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The small cell variant of anaplastic large cell lymphoma.

Since its initial description by Stein et al (1) in 1985, anaplastic large cell lymphoma (ALCL) has been a relatively heterogeneous entity with numerous cytologic, morphologic, phenotypic, and clinical alterations described. Features commonly seen in all types include the appearance of large cells with pleomorphic, often horseshoe-shaped nuclei with dispersed chromatin and multiple or single prominent nucleoli and abundant cytoplasm, a cohesive growth pattern that tends to preferentially invade the lymph node sinuses, and most importantly, the expression of CD30. (2,3) From the late 1980s to the mid 1990s, the association between ALCL and a nonrandom t(2;5)(p23;q35) chromosomal translocation involving the nucleophosmin (NPM) gene and the anaplastic lymphoma kinase (ALK) gene was made. (4-8) This groundbreaking discovery led to the development of reverse transcription-polymerase chain reaction and fluorescence in situ hybridization assays and to immunohistochemical stains directed against the products of this translocation to aid in identifying this mutation. Out of this work arose a more defined, yet still heterogeneous entity--[ALK.sup.+] ALCL--which has unique clinical features compared with ALK-lesions. However, despite this further subclassification as [ALK.sup.+] ALCL, morphologic and prognostic heterogeneity still exists. Currently, more than 8 morphologic variants of primary ALCL exist or have been described, with the common (classic) type, lymphohistiocytic, and small cell variants being the most relevant. This article provides a short review of the small cell variant of [ALK.sup.+] primary ALCL.


The small cell variant of ALCL presents nearly identically to the other [ALK.sup.+] primary ALCL neoplasms, with the exception that leukemic involvement has been more commonly described in the small cell variant. (9-16) Most patients are young at presentation, with a median age of 14 years (range, 4 months--40 years). (9) A few authors have suggested a slight male predominance; however, sufficient statistical data are lacking to support this claim. (9,17) Sites of involvement frequently include peripheral lymph nodes (manifested by prominent adenopathy) and skin (manifested by macular eruptions or subcutaneous nodules). (9,18) Other extranodal sites of involvement may include bone and soft tissue. Most patients present with constitutional symptoms, often with stage III/IV disease at initial diagnosis. (9,12,15,19) Bone marrow involvement is present in approximately 20% of reported cases when detection is aided by immunohistochemistry. (9-16,19)


Hematologic Findings

Leukemic peripheral blood involvement in ALCL is uncommon; however, it has been reported, and an association with the small cell variant of ALCL has been established. (9-16) Leukocytosis is invariably present in the peripheral blood and often involves neutrophils and lymphocytes. The neutrophils are left-shifted with features of toxic granulation, whereas the lymphocytes are a mixture of small- and medium-sized, markedly atypical lymphoid cells, with prominent nuclear irregularities, often dense lobulated nuclei, and azurophilic cytoplasmic granules. (9-11,13,14) These cells may appear similar to "cerebriform" cells seen in Sezary syndrome or "flower" cells seen in adult T-cell lymphoma/leukemia (Figure 1, A). In addition, lymphocytes with abundant basophilic cytoplasm containing small vacuoles are few but should be present in cases with leukemic involvement (9,10) (Figure 1, B).


Cytopathology and Histopathology

As the name implies, the small cell variant of ALCL characteristically has numerous small- and medium-sized lymphocytes that are markedly irregular, often with a "cerebriform" appearance. (9,20,21) Although it is the small cell variant, a minor population of large, pleomorphic "hallmark" cells exist that are present singly or in clusters and may be difficult to identify on routine hematoxylineosin stains alone. Classically, these cells have variations in size and nuclear shape, usually with large, eccentric, horseshoe-shaped nuclei; distinct nucleoli; and abundant amphophilic cytoplasm (2) (Figure 2). These cells are present in all morphologic variants of ALCL, hence the designation as hallmark.




In lymph nodes, the nodal architecture is usually effaced by a diffuse and paracortical infiltrate consisting of small-, medium-, and large-sized cells (9) (Figure 3). This low-power appearance of partially preserved architecture, coupled with an infiltrate of numerous small lymphocytes and rare large cells, suggests an inflammatory process, particularly when macrophages are present. (9,10,14) However, the large cell component of this neoplasm frequently and characteristically is found surrounding small vessels (9,10,18,20-22) and residual lymphatic sinuses (10) (Figure 4). Macrophages are often markedly increased in the small cell variant of ALCL and may display erythrophagocytosis. (9,10,14) Slight vascular proliferation has also been noted in some described cases. (9) Cutaneous lesions often exhibit a similar infiltrate, extending from the superficial dermis to the subcutaneous tissues. (9) This infiltrate within tumor nodules is predominantly diffuse, whereas in macular eruptions, the distribution is more perivascular and periadnexal. Overlying epidermal hyperplasia is present, and focal epidermotropism has been reported. (9) Bone marrow involvement is often very subtle and displays small clusters of small lymphocytes and only rare, scattered, large tumor cells. It is uncommon to see mass lesions within the bone marrow when involved. More developed lesions, which are much less common and often lytic, show fibrosis of the intertrabecular spaces infiltrated by numerous small lymphocytes and scattered, large, transformed cells. (9,14)

