Final Diagnosis -- Malignant Lymphoma


Malignant lymphoma, peripheral T-Cell type, with features of ALK-1 negative anaplastic large cell lymphoma.


Anaplastic large cell lymphoma (ALCL) is a subgroup of lymphomas believed to be of cytotoxic T or NK cell origin and is characterized by the presence of characteristic large anaplastic cells. According to the WHO 2008 classification [1] and the proposed 2016 update of hematologic malignancies [2], ALCL is divided into two primary variants, based on whether or not the characteristic translocation involving the anaplastic lymphoma kinase-1 (ALK-1) gene on chromosome 2 is present [1]. ALK-1 is generally translocated with the nucleophosmin (NPM) gene on chromosome 5, although a few variant translocations have also been described.

Although many peripheral T-cell lymphomas of cytotoxic T/NK origin demonstrate aggressive clinical behavior, ALK-positive ALCL has a characteristic survival curve that is generally better than that of most peripheral T-cell lymphomas, not otherwise specified (PTCL-NOS). Although some controversy exists regarding the classification of ALK-negative ALCL, expression profiling studies and survival data indicate they share more overlapping features with ALK-1 positive ALCL, and patient survival is generally intermediate to that of ALK-1 positive ALCL and PTCL-NOS [3].

ALK-negative ALCL generally occurs in adults between 40 and 65 years of age, with a male-to-female ratio of approximately 1.5:1. Patients frequently present with peripheral or abdominal lymphadenopathy and B symptoms such as fever, night sweats, and weight loss. The primary site tends to be the lymph nodes; however, there is typically stage III-IV disease at the time of initial diagnosis, and bone, soft tissue, and skin may be involved [4].

When lymph nodes are involved, solid sheets of neoplastic cells may efface the normal tissue architecture, or cells may infiltrate sinuses or T-cell areas with a cohesive pattern similar to that of carcinoma. ALK-negative ALCL has numerous histological patterns, and more than one can be seen in a given specimen. The common theme among these is the presence of "hallmark" cells, which are multinucleated large cells in a "wreath-like" arrangement around the cell periphery. The pattern seen in our patient's specimen is the "common pattern." It contains large pleomorphic cells with abundant eosinophilic cytoplasm, multiple nuclei in a wreath-like formation, and basophilic nucleoli. Large cells may occasionally appear similar to Hodgkin-Reed-Sternberg (HRS) cells. Other frequently seen patterns are the "lymphohistiocytic" pattern, with numerous reactive histiocytes that mask the malignant cells, and the "Hodgkin-like" pattern, which mimics the nodular sclerosis variant of Hodgkin lymphoma [1].

With regard to molecular and genetic studies, it is very important to demonstrate the lack of ALK-1 gene rearrangement by using classical cytogenetic analysis or appropriate fluorescence in situ hybridization (FISH) studies with ALK-1 break-apart probes. In the future, further subclassification of ALK-negative ALCLs may also be plausible. A 2014 study of 105 ALCL specimens identified DUSP22 (IRF4) (6p25.3) and TP63 (3q28) chromosomal rearrangements in 30% and 8% of ALK-negative ALCLs, respectively [5]. These rearrangements occurred in isolation and were not seen in ALK-positive ALCLs. Other findings include clonal rearrangement of T-cell receptors and secondary genetic imbalances, such as gains of 1q, 6p, 8q, 12q or deletions of 6q, 4q, 13q [6].

Immunohistologic studies are useful for diagnosing ALK-negative ALCL. The large neoplastic cells generally stain strongly and homogenously with CD30 in Golgi and membranous regions, although diffuse cytoplasmic staining also occurs. Smaller tumor cells are infrequently positive or even negative. Similar to ALK-positive ALCL, ALK-negative ALCL is almost always positive for the pan T-cell marker CD43 and is frequently positive for cytotoxic T-cell markers such as perforin, granzyme B, and/or TIA1. Most neoplastic populations express at least one T-cell marker, but loss of CD3, CD5 or CD8 is common, and some cases have complete loss of T-cell receptor expression [1]. Also, staining with ALK is, by definition, negative.

There are four main entities in the differential diagnosis of ALK-negative ALCL:

  1. ALK-1 positive ALCL, as mentioned above, is the most obvious entity that must be ruled out. It has a similar clinical presentation to ALK-negative ALCL, but occurs more frequently in children and young adults [7]. Although it is very similar morphologically, ALK-negative ALCL cases lack the small cell variant and tend to have cells that are larger, more pleomorphic, and have a higher N:C ratio [8]. Immunostaining for the ALK1 protein or cytogenetic FISH studies with ALK1 break-apart probes are the easiest ways to differentiate these entities, with genetic probe studies being more specific [7]. Other minor translocations will have membranous or cytoplasmic ALK-1 immunohistochemical staining of the large cells [9]. Secondary genetic imbalances consist of gains of 7, 17p, 17q and deletions of 4, 11q, 13q [6].
  2. Primary cutaneous ALCL (PCALCL) typically presents with a solitary or localized ulcerating cutaneous lesion that may infrequently involve regional lymph nodes [10]. This entity generally resembles ALK-negative ALCL morphologically and immunohistochemically, and it also lacks the ALK-1 gene translocation. Staging evaluation and clinical course are generally needed to establish this diagnosis, since the disease remains localized to the skin, by definition.
  3. PTCL, NOS, also has a similar clinical presentation [11]. Its morphological features are diverse, and it may have large pleomorphic cells similar to HRS cells, as well as a mixed inflammatory background. Generally, it lacks the so-called hallmark cells, ALK-1 protein expression, and sheets of large cells. Genetics studies reveal neoplasms with complex karyotypes and aberrations that differ from those of ALCL [11]. These lymphomas are aggressive, with poor response to treatment. In particular, there is a CD30 positive subset of PTCL, NOS (with greater than 80% CD30-positive cells) has a five-year overall survival rate of around 19% [3].
  4. Classical Hodgkin lymphoma (CHL) may occasionally have overlapping features, but the disease tends to be more localized [12], and the large neoplastic cells are generally fewer in number. Although the neoplastic cells are also CD30-positive, CHL is more frequently positive for CD15 and B-cell related markers such as PAX-5 and the transcriptional cofactors OCT-2 and BOB.1. Both ALCL and CHL, however, can be positive for Mum-1/IRF4 in the neoplastic cells. CHL is mostly of B-cell origin, as confirmed by PCR studies showing immunoglobulin gene rearrangements in HRS cells at the single cell level [13]. However, this is generally not practical for clinical diagnosis.

The International Peripheral T-cell lymphoma (IPTL) Project [3] is thus far the largest retrospective study to analyze outcomes of ALCL specimens. 181 samples were utilized, and a significant relationship was found between ALK status and five-year overall survival, with the International Prognostic Index (IPI) as an independent predictor of outcome after stratifying patients into four risk groups based on clinical factors. Five-year overall survival in the lowest risk factor group was found to be around 90%, 70%, and 49% for patients with PCALCL, ALK-positive ALCL, and ALK-negative ALCL, respectively. In a more recent study [5], ALK and DUSP22 rearrangements had similar favorable five-year survival of 85% and 90%, respectively, while TP63 and cases without translocations identified had 15%, and 42% five-year survival, respectively. These results were similar when restricted to patients receiving chemotherapy, but not for those who received stem cell transplants. More studies are currently in progress to characterize the morphologic [14], immunohistochemical, and genetic findings [5, 15, 16] characteristic of these tumors and their responses to treatment.


  1. Swerdlow, S.H., et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Fourth Edition, Lyon: IARC Press, 2008.
  2. Swerdlow, S.H., et al., 2016 Revision of the World Health Organization (WHO) Classification of Lymphoid Neoplasms. Blood. Epub 2016 Mar 15;
  3. Savage, K.J., et al., ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008 Jun 15;111(12):5496-504.
  4. Berge, R.L., et al., ALK-negative anaplastic large-cell lymphoma demonstrates similar poor prognosis to peripheral T-cell lymphoma, unspecified. Histopathology. 2003 Nov;43(5):462-9.
  5. Parrilla Castellar, E.R., et al., ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood. 2014 Aug 28;124(9):1473-80.
  6. Salaverria, I., et al., Genomic profiling reveals different genetic aberrations in systemic ALK-positive and ALK-negative anaplastic large cell lymphomas. Br J Haematol. 2008 Mar;140(5):516-26.
  7. Stein, H., et al., CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood. 2000 Dec 1;96(12):3681-95.
  8. Falini, B., et al., ALK+ lymphoma: clinico-pathological findings and outcome. Blood. 1999 Apr 15;93(8):2697-706.
  9. Falini, B., et al., Lymphomas expressing ALK fusion protein(s) other than NPM-ALK. Blood. 1999 Nov 15;94(10):3509-15.
  10. Willemze, R., et al., WHO-EORTC classification for cutaneous lymphomas. Blood. 2005 May 15;105(10):3768-85.
  11. Rizvi, M.A., et al., T-cell non-Hodgkin lymphoma. Blood. 2006 Feb 15;107(4):1255-64.
  12. Shimabukuro-Vornhagen, A., et al., Lymphocyte-rich classical Hodgkin's lymphoma: clinical presentation and treatment outcome in 100 patients treated within German Hodgkin's Study Group trials. J Clin Oncol. 2005 Aug 20;23(24):5739-45
  13. Kanzler, H., et al., Hodgkin and Reed-Sternberg cells in Hodgkin's disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells. J Exp Med. 1996 Oct 1;184(4):1495-505.
  14. King, R.L., et al., Morphologic Features of ALK-negative Anaplastic Large Cell Lymphomas With DUSP22 Rearrangements. Am J Surg Pathol. 2016 Jan;40(1):36-43.
  15. Boi, M. et al,. PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma. Blood. 2013 Oct 10;122(15):2683-93.
  16. Crescenzo R, Abate F, Lasorsa E, et al. Convergent Mutations and Kinase Fusions Lead to Oncogenic STAT3 Activation in Anaplastic Large Cell Lymphoma. Cancer Cell. 2015;27(4):516-532.
  17. Hapgood, G., Savage, K.J. The biology and management of systemic anaplastic large cell lymphoma. Blood. 2015 Jul 2;126(1):17-25.
  18. Freedman, A.S., Aster, J.C. (2015, August 11). Clinical manifestations, pathologic features, and diagnosis of anaplastic large cell lymphoma, ALK positive. Retrieved from

Contributed by Christopher Suciu, MD and Raymond E. Felgar, MD, PhD

Case IndexCME Case StudiesFeedbackHome