancy. This progression in the context of CLL is called Richter syndrome. Prior to the advent of immunologic markers, such neoplasms were often interpreted as second tumors. However, it has now been established that the supervening large cell lymphoma usually represents a more aggressive morphological expression of the original neoplastic B cells. Blastic transformation to a more acute type of leukemia, as seen in chronic myelocytic leukemia, is uncommonly observed in CLL.

T-cell CLL also exists but accounts for less than 5% of all cases, often presenting with peculiar hematologic and clinical features.” Splenomegaly is massive, lymphadenopathy is mild, and cutaneous lesions and neutropenia are frequent. The neoplastic cells contain cytoplasmic azurophilic granules and exhibit acid phosphatase activity. Intermediate Lymphoma

Diflerentiated

Lymphocytic

(IDL)

IDL lymphoma is a recently recognized entity clinically akin to diffuse WDL and nodular PDL lymphoma. It has immunologic, cytochemical, and histologic characteristics intermediate between those of diffuse WDL and nodular PDL lymphomas. In over half the cases the neoplastic B cells are alkaline phosphatase positive. In normal lymph nodes, the mantle zone around germinal centers contains identical alkaline phosphatase positive B cells. Thus, the IDL apparently arises from lymphocytes comprising the mantle zones of secondary lymphoid follicles.42 Histologically, the pattern varies from diffuse to vaguely nodular. Tiny germinalcenter-like aggregates are frequently seen amid the neoplastic cells. Cytologically this lymphoma contains a mixture of small round lymphocytes (as seen in diffuse WDL lymphoma) and small cleaved lymphocytes (as seen in nodular PDL lymphoma). Clinically these patients have advanced disease with superficial nodal and bone marrow involvement. Over half have deep nodal, splenic, and hepatic involvement. Although bone marrow involvement is common, leukocytosis or a leukemic blood picture is infrequent. The survival is intermediate between that of diffuse WDL and diffuse PDL lymphoma. It is important to recognize this entity, as it should be treated as a “favorable” lymphocytic lymphoma. Poorly Differentiated

Lymphocytic

Lymphoma

This generic term includes a heterogeneous group of lesions that comprise lo-12% of nonHodgkin lymphomas. One clinicopathologic entity that was previously included in this group has now been segregated: lymphoblastic lymphoma (see later). Most of the remaining patients with the diffuse PDL label actually have

208

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tumors composed of small cleaved lymphocytes identical to those of nodular PDL lymphoma. The disease may have started as a nodular lymphoma and transformed to the diffuse phase prior to clinical recognition or biopsy. Most patients with PDL lymphoma are older and have generalized adenopathy often with hepatic and bone marrow involvement. Like their nodular counterpart, the tumor cells have B-cell characteristics. Traditionally the prognosis for diffuse PDL lymphoma has been considered poor, largely because lymphoblastic lymphoma, a rapidly progressive disease, has been included in this group. Today the prognosis of diffuse PDL lymphoma composed of small cleaved follicular center cells appears to be similar to that of nodular PDL lymphoma. Another lymphoma included in this spectrum is a distinctive type composed of lymphoid cells with a broad range of maturation and considerable variation in size, shape, and nuclear chromatin. These pleomorphic lymphoid cells, some of which may simulate Reed-Sternberg cells, are often accompanied by benign epithelioid histiocytes. In cases studied immunologically, the neoplastic cells have had T-cell markers. Waldron6’ has postulated that this tumor arises from peripheral T lymphocytes, as opposed to thymic lymphocytes. The prognosis is poor with survival averaging 9 mo. Mixed Lymphocytic-Histiocytic

