Anaplastic Large Cell Lymphoma Features Presenting Diagnostic Challenges Maria A. Pletneva, MD, PhD; Lauren B. Smith, MD
Anaplastic large cell lymphoma has histopathologic features that necessitate a broad differential diagnosis. Diagnostic considerations include carcinoma, melanoma, and hematopoietic malignancies, including diffuse large B-cell lymphoma, classical Hodgkin lymphoma, myeloid sarcoma, and peripheral T-cell lymphoma, not otherwise specified. Unusual features can include subtle sinusoidal involvement, histiocytic morphology, cytokeratin expression, CD15 expression, and variant patterns of anaplastic lymphoma kinase expression. Cases with unusual morphologic or immunohistochemical findings will be presented to highlight the complexity encountered in practice. (Arch Pathol Lab Med. 2014;138:1290–1294; doi: 10.5858/arpa.2014-0295-CC)
A
naplastic large cell lymphoma (ALCL) is a peripheral Tcell lymphoma typically characterized by large lymphoid cells with abundant cytoplasm and pleomorphic, often horseshoe-shaped nuclei, exhibiting strong, uniform expression of CD30. The anaplastic lymphoma kinase (ALK) expression, or lack thereof, determines whether it is classified as ALK positive or ALK negative, which has prognostic significance. In ALK-positive cases, there is a translocation involving the ALK gene and expression of ALK protein. The most common translocation is t(2;5)(p23;q25), which involves the NPM gene; however, other translocations are also rarely present. In ALKnegative cases, there is no defining translocation. Cases can vary widely in terms of the morphologic features and immunophenotype, which can lead to difficulty in diagnosis. Examples of the unusual morphologic and immunophenotypic findings are presented. Accepted for publication June 2, 2014. From the Department of Pathology, University of Michigan, Ann Arbor. The authors have no relevant financial interest in the products or companies described in this article. Presented in part at the New Frontiers in Pathology: An Update for Practicing Pathologists meeting; University of Michigan; September 26–28, 2013; Ann Arbor, Michigan; and at the European Association for Hematopathology conference; October 20–25, 2012; Lisbon, Portugal. Reprints: Lauren B. Smith, MD, Department of Pathology, 5230 Medical Science I, University of Michigan, 1301 Catherine St, Ann Arbor, MI 48109 (e-mail: [email protected]). 1290 Arch Pathol Lab Med—Vol 138, October 2014
SUBTLE SINUSOIDAL DISEASE WITH PROMINENT REACTIVE FEATURES Sinusoidal disease is a well-known feature of ALCL.1–4 Although not uncommon in and of itself, sinusoidal involvement can be subtle and requires careful histopathologic examination. Occasionally, this finding may be accompanied by other prominent reactive morphologic features, including florid follicular hyperplasia or dermatopathic change. A case presenting in an adolescent girl is shown in Figure 1. The lymph node is very large with numerous, variably sized follicles (Figure 1, A and B). Differential diagnostic considerations included a viral lymphadenitis or autoimmune process; however, close examination of the lymph node sinuses revealed collections of variably sized, atypical cells (Figure 1, C through I). Some of these have the appearance of benign immunoblasts; however, others are ‘‘mummified’’ or have very prominent nucleoli, suggesting a neoplastic process. CD5 (Figure 1, J) strongly marks the clusters of atypical cells and CD30 is strongly positive (Figure 1, K). Anaplastic lymphoma kinase is also positive, with cytoplasmic and nuclear expression consistent with the presence of t(2;5)(p23;q25) translocation (Figure 1, L). Thus, careful examination of sinuses at high magnification is critical. When recognized, the sinusoidal involvement by ALCL may be mistaken for involvement by a carcinoma or diffuse large B-cell lymphoma. In cases such as this, CD30 is an advisable initial immunohistochemical stain. If positive, Tcell markers and ALK can be added, as CD3 is often negative in cases of ALCL.5 HISTIOCYTIC MORPHOLOGY The morphologic spectrum of ALCL is broad and includes common