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Hypocellular Anaplastic Large Cell Lymphoma Mimicking Inflammatory Lesions of Lymph Nodes

Cheuk, W. M.B.B.S.; Hill, Robert W. M.D., F.R.C.P.A.; Bacchi, Carlos M.D.; Dias, Marco Antonio M.D.; Chan, John K. C. M.B.B.S., F.R.C.Path.

American Journal of Surgical Pathology: November 2000 - Volume 24 - Issue 11 - pp 1537-1543
Original Articles

The subgroup of T/null-cell primary systemic anaplastic large cell lymphoma that expresses anaplastic lymphoma kinase (ALK) constitutes a distinctive clinicopathologic entity that exhibits a broad morphologic spectrum. The examples predominated by small cells or showing a mixed cell population can be difficult to recognize as being neoplastic. We report four such cases with a remarkably hypocellular granulation tissue-like appearance, mimicking an inflammatory or reparative process. All patients were young and presented with lymphadenopathy in multiple sites. The lymph node biopsies showed a hypocellular appearance, with wide separation of the small to medium-sized lymphoid cells by edematous or fibromyxoid stroma. There were interspersed spindly neoplastic cells resembling myofibroblasts, sometimes forming short, sweeping fascicles, as well as histiocytes. Occasional large cells with atypical nuclei were identified. The larger lymphoid cells tended to form cuffs around the venules. In two cases, the capsule and fibrous trabeculae were markedly broadened with increased spindly cells, mimicking inflammatory pseudotumor of lymph node. Immunostaining showed dispersed and clustered CD30[plus] ALK[plus] cells, confirming a diagnosis of anaplastic large cell lymphoma. In conclusion, a diagnosis of hypocellular anaplastic large cell lymphoma requires a high index of suspicion. The young age of the patients and the presence of perivascular cuffs of larger lymphoid cells should provide the strongest clues to the correct diagnosis.

From the Departments of Pathology, Queen Elizabeth Hospital, Hong Kong (W.C., J.K.C.C.), Wellington Hospital, Wellington South, New Zealand (B.H.), University of Sao Paulo, Brazil (C.B.), and Faculdade de Ciencias Medicas de Minas Gerais, Brazil (M.A.D.).

Address correspondence and reprint requests to John K. C. Chan, MBBS, FRCPath, Department of Pathology, Queen Elizabeth Hospital, Wylie Road, Kowloon, Hong Kong; e-mail[colon] jkcchan[commat]

Anaplastic large cell lymphoma (ALCL) is associated with a specific t(2;5) translocation that fuses the ALK gene (anaplastic lymphoma kinase) with the NPM (nucleophosmin) gene, leading to the production of a chimeric NPM-ALK protein (p80). 7,15 ALK protein is not expressed in normal or reactive lymphoid cells, and immunoreactivity for ALK indicates the presence of NPM-ALK translocation or a variant translocation involving the ALK gene. 1,9,22,23 ALK expression is found in 53[percnt] to 84[percnt] of ALCLs, 1,3,8,16,22 with the figure varying with the criteria of case selection and proportion of pediatric cases. The ALK[plus] subgroup has emerged as a homogeneous category with primary systemic disease and predominant occurrence in the first three decades of life, often with systemic symptoms and advanced-stage disease. 1,3,7,8,16 Although the neoplasm is aggressive, multiagent chemotherapy can achieve a cure in a high proportion of patients (5-year survival rate 70[percnt] compared with 30[percnt] for the ALK-negative group). 3,8,9,16 Primary cutaneous ALCL is almost always ALK-negative. 27

With the aid of ALK expression as an immunohistochemical marker for ALCL, the recognized morphologic spectrum of this lymphoma type has broadened. A number of subtypes have been recognized, and large cells may be sparse or absent in some cases. 1,3 In this report, we describe four cases of ALK[plus] ALCL with a remarkably hypocellular appearance, mimicking inflammatory or reparative conditions, to draw attention to this potential diagnostic pitfall.