Lymphoma

Like diffuse PDL lymphoma, the diffuse mixed group is not a single lesion but appears to be composed of at least two different entities. The more common type is a B-cell tumor cytologically similar to the nodular mixed form but with a totally diffuse pattern of growth. Cytologically there are small cleaved lymphocytes and larger cells with vesicular nuclei-the so-called histiocytes of Rappaport. As with DPDL lymphomas, it is presumed that these mixed lymphomas were actually nodular at inception. While their clinical features are similar, the prognosis of diffuse mixed lymphoma (median survival of 20 mo) is worse than that of diffuse PDL lymphoma.23 In 1968, Lennert and Mestdagh33 described an uncommon lesion that is still poorly understood and frequently referred to as Lennert’s lymphoma or lymphoepithelioid cellular lym-

AND

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phoma. Even though initially considered to be a type of Hodgkin disease, the tumor is now classified as a form of non-Hodgkin lymphoma akin to diffuse mixed lymphoma. The major and characteristic difference between typical mixed lymphoma and the Lennert lymphoma is the presence in the latter of a high content of epithelioid histiocytes arranged throughout in cords or aggregates. The associated lymphoid cells are moderately pleomorphic. In addition, reactive cells, particularly plasma cells and eosinophils, may be present and cause misinterpretation as Hodgkin disease. With certain exceptions, eg, frequent involvement of Waldeyer ring, skin, epitrochlear nodes, and parotid gland, the clinical characteristics are similar to diffuse mixed lymphoma without epithelioid cells. Prognosis is poor, with median survival less than 2 yr. Large Cell (Histiocytic)

Lymphomas

This group, which comprises about 30% of non-Hodgkin lymphomas, is responsible for many of the controversies concerning classification. One of the present challenges for hematopathologists is the understanding of the diffuse large cell lymphomas (DLCL). Originally they were known as reticulum cell sarcoma. Later they were called histiocytic lymphoma because the malignant cells are similar in size and certain nuclear characteristics to benign histiocytes. It has now been established that the histiocytic lymphomas include a number of immunologically different neoplasms, most being lymphoid rather than truly histiocytic in nature. About 50-60% can be typed as B cells, 515% as T cells, and less than 5% as true histiocytes. In about 30-35% there are no immunologic markers (null cells).*’ Morphologically, the term large cell lymphoma similarly encompasses several subtypes that have in common cells with large diameters, vesicular nuclei, and prominent nucleoli (Figs. 4 and 5). Several clinical features are common to all large cell lymphomas regardless of the morphologic or immunologic subtype. These neoplasms occur in both children and adults, although their incidence increases with age. At the National Cancer Institute (NCI), 40% of patients with DLCL had both infra- and supradiaphragmatic nodal involvement (compared to 90% in nodular lymphomas) and 30% of the patients had stage 1

CLASSIFICATION

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PATHOLOGY

are differences in the gross pathology of involved organs. One or more large destructive tumefactions in the liver or spleen commonly occur in DLCL. In contrast, nodular lymphomas and diffuse PDL lymphoma frequently involve organs in a miliary fashion, with localization to the follicular regions of the splenic white pulp and the portal triads of the liver. In the Lukes classification, DLCL include large cleaved, large noncleaved, true histiocytic, and immunoblastic sarcomas of B- or T-cell types. There is some evidence that DLCL composed of large cleaved cells may have the most favorable prognosis.46*55 Fig. 4. completely x 36).

Diffuse effaced

lymphoma. by proliferating

The

nodal neoplastic

architecture is cells (H 61 E.

or II disease (compared to 10% in nodular lymphomas).‘5 Also characteristic is the frequency with which these tumors occur in extranodal sites. At the NCI, 40% of them were in extranodal sites, principally the gastrointestinal (GI) tract, skin, and bone. Bone marrow and hepatic involvement are uncommon at the time of diagnosis (they are common in nodular lymphomas). Bone marrow infiltration occurring during the course of the disease is a poor prognostic sign; 65% of patients with DLCL in the bone marrow developed leptomeningeal lymphoma.12 In addition to differences in clinical features between nodular lymphomas and DLCL, there

Fig. 5. the large moderate

Diffuse large cell noncleaved cells amount of cytoplasm

(histiocytic) lymphoma. with vesicular nuclei (H 61 E. x g6Ol.