cases as well as morphologic variants such as small cell, lymphohistiocytic, and sarcomatoid.1,6 In all patterns, hallmark cells, with eccentric, horseshoeshaped nuclei, are present in variable proportions. A large number of reactive histiocytes are seen in the lymphohistiocytic variant, sometimes obscuring the admixed malignant cells. However, in some cases of ALCL, the malignant cells themselves may show histiocytic morphology (Figure 2, A through C), with round or bean-shaped nuclei and abundant pale cytoplasm, raising a differential diagnosis that includes myeloid sarcoma with monocytic differentiation and diffuse large B-cell lymphoma. The diagnostic challenge is further confounded by possible expression of myeloid-associated antigens such as CD13 and CD33, Anaplastic Large Cell Lymphoma—Pletneva & Smith
Figure 1. Subtle sinusoidal involvement by anaplastic large cell lymphoma in a case with prominent follicular hyperplasia. A and B, Numerous variably sized follicles are seen at low magnification. C through I, Collections of neoplastic cells with cytologic atypia are present in sinuses. J, The neoplastic cells express CD5. K, The neoplastic cells are strongly positive for CD30. L, The cells are positive for anaplastic lymphoma kinase with nuclear and cytoplasmic positivity (hematoxylin-eosin, original magnifications 320 [A and B], 3100 [C], 3200 [D through F], and 3400 [G through I]; original magnifications 3200 [J through K]; original magnification 3400 [L]).
which may be expressed by neoplastic cells residing in the monocyte gate by flow cytometry.2,7 In the case illustrated in Figure 2, immunohistochemical studies aid in demonstrating that these are T cells by revealing diffuse staining with CD5 (Figure 2, D). CD30 is positive (Figure 2, E) and, in this case, ALK is also positive, with expression in the nucleus and cytoplasm (Figure 2, F). Arch Pathol Lab Med—Vol 138, October 2014
CYTOKERATIN EXPRESSION The marked cellular pleomorphism and variation of ALCL raises a broad differential diagnosis including hematopoietic and nonhematopoietic neoplasms. A panel of immunohistochemical stains that includes CD43, CD45 (LCA), pancytokeratin, Melan-A, and S-100 is often helpful, but unexpected expression may cause more confusion than Anaplastic Large Cell Lymphoma—Pletneva & Smith 1291
Figure 2. Anaplastic large cell lymphoma may exhibit histiocytic morphology. Neoplastic T cells with round or bean-shaped nuclei form clusters and small sheets (hematoxylin-eosin, original magnifications 320 [A], 3100 [B], and 3400 [C]; CD5, original magnification 3200 [D]; CD30, original magnification 3200 [E]; anaplastic lymphoma kinase, original magnification 3400 [F]).
clarity. Importantly, cases of ALCL may show variable cytokeratin expression,8–10 and a subset of carcinomas can express CD30. In the case shown in Figure 3, A through F, the cells are variably sized with abundant, eosinophilic cytoplasm. The cytokeratin AE1/AE3 stain shown in Figure
3, B, shows expression in a subset of cells with variable intensity. Cytokeratins 7 and 20 are negative (not shown). CD43 can be a helpful screening marker for hematopoietic neoplasms when working up a tumor of unknown origin, as expression is limited to a small subset of tumors including
Figure 3. Anaplastic large cell lymphoma may aberrantly express cytokeratin. A, Neoplastic cells exhibit variable size, nuclear pleomorphism, and abundant eosinophilic cytoplasm. B, A subset of the cells aberrantly express cytokeratin AE1/AE3. C through F, The cells are positive for CD4, CD25, CD30, and anaplastic lymphoma kinase (hematoxylin-eosin, original magnification 3400 [A]; original magnifications 3400 [B through F]). 1292 Arch Pathol Lab Med—Vol 138, October 2014
Anaplastic Large Cell Lymphoma—Pletneva & Smith
Figure 4. Anaplastic large cell lymphoma may aberrantly express CD15. A and B, Neoplastic cells show cytologic atypia and pleomorphism and form sheets with geographic areas of necrosis. C, CD15. D, CD30. E, CD45 LCA. F, CD2 (hematoxylin-eosin, original magnifications 3200 [A] and 3400 [B]; original magnifications 3400 [C through F]).