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The four cases were retrieved from the consultation files of one of the authors. The clinical and follow-up information was obtained. Formalin-fixed, paraffin-embedded lymph node biopsies were available for study. Four-[mgr]m thick sections were stained with hematoxylin and eosin. Immunohistochemical staining was performed using the labeled streptavidin-biotin peroxidase technique on the Ventana ES or NEXES automated immunostainer (Ventana Medical Systems, Inc., Tucson, AZ). The antibodies are listed in Table 1. In addition, immunostaining for CD68 (PGM1,1[colon]200, Dako, Glostrup, Denmark) was also performed.

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Clinical Features

The clinical findings are summarized in Table 2. The patients, three females and one male, were aged 10 months to 24 years. The main clinical manifestations included generalized lymphadenopathy with or without fever, weight loss, and poor general state.

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Histologic Findings

At low magnification, the lymph nodes showed loss of the normal architecture and a remarkably hypocellular, [ldquo]washed out[rdquo] appearance (Figs. 1, 2, and 3). Hypocellular areas accounted for 60[percnt], 100[percnt], 90[percnt], and 90[percnt] of the nodal tissue in case nos. 1, 2, 3, and 4, respectively. In two cases (case nos. 1 and 4), edematous and fibrocellular proliferation in the fibrous capsule and fibrous trabeculae of the node produced a pattern reminiscent of inflammatory pseudotumor of lymph node (Fig. 3C).

The hypocellular appearance resulted from loose disposition of lymphoid cells and histiocytes in an edematous to fibromyxoid stroma rich in venules (Figs. 1, 2, and 3). The lymphoid population comprised a mixture of small and medium-sized cells admixed with occasional large cells. The small cells had round or irregular nuclei, dense chromatin, and scanty cytoplasm. The medium-sized cells often had irregularly folded nuclei, coarsely granular chromatin, and a moderate amount of amphophilic cytoplasm (Figs. 1B and 2B). The large cells resembled immunoblasts or showed features of hallmark cells, which were large cells with eccentrically located reniform or embryo-like nucleus, prominent Golgi zone, and abundant amphophilic cytoplasm (Fig. 3B, D). There were admixed spindly cells, which sometimes formed short, sweeping fascicles or storiform arrays (Figs. 2A and 3B). In case nos. 1 and 4, considerable numbers of large cells forming aggregates were present in small foci (Fig. 3D). In all cases, cuffing of the larger cells around the venules was identified at least focally (Fig. 4).

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Immunohistochemical Findings

Immunostaining for CD30 and ALK revealed a surprisingly greater number of neoplastic cells than could be appreciated on routine histologic sections (Table 1). The positive cells were isolated or in small aggregates (Figs. 1C and 2C). Most of the medium-sized and large cells were positive for these markers, whereas the smaller cells were either negative or showed weak staining. The accentuation of positive cells around the blood vessels was evident in all four cases, at least focally (Fig. 1C). ALK staining was observed in both the nuclei and cytoplasm of the tumor cells (Fig. 2C). Some spindly cells were also highlighted by ALK and CD30, indicating that they were neoplastic (Fig. 2C). EMA was expressed in three of the four cases. The atypical cells in two cases were CD3-positive, whereas those in the other two cases were CD3-negative but CD45RO-positive, supporting a T-cell lineage in all four cases. Variable numbers of histiocytes were highlighted by CD68, and they were particularly numerous in case no. 1.