Note and a

Undiflerentiated Lymphoma, Burkitt Burkitt (Pleomorphic) Types

and Non-

The pathologic entity, Burkitt lymphoma (BL), was first brought to international attention in 1958 by Denis Burkitt, a surgeon working in Uganda. After the initial reports, confusion and controversy regarding this neoplasm mounted and in 1967 an expert committee commissioned by the World Health Organization met and formalized a histopathologic definition of the tumor.7 Subsequently, this lymphoma has attracted attention that far outweighs its incidence. Endemic in certain parts of Africa, it occurs sporadically in many other areas of the world. Although endemic and sporadic cases are indistinguishable cytologically, cytochemically, and immunologically, there are important clinical and serologic differences between them.‘*3 Burkitt lymphoma is characterized by rapidly growing solid tumors. Both endemic and sporadic cases occur over a wide age range, but BL is clearly a tumor of childhood, comprising about l-2% of all childhood neoplasms. Endemic patients are younger (median age 6-8 yr) than sporadic ones (median age lo-12 yr). Maxillomandibular presentations occur primarily in younger patients with abdominal presentations (ileocecal, retroperitoneal, ovarian) predominate in older patients. Extranodal sites are commonly involved. Peripheral lymph nodes may be involved but the adenopathy is usually localized. In contrast to lymphoblastic lymphoma, pulmonary, mediastinal, or pleural involvement are distinctly uncommon on presentation. The bone marrow is usually free of tumor at presentation but extensive infiltration may occur during the

CALLIHAN

210

course of the disease. As with DLCL, bone marrow involvement is associated with an increased risk of leptomeningeal involvement and portends a poor prognosis.‘.3,63 An overt leukemic presentation is extremely rare but in about 5% of patients (those with extensive visceral disease) the peripheral blood eventually contains circulating neoplastic cells. The histopathologic features of BL are specific. It consists of a monotonous proliferation of primitive or blastic cells (small noncleaved follicular center cells in the Lukes classification). Since BL has a brisk mitotic rate and a high growth fraction, benign macrophages containing nuclear debris are usually present in abundance. These macrophages impart a “starry sky” appearance, in which the nuclei of the neoplastic cells approximate in size the nuclei of the macrophages. The uniformly round to oval nuclei contain 2-5 conspicuous nucleoli. The cytoplasm contains neutral lipid-laden vacuoles. BL is related to some B lymphocytes of normal germinal centers.40 From an etiologic standpoint, evidence implicating the EpsteinBarr virus (EBV) is much stronger for endemic than for sporadic cases. The endemic cases have a high antibody titer to EBV, and in 80-90% of cases, viral genome can be identified within the malignant cells. In the sporadic cases, in contrast, antibody titers are variable and only 1O-20% contain detectable viral genome. Regarding prognosis, combination chemotherapy has produced 2 yr survival rates (and possible cures) of 54% in both endemic and sporadic cases.63 Undifferentiated non-Burkitt (pleomorphic) lymphoma shares some features (high mitotic rate, starry sky appearance) with BL. Cytologically the neoplastic cells are similar in median diameter to BL cells but show a greater range of nuclear sizes and shapes; binucleate forms and cells with single central prominent nucleoli may be present. There are also clinical features unlike those of typical BL. The median age of patients with undifferentiated non-Burkitt lymphoma is 34 yr, with a range extending from the first to the seventh decade.23 Although fewer patients than those with BL have disseminated disease, the course is usually rapid and the prognosis is poor. The median survival is 10 mo.