colon, lung, and adenoid cystic carcinomas.11 CD30 is a more reliable marker in screening for ALCL, as one-third of cases will lack expression of CD43, but all cases, by definition, are positive for CD30.6 Once CD30 expression is confirmed, other T-cell markers can be pursued. Although CD3 is often negative, CD2 and CD4 are often positive.1 In this case, the neoplastic cells expressed CD4 (Figure 3, C) and CD25 (Figure 3, D). CD30 expression was strong and
uniform (Figure 3, E) and ALK was positive with nuclear and cytoplasmic expression (Figure 3, F). CD15 EXPRESSION Rare cases of ALCL, typically ALK negative, may demonstrate aberrant expression of CD15; however, in these cases the morphologic features and judicious use of additional immunohistochemical markers can prevent Figure 5. Immunohistochemical patterns of anaplastic lymphoma kinase (ALK) expression. A, Strong nuclear and diffuse cytoplasmic expression of ALK seen with NPM/ALK translocation. B and C, A subset of cells should have both nuclear and cytoplasmic staining. D, Cytoplasmic staining is consistent with a variant ALK translocation (original magnifications 3400).
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misdiagnosis.2,12 Cases with sheets of atypical large cells would be highly unusual in untreated classical Hodgkin lymphoma and should prompt reconsideration of the diagnosis. Although syncytial areas may be present, classical Hodgkin lymphoma is typically associated with a mixed inflammatory background. If the entire tumor is composed of large atypical cells, ALCL is the more likely diagnosis in a neoplasm that expresses CD30. In cases with large syncytial areas, it is important to consider and exclude other entities in the differential diagnosis, including diffuse large B-cell lymphoma and ALCL. If CD20 is negative, other helpful immunohistochemical markers for establishing a diagnosis of classical Hodgkin lymphoma include PAX-5 (which rarely may be positive in ALCL),13 pan–T-cell markers, and cytotoxic markers such as TIA-1, perforin, and granzyme. Again, CD2 and CD4 can be helpful screening markers for ALCL, as they are the most likely T-cell markers to be positive. LCA may also be useful, as ALCL may be positive and classical Hodgkin lymphoma should be negative. In any case where the morphology is syncytial and the inflammatory background is not prominent, the use of additional immunohistochemical stains is warranted. These cases demonstrate the importance of not relying on immunohistochemistry entirely, as recognition of incongruous morphologic features can be essential. The case of ALCL illustrated in Figure 4 shows sheets of large cells with abundant eosinophilic cytoplasm and geographic areas of necrosis (Figure 4, A and B). CD15 is strongly expressed on the neoplastic cells (Figure 4, C). CD30 is also strongly positive (Figure 4, D). LCA is positive with variable intensity (Figure 4, E) and CD2 is also positive in a subset of cells (Figure 4, F). PATTERNS OF ALK EXPRESSION BY IMMUNOHISTOCHEMISTRY As previously discussed, ALK-positive ALCL is defined by translocations involving the ALK gene. ALK–positive ALCL has a better prognosis than ALK-negative ALCL.1,2 Under normal conditions, ALK is involved in the development of the nervous system, but levels of ALK mRNA and protein decrease rapidly in the early weeks of life.14 Thus, immunohistochemical detection of ALK expression is an extremely useful diagnostic tool that has become an accurate surrogate for molecular/cytogenetic testing. In the majority of ALK-positive cases, ALK translocation involves the NPM gene, with subsequent translation of a fusion protein capable of shuttling between the cytoplasm and the nucleus. Therefore, nuclear and diffuse cytoplasmic expression of ALK is expected (Figure 5, A). The ALK staining pattern may not be strong and uniform in the nuclei in every case; however, a subset of the cells should have both nuclear and cytoplasmic staining (as shown in Figure 5, B and C). Translocations involving variant partner genes are associated with differential ALK expression, such as cytoplasmic
