Diagnostic Dilemmas That Impact Treatment Decisions in Lymphoma
Case Presenters: Randy D. Gascoyne, MD Clinical Professor of Pathology – UBC, Hematopathologist – BC Cancer Agency, Medical Director, Provincial Lymphoma Pathology Program, Research Director, Centre for Lymphoid Cancers, Distinguished Scientist BCCRC, Department of Pathology and Experimental Therapeutics, BC Cancer Agency & BC Cancer Research Centre, Vancouver, British Columbia
Eric D. Hsi, MD, Section Head of Hematopathology, Chair, Department of Clinical Pathology
Robert Tomsich, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio
Commentator: Julie M. Vose, MD, MBA, Neumann M. and Mildred E. Harris Professor, Chief, Division of Hematology/Oncology, University of Nebraska Medical Center, Omaha, Nebraska
Abstract: Prognosis in lymphoma varies widely according to the particular subtype, as does the treatment approach. Expert hematopathology review, incorporating current immunohistochemistry, genetic analysis, and fluorescent in situ hybridization (FISH), may be required to ensure an accurate diagnosis and optimal treatment. CD30 expression can be seen in a wide range of lymphomas, including Hodgkin lymphoma, anaplastic large cell lymphomas, cutaneous T-cell lymphomas, and B-cell lymphomas. The introduction of targeted therapies, such as brentuximab vedotin, makes it imperative to establish robust CD30 immunohistochemical assays in the laboratory and should encourage the judicious use of CD30 testing in order to identify potential candidates for novel therapy. Diagnosis of these patients requires close collaboration between hematopathologists and clinicians. This monograph presents 2 case studies in which immunohistochemistry changed a lymphoma diagnosis and provides a commentary on the importance of accurate diagnosis of lymphoma subtypes.
Diagnosis of ALK-Positive Anaplastic Large Cell Lymphoma Based on CD30 Testing
Randy D. Gascoyne, MD, Clinical Professor of Pathology – UBC, Hematopathologist – BC Cancer Agency, Medical Director, Provincial Lymphoma Pathology Program, Research Director, Centre for Lymphoid Cancers, Distinguished Scientist BCCRC Department of Pathology and Experimental Therapeutics, BC Cancer Agency & BC Cancer Research Centre, Vancouver, British Columbia
The patient was a 35-year-old man who presented with systemic symptoms and lymphadenopathy involving the neck, axilla, and groin. His systemic symptoms included weight loss, fever, and night sweats. His general practitioner referred him to a surgeon. Because a diagnosis of lymphoma was suspected clinically, the surgeon did not perform a fine needle aspirate, but went straight to an open biopsy. The biopsy was performed at a hospital in British Columbia that had the ability to perform routine tissue processing (hematoxylin and eosin [H&E] sections) and a limited immunohistochemical panel. A portion of the fresh lymph node was sent for flow cytometry at the Vancouver Cancer Center (VCC). In the days following the biopsy, the VCC received the report, a complete set of slides, and a representative paraffin block. The slide set included several H&E sections, as well as CD20 and CD3 immunostains.
CD30 testing was not performed, an omission that will prove to be important in this case. Because all suspected cases of lymphoid cancer in British Columbia are centrally reviewed, this case was referred to the lymphoma pathology group at the VCC. The submitting diagnosis was peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) based on absence of CD20 staining and membranous CD3 expression. Central review of the morphology revealed a diffuse infiltrate of large, neoplastic cells with frequent mitoses (Figure 1). Some hallmark cells were also identified, as was a moderate degree of sinusoidal infiltration. Additional immunohistochemistry testing found some pan–T-cell antigen loss, including CD2 and CD5, which is not uncommon. The fresh material that was sent for flow cytometry similarly showed an abnormal phenotype with loss of the same pan–T-cell markers as seen by immunohistochemistry. Molecular genetic studies performed at the VCC showed the presence of a T-cell clone.
No IGH rearrangements were detected. Flow cytometric studies and molecular genetic tests were also performed at the VCC. Following initial review of all the submitted material, the favored diagnosis was anaplastic large cell lymphoma (ALCL). Additional immunohistochemistry testing was performed, including for CD30, anaplastic lymphoma kinase (ALK), EMA, Ki67, TIA-1, Granzyme B, and perforin. The results of these tests led to a diagnosis of ALKpositive ALCL with strong and uniform membranous and Golgi CD30 staining (Figure 2). Based on the revised diagnosis, the patient was enrolled in a clinical trial testing brentuximab vedotin, a targeted agent for CD30. It is used in the treatment of CD30-positive lymphomas—Hodgkin lymphoma, in particular, but also ALCL (Figure 3).1-3 Brentuximab vedotin was administered with chemotherapy, and the patient achieved a complete response and has maintained it. This case highlights the value of central review for complex hematolymphoid pathology as well as the need for expanded panels of immunohistochemistry with other ancillary tests in order to establish a definite diagnosis and an accurate subclassification of all lymphoid cancers.