Lymphoblastic

AND

BERARD

Lymphoma

Previously included in the diffuse PDL lymphoma group, lymphoblastic lymphoma (LBL) has now been segregated as a separate clinicopathologic entity.45 This tumor, formerly referred to as lymphosarcoma of childhood or Sternberg sarcoma, accounts for about 30-35% of childhood but less than 5% of adult nonHodgkin lymphomas. Histologically LBL consists of a diffuse proliferation of cells with scant cytoplasm and round to convoluted nuclei. The chromatin is finely dispersed and nucleoli are inconspicuous (Fig. 6). As with BL, there is a high mitotic rate; a starry sky appearance may be present. This tumor exhibits several characteristic clinical features. Children and adolescents are primarily affected, but cases have been reported up to the eighth decade. A supradiaphragmatic presentation is most common, with mediastinal masses in 50% of cases. Subdiaphragmatic and extranodal presentations occur (pleura, breasts, gonads, skin, tonsils) although one site, the gastrointestinal tract, is infrequently involved (in distinct contrast to BL). The tumor has a poor prognosis as it rapidly spreads to the bone marrow, blood, and cerebrospinal fluid. The median survival was 8 mo in Nathwani’s series.45 As suggested by its clinical presentation, the tumor is histogenetically related to the thymus gland.53 In addition to T-cell markers, the cells

Lymphoblastic lymphoma. Fig. 6. of cells with round and convoluted uted chromatin (H 61 E, x 960).

Uniform nuclei and

proliferation finely distrib-

CLASSIFICATION

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211

usually show features normally found in immature thymocytes. Terminal deoxynucleotidyl transferase, for example, is characteristically identified in the malignant cells4’ and a variable percentage may have complement receptors and strong focal acid phosphatase activity. Additional evidence of the T-cell nature of this tumor is its selective involvement of the paracortical regions. HODGKIN

DISEASE

Hodgkin disease(HD), a complex disorder of the immune system with characteristic pathologic and clinical features, accounts for about 40% of lymphomas in the U.S. The diagnosis of HD requires Reed-Sternberg (RS) cells and their mononuclear counterparts, both of which are consideredto be the neoplastic elements, in a polymorphous background of benign-appearing, presumably normal cells. The finding of a RS cell, a large cell with mirror-image nuclei each containing a single eosinophilic nucleolus that looks like an inclusion body, is not pathognomanic of HD. Such cells have been seen in a variety of neoplastic and reactive conditions, including infectious mononucleosis.37,56It is essentialthat the diagnosisof HD be made only when the RS cells are present in an appropriate background. Except for nodular sclerosis,the subclassification of HD is based primarily on the numerical

Fig. 7. Mixed cellularity Hodgkin disease. (A) The cells (H & E, x 48). (B) Classical binucleate Reed-Sternberg Hodgkin disease (H & E. x 880).

architacture cells

frequency of RS cells and their mononuclear counterparts in comparison to reactive elements, particularly small lymphocytes. The subtypes vary in incidence in different regions of the world, and the percentages used here pertain to the U.S. Lymphocytic predominance (LPHD), which accounts for about 15% of all cases, contains the fewest neoplastic cells (less than 5 per hpf), so that multiple sections establish the diagnosis. The rarity of RS cells in a node otherwise effaced by small lymphocytes may lead to an erroneous diagnosis of diffuse WDL lymphoma. Such a diagnosis in a patient under age 40 should be suspect, and the pathologist should be asked to reexamine the slides. There may be involvement of only the paracortex of an otherwise reactive node. The cellular proliferation in LP may be diffuse or vaguely nodular, so that the pattern is not infrequently mistaken for nodular non-Hodgkin lymphoma.34 Most patients with LP are asymptomatic males with low stage (I and II), a prognostically favorable state. Accounting for 30% of HD, the mixed cellularity (MC) form contains 5-l 5 neoplastic cells per hpf (Fig. 7). Eosinophils, neutrophils, benign histiocytes, and plasma cells may be present, as well as foci of necrosis and disorderly fibrosis. While MCHD frequently produces B symptoms, it occurs in all clinical stagesand has a prognosis intermediate between the LP and LD types. Lesions containing more than 15 neoplastic