1294 Arch Pathol Lab Med—Vol 138, October 2014
(Figure 5, D), granular, or membrane staining. Non–NPM/ ALK translocations occur in approximately 20% to 25% of cases, and evidence suggests that variant translocations portend a more favorable prognosis.15 SUMMARY The morphologic spectrum of ALCL is broad. Histologic and immunohistochemical variations may complicate diagnosis. It is important to recognize that rare cases may have subtle morphologic features, including prominent reactive background. ALCL may resemble other malignancies, including myeloid sarcoma. Rare cases may be positive for CD15 or cytokeratin. In addition, ALK may or may not be positive, and positive cases may show variant translocations. Understanding the rare variants can facilitate recognition of unusual cases. We would like to thank Elena Ivan, MD, for her work on the case with expression of CD15. We would also like to thank Yuri Fedoriw, MD, for helpful comments on the manuscript. References 1. Jaffe ES. Anaplastic large cell lymphoma: the shifting sands of diagnostic hematopathology. Mod Pathol. 2001;14(3):219–228. 2. Medeiros LJ, Elenitoba-Johnson KS. Anaplastic large cell lymphoma. Am J Clin Pathol. 2007;127(5):707–722. 3. Ferreri AJ, Govi S, Pileri SA, Savage KJ. Anaplastic large cell lymphoma, ALK-negative. Crit Rev Oncol Hematol. 2013;85(2):206–215. 4. Ferreri AJ, Govi S, Pileri SA, Savage KJ. Anaplastic large cell lymphoma, ALK-positive. Crit Rev Oncol Hematol. 2012;83(2):293–302. 5. Delsol G, Al Saati T, Gatter K, et al. Coexpression of epithelial membrane antigen (EMA), Ki-1 and interleukin-2 receptor by anaplastic large cell lymphomas: diagnostic value in so-called malignant histiocytosis. Am J Pathol. 1988;130(1):59–70. 6. Delsol G, Falini B, Muller-Hermelink HK, et al. Anaplastic large cell ¨ lymphoma (ALCL), ALK-positive. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:312–316. 7. Juco J, Holden JT, Mann KP, Kelley LG, Li S. Immunophenotypic analysis of anaplastic large cell lymphoma by flow cytometry. Am J Clin Pathol. 2003;119(2): 205–212. 8. Gustmann C, Altmannsberger M, Osborn M, Griesser H, Feller AC. Cytokeratin expression and vimentin content in large cell anaplastic lymphomas and other non-Hodgkin’s lymphomas. Am J Pathol. 1991;138(6):1413–1422. 9. Zhang Q, Ming J, Zhang S, Li B, Han X, Qiu X. Cytokeratin positivity in anaplastic large cell lymphoma: a potential diagnostic pitfall in misdiagnosis of metastatic carcinoma. Int J Clin Exp Pathol. 2013;6(4):798–801. 10. Nguyen TT, Kreisel FH, Frater JL, Bartlett NL. Anaplastic large cell lymphoma with aberrant expression of multiple cytokeratins masquerading as metastatic carcinoma of unknown primary. J Clin Oncol. 2013;31(33):443–445. 11. Seethala RR, Pasha TL, Raqhunath PN, Livolsi VA, Zhang PJ. The selective expression of CD43 in adenoid cystic carcinoma. Appl Immunohistochem Mol Morphol. 2008;16(2):165–172. 12. Barry TS, Jaffe ES, Sorbara L, Raffeld M, Pittaluga S. Peripheral T-cell lymphomas expressing CD30 and CD15. Am J Surg Pathol. 2003;27(12):1513– 1522. 13. Feldman AL, Law ME, Inwards DJ, Dogan A, McClure RF, Macon WR. PAX5-positive T-cell anaplastic large cell lymphomas associated with extra copies of the PAX5 gene locus. Mod Pathol. 2010;23(4):593–602. 14. Hallberg B, Palmer RH. Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nat Rev Cancer. 2013;13(10):685–700. 15. Falini B, Pulford K, Pucciarini A, et al. Lymphomas expressing ALK fusion protein(s) other than NPM-ALK. Blood. 1999;94(10):3509–3515.