Close examination of Wright-stained aspirate smears for rare, large lymphocytes with abundant basophilic cytoplasm containing small vacuoles, as depicted in Figure 1, B, is often helpful in recognizing bone marrow involvement. Involvement of pleural fluid and cerebrospinal fluid has also been described. (9,11-15) Solid organ involvement shows an infiltrate of small, irregular lymphocytes, and rare, large lymphocytes. (9) More subtle involvement may require analysis with immunohistochemical stains. The small cell variant of ALCL has been reported in association with the common variant, the lymphohistiocytic variant, as well as in association with the dual occurrence of the common and lymphohistiocytic variants. (16) Along these lines several cases have been reported describing the transformation of the small cell variant to common ALCL and vice versa. (15,16) It has been suggested that transformation of the small cell variant to common ALCL is a sign of a rapidly deteriorating clinical course, with 75% of patients in one study dying in less than a year. (15)


The expression of CD30 is a defining characteristic of ALCL and all of its morphologic variants, even the small cell variant. However, the small cell variant of ALCL displays characteristic differential staining of the small, medium, and large cells. CD30 expression in the large cells is readily apparent and confined to the cell membrane and Golgi region, whereas the small- and medium-sized cells exhibit weak or negative immunostaining for CD30 (2,9,10,14,18) (Figure 5, A). Epithelial membrane antigen is expressed in essentially all cases of the small cell variant, exhibiting a cell membrane and Golgi staining pattern similar to that of CD30, although only a proportion of the malignant cells will be positive (18,21) (Figure 5, B). A T-cell phenotype has been identified in all reported cases of the small cell variant (9,18,21); however, a "null-cell" phenotype may exist, similar to that found in the other variants of ALCL, depending on the extent of the immunohistochemical investigation. As with other ALCL cases, CD3 is commonly negative, as well as CD8, whereas CD2, CD5, and CD4 are positive in most cases. (2,18) A significant proportion of cases exhibit expression of at least one cytotoxic marker (TIA1, granzyme B, and perforin), and Epstein-Barr virus is reliably negative. (2) Immunopositivity for ALK is present in all reported cases of the small cell variant and is usually nuclear. (2,9,18,21) Similar to CD30, expression of ALK may be heterogeneous between the large and small cells, with the large cells staining strongly and only a proportion of the small cells staining (Figure 5, C).



Approximately 80% to 85% of [ALK.sup.+] ALCLs contain the characteristic t(2;5)(p23;q35) translocation, resulting in the fusion of the NPM and ALK genes. The other 15% to 20% display some variant translocation of ALK to a gene other than NPM. (21) Additional findings of chromosomal abnormalities have been reported on a case-by-case basis to include trisomies, deletions, and 3-break rearrangements. (9,10,14,15,19,22)

Fluorescence in situ hybridization and reverse transcription-polymerase chain reaction can be used to detect the t(2;5) translocation. Fluorescence in situ hybridization with the ALK break-apart probe has the benefit of detecting all the variant translocations involving ALK. Immunohistochemistry for ALK is frequently used as a surrogate marker for ALK translocations. The subcellular location of ALK immunostaining may reflect the underlying translocation, with an NPM-ALK fusion typically resulting in both nuclear and cytoplasmic staining. The underlying cause for the more prevalent nuclear staining of ALK in the small cell variant is uncertain. Like other variants of ALCL, the small cell variant shows clonal T-cell rearrangements in most cases. (2,3,10,21)


Based on the presenting clinical features, examination of the peripheral blood smear, and even the architectural changes identified within lymph node biopsies of the small cell variant of ALCL, an inflammatory process is highly suggested. Lymphocytosis composed mainly of T-cells is commonly present in viral infections. Partially effaced lymph nodes with rare large cells and macrophages are also suggestive of an inflammatory process, and often a diagnosis of malignant neoplasm is considered only when there is no response to antibiotic therapy. (9,10,14) However, staining with CD30 antibodies is helpful in diagnosing the small cell variant because the large cells, which often infiltrate singly and are difficult to recognize in routine sections, become readily apparent upon immunostaining. (9,22) Furthermore, the location of large [CD30.sup.+] cells can be used to help distinguish between reactive and malignant processes. In benign lymph nodes, [CD30.sup.+] large cells tend to be located within or near the edges of the B-cell follicles and do not show the tendency to be located around small vessels or within sinuses as in the small cell variant of ALCL. Multiple lymphoid and nonlymphoid markers should be performed in parallel with CD30 because CD30 expression is not specific for ALCL and is identified in immunoblasts, (23-25) other B-cell and T-cell lymphoid neoplasms, (1,25) and also in nonhematopoietic neoplasms. (25,26)