and

of the node mononuclear

is effaced variants

by a polymorphous are easily detected

proliferation in this type

of of

212

cells per hpf, often with bizarre “sarcomatoid” variants and a paucity of lymphocytes, are designated as the lymphocytic depletion (LD) form, and account for 15% of HD. Fibrosis and necrosis are common. In some instances, distinguishing this type of HD from DLCL is difficult if not impossible. Most patients with LDHD are older, symptomatic, and are in stage III or IV at presentation.5’47 Since the relative number of lymphocytes correlates directly with prognosis, this type is the most unfavorable. In patients in whom biopsies were performed after initial diagnosis, progression from LP to MC to LD may sometimes be observed. The nodular sclerosing (NS) form accounts for the remaining 40% of cases. Several distinctive criteria must be fulfilled before this diagno-

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sis can be established. In typical NS Hodgkin disease, the capsule of the lymph node is thickened, collagenous bands arising from the capsule subtend the node into nodules, and “lacunar cell variants” of RS cells occur in clusters (Fig. 8). A lacunar cell is a large cell with abundant, slightly eosinophilic cytoplasm, a multilobated nucleus, and multiple small nucleoli. In formalin fixed material, the cytoplasm of these cells often retracts and the nuclei appear to be sitting in lacunae. In some cases of NSHD, fibrotic bands and nodularity are absent or minimal but the clusters of lacunar cells are still present. Such a histologic picture is termed the cellular phase or presclerotic phase. The clinical features of the NS form are different from the other three types of HD. First,

CLASSIFICATION

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PATHOLOGY

it is the only type in which females are affected more often than males. Second, older patients are infrequently affected, the peak incidence occurring in adolescence and young adulthood. Third, the majority of patients have stage II disease at presentation with involvement of the mediastinum and supraclavicular areas. Prognosis is excellent with low stage disease but considerably less favorable in patients with advanced disease.” RARE LYMPHORETICULAR Mycosis

Fungoides,

NEOPLASMS

Shzary Syndrome

Even though rare and not the only lymphoreticular tumors that involve the skin, mycosis fungoides and SCzary syndrome deserve special mention because of their unique immunologic and cytologic aspects (see Kiely, p 261, this issue). In addition to exhibiting T-cell markers, the neoplastic cells of both conditions show an extreme degree of nuclear lobulation and infolding and have been described as cerebriform.38 Mycosis fungoides has three progressive stagesof cutaneous involvement (erythematous, plaque, and tumor) and in about 75% of patients disseminatesto nodes and viscera.” In contrast, Sezary syndrome is characterized by generalized erythroderma without circumscribed tumors. The peripheral blood is involved out of proportion to the bone marrow, but widespread dissemination may eventually occur. Stzary syndrome is considered a leukemic variant of mycosis fungoides by most observers. Based on the observation that the neoplastic cells from some patients aid in the in vitro differentiation of B cells into immunoglobulin secreting cells, it has been postulated that Sezary syndrome is a malignancy of helper T cells.” Malignant Histiocytosis Reticulosis)

(Histiocytic

Medullary

In contrast to the rare examples of DLCL composedof true histiocytes, the neoplastic cells of malignant histiocytosis are always true histiocytes (seeKiely, p 261). This disorder, described by Scott and Robb-Smith5* in 1939, is a distinct clinicopathologic entity characterized by the abrupt onset of cytopenia, fever, and hepatosplenomegaly. Involved tissuescontain a proliferation of atypical histiocytes with ingested cellular and particulate material. In classical

cases,the neoplastic histiocytes are distinctively distributed throughout sinusoids of the liver, spleen, lymph nodes, and bone marrow. Although a chronic form of the diseasehas been reported,” the majority of patients have a short course with a median survival of 6 mos6’ THE LEUKEMIAS