Anaplastic Large Cell Lymphoma—Pletneva & Smith
Anaplastic large cell lymphoma has histopathologic features that necessitate a broad differential diagnosis. Diagnostic considerations include carcinoma, melanoma, and hematopoietic malignancies, including diffuse large B-cell lymphoma, classical Hodgkin lymphoma, myeloid sarcoma, and peripheral T-cell lymphoma, not otherwise specified. Unusual features can include subtle sinusoidal involvement, histiocytic morphology, cytokeratin expression, CD15 expression, and variant patterns of anaplastic lymphoma kinase expression. Cases with unusual morphologic or immunohistochemical findings will be presented to highlight the complexity encountered in practice. (Arch Pathol Lab Med. 2014;138:1290–1294; doi: 10.5858/arpa.2014-0295-CC)
A
naplastic large cell lymphoma (ALCL) is a peripheral Tcell lymphoma typically characterized by large lymphoid cells with abundant cytoplasm and pleomorphic, often horseshoe-shaped nuclei, exhibiting strong, uniform expression of CD30. The anaplastic lymphoma kinase (ALK) expression, or lack thereof, determines whether it is classified as ALK positive or ALK negative, which has prognostic significance. In ALK-positive cases, there is a translocation involving the ALK gene and expression of ALK protein. The most common translocation is t(2;5)(p23;q25), which involves the NPM gene; however, other translocations are also rarely present. In ALKnegative cases, there is no defining translocation. Cases can vary widely in terms of the morphologic features and immunophenotype, which can lead to difficulty in diagnosis. Examples of the unusual morphologic and immunophenotypic findings are presented. Accepted for publication June 2, 2014. From the Department of Pathology, University of Michigan, Ann Arbor. The authors have no relevant financial interest in the products or companies described in this article. Presented in part at the New Frontiers in Pathology: An Update for Practicing Pathologists meeting; University of Michigan; September 26–28, 2013; Ann Arbor, Michigan; and at the European Association for Hematopathology conference; October 20–25, 2012; Lisbon, Portugal. Reprints: Lauren B. Smith, MD, Department of Pathology, 5230 Medical Science I, University of Michigan, 1301 Catherine St, Ann Arbor, MI 48109 (e-mail: [email protected]). 1290 Arch Pathol Lab Med—Vol 138, October 2014
SUBTLE SINUSOIDAL DISEASE WITH PROMINENT REACTIVE FEATURES Sinusoidal disease is a well-known feature of ALCL.1–4 Although not uncommon in and of itself, sinusoidal involvement can be subtle and requires careful histopathologic examination. Occasionally, this finding may be accompanied by other prominent reactive morphologic features, including florid follicular hyperplasia or dermatopathic change. A case presenting in an adolescent girl is shown in Figure 1. The lymph node is very large with numerous, variably sized follicles (Figure 1, A and B). Differential diagnostic considerations included a viral lymphadenitis or autoimmune process; however, close examination of the lymph node sinuses revealed collections of variably sized, atypical cells (Figure 1, C through I). Some of these have the appearance of benign immunoblasts; however, others are ‘‘mummified’’ or have very prominent nucleoli, suggesting a neoplastic process. CD5 (Figure 1, J) strongly marks the clusters of atypical cells and CD30 is strongly positive (Figure 1, K). Anaplastic lymphoma kinase is also positive, with cytoplasmic and nuclear expression consistent with the presence of t(2;5)(p23;q25) translocation (Figure 1, L). Thus, careful examination of sinuses at high magnification is critical. When recognized, the sinusoidal involvement by ALCL may be mistaken for involvement by a carcinoma or diffuse large B-cell lymphoma. In cases such as this, CD30 is an advisable initial immunohistochemical stain. If positive, Tcell markers and ALK can be added, as CD3 is often negative in cases of ALCL.5 HISTIOCYTIC MORPHOLOGY The morphologic spectrum of ALCL is broad and includes common cases as well as morphologic variants