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ALK[plus] T/null-cell ALCL is a distinctive lymphoma type with a broad spectrum of morphology. Some recognized variants are common-type, monomorphic, small cell, mixed cell, lymphohistiocytic, giant cell, and sarcomatoid. 1,3,7,8,12,14,18,21 Different variants may coexist in a single lymph node, and transformation from one variant to another may be observed in successive biopsies from a single patient, indicating that the variants are merely different morphologic manifestations of the same disease process. There can be significant variations in the size of the neoplastic cells and the proportion of reactive lymphocytes and histiocytes. The small cell, mixed cell, and lymphohistiocytic subtypes pose the greatest problem in diagnosis and are not uncommonly misdiagnosed as reactive lymphadenopathies. Although hallmark cells, defined as large cells with eccentric embryo-like or reniform nuclei, multiple small nucleoli, and distinct eosinophilic Golgi zone in the ample cytoplasm, have been described as being characteristic of ALK[plus] ALCL, 1 they can be difficult to find, relatively small, and sometimes difficult to distinguish from immunoblasts. Immunostaining for CD30 and ALK is most helpful for confirming or refuting the diagnosis. Because ALK[plus] ALCL is an aggressive and yet highly curable lymphoma, missing the diagnosis or delay in diagnosis can potentially jeopardize the outcome. Among the three patients in this series with follow-up information, one showed spontaneous regression; this is a most uncommon occurrence in primary systemic (nodal) ALCL, in contrast to primary cutaneous ALCL which is associated with a regression rate of 18[percnt] to 44[percnt]. 3,8,19,27

Hypocellularity is not a well-recognized or perhaps rare phenomenon in lymphoma, although hypocellular acute myeloid leukemia has already been recognized for nearly two decades. 13,26 Sarcomatoid features with myxoid stroma and spindly cells was first described in an example of anaplastic large cell lymphoma in 1990, and subsequently recognized in rare cases of large B-cell lymphoma and monocytic neoplasm. 4,10,11,17,24,25 However, the neoplastic nature of the disease process is obvious in these cases as a result of the presence of numerous large neoplastic cells. Hypocellular ALCL as described in this report differs in showing predominantly edematous rather than myxoid change and deceptively subtle cytologic atypia.

Hypocellular ALK[plus] ALCL does not appear to represent a specific subtype of ALCL, but is rather an uncommon growth pattern that can be observed in the various known subtypes of ALCL. All four cases reported herein may be considered to fall into the mixed cell category, but they also show features of lymphohistiocytic variant (case no. 1), small cell variant (case no. 3), and focally common-type (case nos. 1 and 4). The hypocellular appearance in ALCL with edema, fibrosis, and spindly cells impart a reparative or inflammatory quality, raising the differential diagnoses such as inflammatory pseudotumor of lymph node and reactive lymphadenopathies. In fact, in three of four cases included in this report, these represented the initial provisional diagnoses. Lymphoma may not be considered at all because the hypocellular quality differs from the generally cell-rich appearance of lymphomas. Inflammatory pseudotumor of lymph node is characterized by predominant involvement of the connective tissue framework, with edematous to sclerosed mesenchymal tissue containing bland-looking spindly or plump cells, small blood vessels, and mixed inflammatory cells. 2,6,20 In contrast to hypocellular ALCL, the parenchyma of the node is relatively spared and there is no atypia in the spindly cells and lymphoid cells. Some reactive lymphadenopathies may have a hypocellular appearance, such as vascular transformation of sinuses, segmental infarction of lymph node, late phase of HIV-associated lymphadenopathy, and Kikuchi lymphadenitis with reparative change, but they lack atypical lymphoid cells.

A number of histologic clues may point toward the correct diagnosis in hypocellular ALCL. The lymph node architecture is always effaced. Even in the hypocellular areas or among the inflammatory infiltrate, occasional tumor cells can be found and their cytologic atypia exceeds that accountable by inflammatory or reactive changes. The large lymphoid cells tend to cluster around blood vessels, and this should constitute a highly important clue to the diagnosis. 1,5,14 Finally, the identity of neoplastic cells is readily revealed by immunostaining for CD30 and ALK.

In conclusion, ALK[plus] ALCL may present as a hypocellular lesion mimicking reactive or reparative lesions. A correct diagnosis requires a high index of suspicion in the appropriate clinical context and judicious application of immunohistochemistry.

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Anaplastic large cell lymphoma; Lymphoma; Hypocellular lymphoma; Anaplastic lymphoma kinase; Immunohistochemistry; Inflammatory pseudotumor; Reactive lymphadenopathy

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