Among the acute leukemias, lymphoblastic and myeloblastic forms differ in age distribution, response to therapy, morphology, and certain signs and symptoms, but they are similar with respect to mode of presentation, laboratory findings, and complications. Accurate subclassifications is essential to selection of optimal therapy. In a minority of patients with acute leukemia, however, the neoplastic cells do not show sufficient maturation to be classified morphologically on Wright- or Giemsa-stained smears. In such cases other tests may sometimes be helpful. These tests include cytochemical stains, karyotyping, ultrastructural examination, lysozyme assay, and assessmentof cell markers (antigens, enzymes, and receptors). As detailed by a French, American, and British cooperative group,6 there are certain cytochemical tests of diagnostic value that should be used in every new case of acute leukemia. Some stains are useful in distinguishing between myeloid and lymphoid leukemias, eg, myeloperoxidase, Sudan Black B, and the Leder naphthol-ASD-chloroacetate esterase are positive in all myeloid leukemias. The Leder stain is useful in distinguishing monocytes from myelocytes. Acute

Lymphoblastic

Leukemia

Some of the most impressive advances in cancer therapy have been made in acute lymphoblastic leukemia (ALL). Progress has also been made in understanding the nature of the neoplastic cells through immunologic, cytochemical, and flow cytometric techniques. ALL, which accounts for about 80% of acute leukemias under 18 yr of age, is heterogeneouswith respect to morphology, clinical manifestations, and immunologic markers. It may be subdivided on the basis of immunologic markers into common, T cell, B cell, pre-B cell, and unclassified types.‘6*24 Each immunologic type has distinctive clinical and occasionally morphologic features. In children and to a certain extent

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in adults, the prognosis depends on the immunologic characteristics of the proliferating lymphoblasts. Common ALL, which comprises about 7075% of cases, shows a nearly equal sex distribution and occurs predominantly in young children (median age about 5 yr). Only rare patients have a thymic mass or an initial white blood cell count greater than 105/mm3. Although lacking T- or B-cell markers, the lymphoblasts contain the common ALL antigen24 and have high levels of terminal deoxynucleotidyl transferase (TdT).4’ The prognosis of common ALL is good, with about 40-50% of patients achieving long term remission. The second largest subtype (about 20%) of ALL is T-cell ALL. This group shares many clinical and cytologic features with lymphoblastic lymphoma (Fig. 9).‘4,25 In fact, T-cell ALL and lymphoblastic lymphoma are simply different clinical presentations of a single disease. In contrast to common ALL, the median age is older (about 12 yr) and males are affected three times more frequently than females. Leukocyte counts greater than 105/mm3 at the time of diagnosis are not infrequent and a thymic mass is present in 50% of the patients. In addition, there is a higher incidence of leptomeningeal involvement at presentation and leptomeningeal and testicular involvement on relapse than in

Fig. 9. Acute lymphoblastic marrow contains cells that are those of lymphoblastic lymphoma. (H & E. x 1060).

leukemia. cytologically Compare

The bone similar to with Fig. 6.

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common ALL.’ As with common ALL, the cells are TdT positive. High leukocyte count, mediastinal mass, T-cell markers, and central nervous system involvement are indicators of an unfavorable prognosis. The median duration of complete response is 9 mo and less than 20% are alive at 2.5 yr.18 In less than 5% of ALL, the malignant cells have B-cell markers. While the clinical features of this type are similar to common ALL, the cytology of the neoplastic cells is quite distinctive. The lymphoblasts are usually morphologically, immunologically, and cytochemically identical to the cells of Burkitt lymphoma. TdT activity is absent. The prognosisis poor and most patients are dead within 9 mo. A fourth subset is pre-B-cell ALL.59 Except for detectable cytoplasmic immunoglobulin, these lymphoblasts are identical to those of common ALL and the patients respond well to chemotherapy. The final form of ALL (5-10% of cases) is termed “unclassified,” since the malignant cells lack any of the previously described markers. This group is heterogeneous and may well include more than one subtype. Acute