such as small cell, lymphohistiocytic, and sarcomatoid.1,6 In all patterns, hallmark cells, with eccentric, horseshoeshaped nuclei, are present in variable proportions. A large number of reactive histiocytes are seen in the lymphohistiocytic variant, sometimes obscuring the admixed malignant cells. However, in some cases of ALCL, the malignant cells themselves may show histiocytic morphology (Figure 2, A through C), with round or bean-shaped nuclei and abundant pale cytoplasm, raising a differential diagnosis that includes myeloid sarcoma with monocytic differentiation and diffuse large B-cell lymphoma. The diagnostic challenge is further confounded by possible expression of myeloid-associated antigens such as CD13 and CD33, Anaplastic Large Cell Lymphoma—Pletneva & Smith
Figure 1. Subtle sinusoidal involvement by anaplastic large cell lymphoma in a case with prominent follicular hyperplasia. A and B, Numerous variably sized follicles are seen at low magnification. C through I, Collections of neoplastic cells with cytologic atypia are present in sinuses. J, The neoplastic cells express CD5. K, The neoplastic cells are strongly positive for CD30. L, The cells are positive for anaplastic lymphoma kinase with nuclear and cytoplasmic positivity (hematoxylin-eosin, original magnifications 320 [A and B], 3100 [C], 3200 [D through F], and 3400 [G through I]; original magnifications 3200 [J through K]; original magnification 3400 [L]).
which may be expressed by neoplastic cells residing in the monocyte gate by flow cytometry.2,7 In the case illustrated in Figure 2, immunohistochemical studies aid in demonstrating that these are T cells by revealing diffuse staining with CD5 (Figure 2, D). CD30 is positive (Figure 2, E) and, in this case, ALK is also positive, with expression in the nucleus and cytoplasm (Figure 2, F). Arch Pathol Lab Med—Vol 138, October 2014
CYTOKERATIN EXPRESSION The marked cellular pleomorphism and variation of ALCL raises a broad differential diagnosis including hematopoietic and nonhematopoietic neoplasms. A panel of immunohistochemical stains that includes CD43, CD45 (LCA), pancytokeratin, Melan-A, and S-100 is often helpful, but unexpected expression may cause more confusion than Anaplastic Large Cell Lymphoma—Pletneva & Smith 1291
Figure 2. Anaplastic large cell lymphoma may exhibit histiocytic morphology. Neoplastic T cells with round or bean-shaped nuclei form clusters and small sheets (hematoxylin-eosin, original magnifications 320 [A], 3100 [B], and 3400 [C]; CD5, original magnification 3200 [D]; CD30, original magnification 3200 [E]; anaplastic lymphoma kinase, original magnification 3400 [F]).
clarity. Importantly, cases of ALCL may show variable cytokeratin expression,8–10 and a subset of carcinomas can express CD30. In the case shown in Figure 3, A through F, the cells are variably sized with abundant, eosinophilic cytoplasm. The cytokeratin AE1/AE3 stain shown in Figure
3, B, shows expression in a subset of cells with variable intensity. Cytokeratins 7 and 20 are negative (not shown). CD43 can be a helpful screening marker for hematopoietic neoplasms when working up a tumor of unknown origin, as expression is limited to a small subset of tumors including
Figure 3. Anaplastic large cell lymphoma may aberrantly express cytokeratin. A, Neoplastic cells exhibit variable size, nuclear pleomorphism, and abundant eosinophilic cytoplasm. B, A subset of the cells aberrantly express cytokeratin AE1/AE3. C through F, The cells are positive for CD4, CD25, CD30, and anaplastic lymphoma kinase (hematoxylin-eosin, original magnification 3400 [A]; original magnifications 3400 [B through F]). 1292 Arch Pathol Lab Med—Vol 138, October 2014
Anaplastic Large Cell Lymphoma—Pletneva & Smith
Figure 4. Anaplastic large cell lymphoma may aberrantly express CD15. A and B, Neoplastic cells show cytologic atypia and pleomorphism and form sheets with geographic areas of necrosis. C, CD15. D, CD30. E, CD45 LCA. F, CD2 (hematoxylin-eosin, original magnifications 3200 [A] and 3400 [B]; original magnifications 3400 [C through F]).
