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).
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.
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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Keywords:© 2000 Lippincott Williams & Wilkins, Inc.
Anaplastic large cell lymphoma; Lymphoma; Hypocellular lymphoma; Anaplastic lymphoma kinase; Immunohistochemistry; Inflammatory pseudotumor; Reactive lymphadenopathy