Myeloblastic

Leukemia

and Its Variants

Various types of acute myeloblastic leukemia (AML) exist and are classified on the basis of cellular origin and degree of maturation.6 In AML, the predominant abnormal cell in the bone marrow and blood is the myeloblast. Maturation may be minimal and discernible only by using special stains, or conversely, may be readily evident. Abnormal cytoplasmic maturation sometimesresults in the formation of Auer rods, aberrant pink-staining cylindrical granules seen in the blasts of about l&15% of patients. Dysmyelopoietic cells may also be present. In acute promyelocytic leukemia (APL) more than half of the cells in the marrow have heavy cytoplasmic granulation. The granules stain variably and may be abnormally coarse. Bundles of Auer rods (“faggot cells”) are frequently noted. The nuclei of these abnormal myelocytes are still immature and variable in size and shape. It is important to recognize APL becauseof its predilection to hypofibrinogenemic bleeding.s4 Thromboplastic activity released from the leukemic cells causesdisseminated intravascular

CLASSIFICATION

AND

coagulation, clinically manifested as large rapidly spreading ecchymoses. Another variant of AML is acute monoblastic leukemia. In this type essentially all the abnormal cells have monocytoid nuclear and cytoplasmic features. Azurophilic granules, vacuoles, and phagocytized debris may be present. The diagnosis of acute monoblastic leukemia requires confirmation with cytochemical methods, using fluoride-inhibited esterase reactions. It is unknown whether monoblastic leukemia is a distinct entity or merely represents one end of the morphologic spectrum of AML, since monoblasts and myeloblasts have a common stem cell. In acute myelomonoblastic leukemia both myelocytic and monocytic forms are present, but at least 20% of the nucleated cells must have monocytoid features. The cells in the peripheral blood are usually more monocytoid than those in the bone marrow. Infiltration of gingiva and skin commonly occurs in both monoblastic and myelomonoblastic leukemia. A final variant of AML is erythroleukemia, in which a majority of the nucleated cells are erythroid; many show dyserythropoietic changes, eg, bizarre nuclear and cytoplasmic shapes and sizes and megaloblastic forms. There is usually also an increase in the percentage of immature myeloid cells, some of which may contain Auer rods. Megakaryocytic abnormalities may be present. Erythroleukemia is a difficult diagnosis because certain acquired or idiopathic dysmyelopoietic syndromes may mimic it. Such syndromes include primary or secondary sideroblastosis, vitamin B,, and folate deficiency, and cytotoxic drug reactions. The prognosis for all types of AML is still poor, although aggressive chemotherapy and bone marrow transplantation have made some impact on survival. Chronic

Myelocytic

215

PATHOLOGY

Leukemia

This is a diseasethat affects stem cells pluripotent for granulocytes, monocytes, megakaryocytes, and erythrocytes. It is characterized by extreme elevation of the leukocyte count due to the presence in the peripheral blood of mature and immature myeloid cells. Chronic myelocytic leukemia (CML) may develop de novo or as an end stage of another myeloproliferative disorder. In 85-90% of casesthere is a unique karyotypic

abnormality, the Philadelphia chromosome (Ph’) in cells of the myeloid, erythroid, and megakaryocytic series.Ph’ is a G group chromosome, number 22, from which a portion of the long arm has been translocated to chromosome number 9. Another useful test is the leukocyte alkaline phosphatasescore, which is abnormally low to absent in 90% of patients. CML affects all agesbut is most frequent in middle age. Moderate to massivesplenomegaly is present in almost all patients. The spleen size correlates well with the leukocyte count, so that if a patient has a large spleen and a leukocyte count less than 10s/mm3one should consider myelofibrosis with myeloid metaplasia rather than CML. An important feature of CML is the accelerated phase or blastic crisis.” This phase, which represents progression of CML to an acute leukemia-like picture, is the proximate cause of death in about 80% of patients. Some patients actually present in the blastic crisis of CML. Most patients who enter the accelerated phase develop an AML-like picture, but 25-30% manifest a lymphoid blastic crisis resembling ALL.4 The blast cells look like lymphoblasts, express lymphoblastic markers, and frequently respond to regimens usedto treat ALL. Granulocytic