colon, lung, and adenoid cystic carcinomas.11 CD30 is a more reliable marker in screening for ALCL, as one-third of cases will lack expression of CD43, but all cases, by definition, are positive for CD30.6 Once CD30 expression is confirmed, other T-cell markers can be pursued. Although CD3 is often negative, CD2 and CD4 are often positive.1 In this case, the neoplastic cells expressed CD4 (Figure 3, C) and CD25 (Figure 3, D). CD30 expression was strong and
uniform (Figure 3, E) and ALK was positive with nuclear and cytoplasmic expression (Figure 3, F). CD15 EXPRESSION Rare cases of ALCL, typically ALK negative, may demonstrate aberrant expression of CD15; however, in these cases the morphologic features and judicious use of additional immunohistochemical markers can prevent Figure 5. Immunohistochemical patterns of anaplastic lymphoma kinase (ALK) expression. A, Strong nuclear and diffuse cytoplasmic expression of ALK seen with NPM/ALK translocation. B and C, A subset of cells should have both nuclear and cytoplasmic staining. D, Cytoplasmic staining is consistent with a variant ALK translocation (original magnifications 3400).
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Anaplastic Large Cell Lymphoma—Pletneva & Smith 1293
misdiagnosis.2,12 Cases with sheets of atypical large cells would be highly unusual in untreated classical Hodgkin lymphoma and should prompt reconsideration of the diagnosis. Although syncytial areas may be present, classical Hodgkin lymphoma is typically associated with a mixed inflammatory background. If the entire tumor is composed of large atypical cells, ALCL is the more likely diagnosis in a neoplasm that expresses CD30. In cases with large syncytial areas, it is important to consider and exclude other entities in the differential diagnosis, including diffuse large B-cell lymphoma and ALCL. If CD20 is negative, other helpful immunohistochemical markers for establishing a diagnosis of classical Hodgkin lymphoma include PAX-5 (which rarely may be positive in ALCL),13 pan–T-cell markers, and cytotoxic markers such as TIA-1, perforin, and granzyme. Again, CD2 and CD4 can be helpful screening markers for ALCL, as they are the most likely T-cell markers to be positive. LCA may also be useful, as ALCL may be positive and classical Hodgkin lymphoma should be negative. In any case where the morphology is syncytial and the inflammatory background is not prominent, the use of additional immunohistochemical stains is warranted. These cases demonstrate the importance of not relying on immunohistochemistry entirely, as recognition of incongruous morphologic features can be essential. The case of ALCL illustrated in Figure 4 shows sheets of large cells with abundant eosinophilic cytoplasm and geographic areas of necrosis (Figure 4, A and B). CD15 is strongly expressed on the neoplastic cells (Figure 4, C). CD30 is also strongly positive (Figure 4, D). LCA is positive with variable intensity (Figure 4, E) and CD2 is also positive in a subset of cells (Figure 4, F). PATTERNS OF ALK EXPRESSION BY IMMUNOHISTOCHEMISTRY As previously discussed, ALK-positive ALCL is defined by translocations involving the ALK gene. ALK–positive ALCL has a better prognosis than ALK-negative ALCL.1,2 Under normal conditions, ALK is involved in the development of the nervous system, but levels of ALK mRNA and protein decrease rapidly in the early weeks of life.14 Thus, immunohistochemical detection of ALK expression is an extremely useful diagnostic tool that has become an accurate surrogate for molecular/cytogenetic testing. In the majority of ALK-positive cases, ALK translocation involves the NPM gene, with subsequent translation of a fusion protein capable of shuttling between the cytoplasm and the nucleus. Therefore, nuclear and diffuse cytoplasmic expression of ALK is expected (Figure 5, A). The ALK staining pattern may not be strong and uniform in the nuclei in every case; however, a subset of the cells should have both nuclear and cytoplasmic staining (as shown in Figure 5, B and C). Translocations involving variant partner genes are associated with differential ALK expression, such as cytoplasmic