Once the T-cell phenotype has been determined, the differential diagnosis for a predominantly small, T-cell lymphoproliferative lesion with CD30 positivity includes the primary cutaneous [CD30.sup.+] lymphoproliferative disorders (primary cutaneous ALCL, lymphomatoid papulosis, and borderline lesions) (2); peripheral T-cell lymphoma, not otherwise specified; and angioimmunoblastic T-cell lymphoma. (2,3) If cutaneous lesions are not present, it is easy to rule out the primary cutaneous [CD30.sup.+] lymphoproliferative disorders. If cutaneous lesions are present, clinical features are often helpful in favoring either a primary cutaneous or systemic disorder. The young age and frequent nodal involvement seen in the small cell variant of ALCL is unusual for primary cutaneous [CD30.sup.+] lesions, and caution should be taken when making the diagnosis of primary cutaneous disease in patients with these clinical features. (9) Moreover, lymphomatoid papulosis commonly manifests as recurrent crops of papules that spontaneously regress without lymph node involvement, unlike the unremitting cutaneous lesions of ALCL. (2) Peripheral T-cell lymphoma, not otherwise specified, can express CD30; however, the morphology and lack of ALK and epithelial membrane antigen expression allow for distinction from ALCL. Angioimmunoblastic T-cell lymphoma characteristically displays a marked proliferation of arborizing vessels and atretic or absent follicle centers. (2) Follicle structures are partially preserved in the small cell variant of ALCL, and although a vascular proliferation is identified, it is modest at most. (9) [CD30.sup.+] large cells are randomly distributed throughout nodal specimens of angioimmunoblastic T-cell lymphoma. Additional analysis with markers for EBER, CD10, BCL6, CXCL-13, and PD-1 (which are positive in angioimmunoblastic T-cell lymphoma) should be performed. CD21 or CD23 is also helpful to highlight expanded follicular dendritic cell meshworks that are present in angioimmunoblastic T-cell lymphoma and not in the small cell variant of ALCL. CD30 positivity coupled with ALK positivity essentially confirms the diagnosis of ALCL.


Currently, no standardized therapy has been established for the small cell variant of ALCL. Combination chemotherapy, high-dose chemotherapy with stem cell support, bone marrow transplantation, and hematopoietic stem cell transplantation have all been used along with other adjuvant therapies. (14,17,20) Some authors have proposed conducting randomized studies comparing combination chemotherapy versus high-dose chemotherapy with stem cell support to compare survival; however, none have been carried out to date. (21) Shiota et al (27) first reported that ALK+ systemic ALCLs benefit more from chemotherapy than ALK2 forms and have a better 5-year survival. Within the subset of [ALK.sup.+] systemic ALCLs, the small cell variant has been shown to more commonly have peripheral blood involvement, transform to and from common type ALCL, and have an overall poorer prognosis than the other variants. (10-14,17,22,28) Two-year survival in patients with the small cell variant of ALCL has been reported as 50%, as compared with 73% in the common type. (28,29) Despite being [ALK.sup.+], as noted above, some cases of the small cell variant of ALCL are very aggressive. (9,10,12,13,15,16) Whether this is related to the disseminated nature of the tumor in many patients or to truly more aggressive tumor biology is not well understood.


The small cell variant of ALCL is often difficult to recognize. It should be considered in the differential diagnosis of any young patient presenting with constitutional symptoms and prominent adenopathy, with or without associated skin findings. Given the subtle findings of this variant of ALCL, the importance of using CD30 and ALK immunohistochemical stains in clinically and histologically suspicious cases cannot be overemphasized. Furthermore, given the high propensity of this variant to disseminate to bone marrow and peripheral blood, examination of peripheral blood should be performed to look for atypical lymphocytes, especially rare, large lymphocytes with basophilic cytoplasm and fine vacuoles. Immunohistochemical stains should be performed liberally on bone marrow specimens. Lastly, based on small series reviews and individual case reports, the small cell variant may be a more aggressive lymphoma than other ALCLs displaying ALK expression.


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Thomas A. Summers Jr, MD; Joel T. Moncur, MD

Accepted for publication September 29, 2009.

From the Department of Pathology and Laboratory Services, Walter Reed Army Medical Center, Washington, DC.

The authors have no relevant financial interest in the products or companies described in this article.

The opinions and assertions expressed are solely those of the authors and are in no way to be construed to represent the opinions and assertions of the United States Government, the United States Department of Defense, or the Departments of the Army or Navy.

Reprints: Thomas A. Summers Jr, MD, Department of Anatomic Pathology, Building 2, 6900 Georgia Ave NW, Washington, DC 20307 (e-mail:
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Author:Summers, Thomas A., Jr.; Moncur, Joel T.
Publication:Archives of Pathology & Laboratory Medicine
Date:Nov 1, 2010
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