Sarcoma

(Chloroma)

These are terms applied to localized tumors, usually extramedullary, of the myeloid series. Such tumors are important for two reasons. First, they may appear prior to the onset of overt AML or blastic crisis of CML, although they may occur in the chronic phaseof CML. Secondly, they must be distinguished from other neoplasms,especially diffuse large cell lymphoma. This distinction may be facilitated by employing the Leder (napthol-ASD-chloroacetate esterase) stain.3’ Chloroma has been reported in many sites, including orbit, breast, meninges,bones,gonads, GI tract, lymph nodes, soft tissue, and heart. Although orbital presentation is most common in children, the epidural spaceis most frequently involved in adults. Chronic

Lymphocytic

Leukemia

Chronic lymphocytic leukemia (CLL) is a generalized progressive diseasecharacterized by excessiveproliferation of long-lived, immunolog-

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ically incompetent lymphocytes. It is the most common type of leukemia in the U.S., affecting mainly patients over 40 yr of age. The onset is so insidious that about 25% of patients have no symptoms at the time of diagnosis. Leukemic

Conversion

of Lymphomas

In lymphomas, the peripheral blood usually doesnot contain morphologically abnormal cells at the time of presentation and diagnosis. However, with time and progression of the disease,abnormal cells may appear in the blood. Leukemic progression of lymphoblastic lymphoma (LBL) is very common, usually occurring within,12 mo of diagnosis. The appearance of a mediastinal massis a good predictor for progression of LBL to a leukemic phase.25About 4045% of casesof well differentiated lymphocytic malignancies are manifested as CLL. Ten to 15% of patients with nodular PDL lymphoma develop a leukemic phasecharacterized either by lymphoblastic features or by the typical cytology of a clefted lymphocyte or “buttock” cell.” Leukemic progression of the lymphoblastic type portends a poor prognosis (median survival of 2 mo in contrast to a median survival of about 43 mo in caseswith buttock cells). In DLCL (histiocytic), fewer than 5% of patients develop blood involvement, almost invariably as a terminal event in the presence of extensive visceral disease.17 Hairy Cell Leukemia Reticuloendotheliosis)

(Leukemic

This unusual chronic leukemia predominantly affects older malesand hasdistinctive pathologic

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features.43 Marker studies have shown the neoplastic cells to possesscharacteristics common to both B lymphocytes and monocytes. Patients present with massive splenomegaly, minimal adenopathy, and pancytopenia.‘3 Usually, attempted aspiration of bone marrow yields a dry tap and biopsy disclosesa marrow packed with neoplastic cells entrapped in a tight network of reticulin (see Kiely, p 261). Circulating “hairy cells,” with numerous irregular cytoplasmic processes,are noted, although a frankly leukemic picture is uncommon. A useful diagnostic procedure is the cytochemical demonstration of tartrate-resistant acid phosphatasein the neoplastic cells.30 Hairy cell leukemia differs distinctly from other leukemias and lymphomas in that splenectomy alone may lead to prolonged remission while chemotherapy often has an adverse effect.

Dysmyelopoietic

Syndromes

These syndromes result from ineffective production and abnormal maturation of hematopoietic cells.57Characterized by both quantitative and qualitative changes, they frequently progress to AML or acute myelomonocytic leukemia within 24 mo of onset. The classification of dysmyelopoietic syndromes encompasses both secondary and idiopathic types. The secondary types include vitamin B,, and folic acid deficiency, sideroblastosis, and side effects of certain drugs, while the idiopathic types include aplastic anemia, refractory anemia with excess of blast cells, paroxysmal nocturnal hemoglobulinuria, and sideroblastic anemia.

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