1294 Arch Pathol Lab Med—Vol 138, October 2014
(Figure 5, D), granular, or membrane staining. Non–NPM/ ALK translocations occur in approximately 20% to 25% of cases, and evidence suggests that variant translocations portend a more favorable prognosis.15 SUMMARY The morphologic spectrum of ALCL is broad. Histologic and immunohistochemical variations may complicate diagnosis. It is important to recognize that rare cases may have subtle morphologic features, including prominent reactive background. ALCL may resemble other malignancies, including myeloid sarcoma. Rare cases may be positive for CD15 or cytokeratin. In addition, ALK may or may not be positive, and positive cases may show variant translocations. Understanding the rare variants can facilitate recognition of unusual cases. We would like to thank Elena Ivan, MD, for her work on the case with expression of CD15. We would also like to thank Yuri Fedoriw, MD, for helpful comments on the manuscript. References 1. Jaffe ES. Anaplastic large cell lymphoma: the shifting sands of diagnostic hematopathology. Mod Pathol. 2001;14(3):219–228. 2. Medeiros LJ, Elenitoba-Johnson KS. Anaplastic large cell lymphoma. Am J Clin Pathol. 2007;127(5):707–722. 3. Ferreri AJ, Govi S, Pileri SA, Savage KJ. Anaplastic large cell lymphoma, ALK-negative. Crit Rev Oncol Hematol. 2013;85(2):206–215. 4. Ferreri AJ, Govi S, Pileri SA, Savage KJ. Anaplastic large cell lymphoma, ALK-positive. Crit Rev Oncol Hematol. 2012;83(2):293–302. 5. Delsol G, Al Saati T, Gatter K, et al. Coexpression of epithelial membrane antigen (EMA), Ki-1 and interleukin-2 receptor by anaplastic large cell lymphomas: diagnostic value in so-called malignant histiocytosis. Am J Pathol. 1988;130(1):59–70. 6. Delsol G, Falini B, Muller-Hermelink HK, et al. Anaplastic large cell ¨ lymphoma (ALCL), ALK-positive. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:312–316. 7. Juco J, Holden JT, Mann KP, Kelley LG, Li S. Immunophenotypic analysis of anaplastic large cell lymphoma by flow cytometry. Am J Clin Pathol. 2003;119(2): 205–212. 8. Gustmann C, Altmannsberger M, Osborn M, Griesser H, Feller AC. Cytokeratin expression and vimentin content in large cell anaplastic lymphomas and other non-Hodgkin’s lymphomas. Am J Pathol. 1991;138(6):1413–1422. 9. Zhang Q, Ming J, Zhang S, Li B, Han X, Qiu X. Cytokeratin positivity in anaplastic large cell lymphoma: a potential diagnostic pitfall in misdiagnosis of metastatic carcinoma. Int J Clin Exp Pathol. 2013;6(4):798–801. 10. Nguyen TT, Kreisel FH, Frater JL, Bartlett NL. Anaplastic large cell lymphoma with aberrant expression of multiple cytokeratins masquerading as metastatic carcinoma of unknown primary. J Clin Oncol. 2013;31(33):443–445. 11. Seethala RR, Pasha TL, Raqhunath PN, Livolsi VA, Zhang PJ. The selective expression of CD43 in adenoid cystic carcinoma. Appl Immunohistochem Mol Morphol. 2008;16(2):165–172. 12. Barry TS, Jaffe ES, Sorbara L, Raffeld M, Pittaluga S. Peripheral T-cell lymphomas expressing CD30 and CD15. Am J Surg Pathol. 2003;27(12):1513– 1522. 13. Feldman AL, Law ME, Inwards DJ, Dogan A, McClure RF, Macon WR. PAX5-positive T-cell anaplastic large cell lymphomas associated with extra copies of the PAX5 gene locus. Mod Pathol. 2010;23(4):593–602. 14. Hallberg B, Palmer RH. Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nat Rev Cancer. 2013;13(10):685–700. 15. Falini B, Pulford K, Pucciarini A, et al. Lymphomas expressing ALK fusion protein(s) other than NPM-ALK. Blood. 1999;94(10):3509–3515.
Anaplastic Large Cell Lymphoma—Pletneva & Smith