CD30 expression is characteristic of a number of lymphoid cancers, with the 2 prototypical examples being classical Hodgkin lymphoma and ALCL.4,5 In ALCL, strong and uniform expression of CD30 is a characteristic finding.5 This staining pattern should prompt one to then perform the ALK immunostains required to distinguish ALK-positive ALCL from ALK-negative ALCL. Importantly, a number of other non-Hodgkin lymphomas also express CD30, including both B-cell and T-cell subtypes.6,7 Some degree of CD30 expression can be seen across the spectrum of T-cell lymphomas.
Typically, this expression is heterogeneous and thus can be distinguished from the strong and uniform CD30 expression seen in ALCL. Distinguishing between some PTCLs with high CD30 expression and ALCL can be a challenge. A review of the pathology by an expert in the field can be beneficial in such cases. More recently, CD30 expression has been examined in large cohorts of diffuse large B-cell lymphoma (DLBCL).8 It is heterogeneously expressed in approximately 15% to 20% of cases and seems to be associated with a favorable outcome. It can be seen in both cell-of-origin subtypes (germinal center B cell and activated B cell). CD30 expression is enriched in patients with DLBCL who show concomitant expression of the Epstein-Barr virus; the prognosis for these patients is markedly inferior to that associated with typical DLBCL.9 The introduction of targeted therapies, such as brentuximab vedotin, now makes it imperative to establish robust CD30 immunohistochemical assays in the laboratory and should encourage the judicious use of CD30 testing in order to identify potential candidates for novel therapy.
The accurate diagnosis and reliable classification of lymphoid malignancies requires an open biopsy for adequate assessment of the tumor. In cases where there is a high index of clinical suspicion of an underlying lymphoid cancer, fine needle aspirates are not acceptable for initial diagnosis and should be passed over in favor of an open biopsy that includes complete lymphoma protocol studies. This approach results in a net savings for the healthcare system and helps to avoid duplicate testing. In a small subset of cases, the distinction between PTCL-NOS with CD30 high expression and systemic ALCL can be challenging, and these difficult cases benefit from secondary review and an expanded immunohistochemical panel.
Dr Gascoyne consults for Seattle Genetics, Celgene, Genentech, Janssen, Roche, and Infinity, and he receives research support from Celgene and Roche Canada.
1. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189.
2. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363(19):1812-1821.
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Undiagnosed Mycosis Fungoides With Transformation to Large Cell Peripheral T-Cell Lymphoma
Eric D. Hsi, MD, Section Head of Hematopathology Chair, Department of Clinical Pathology, Robert Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio
A 42-year-old woman with a remote history of Hodgkin lymphoma (HL) diagnosed in 1988 presented to a surgeon with adenopathy. The patient had been well until 6 months prior, when she developed axillary lymphadenopathy. She had experienced night sweats for the previous month, and she also reported pruritus. Other than the previous diagnosis of lymphoma, her medical history was not significant. Physical examination showed axillary, cervical, and supraclavicular lymphadenopathy. A cervical lymph node was biopsied. H&E staining for CD3, CD20, CD15, and CD30 was performed (Figures 1-3). A diagnosis of classical HL was considered. The lymph node biopsy was followed by a forearm skin biopsy. A more detailed review of systems revealed a pruritic skin rash, predominantly in the axillae, that had persisted for 20 years. The patient also had a dry cough.
Physical examination showed the previously mentioned lymphadenopathy as well as erythematous plaques on the forearms and legs. A complete blood count showed mild thrombocytosis (460 Å~ 109/L), but was otherwise normal. The skin biopsy revealed a dense upper dermal lymphoid infiltrate composed of small and intermediate-sized lymphocytes, some of which demonstrated nuclear irregularity and deep clefts. The infiltrate was band-like, but infiltration of the epidermis was present. Some of these lymphocytes displayed a cytoplasmic clearing or “halo” effect along the dermal-epidermal junction, and collections of several lymphocytes in the epidermis were present. Immunophenotyping showed that the vast majority of lymphocytes expressed CD3 and CD4, but lacked CD20, CD8, and CD7 (Figures 4 and 5). Polymerase chain reaction (PCR) studies for the T-cell receptor γ gene rearrangement showed 2 dominant peaks by capillary electrophoresis at the 230 and 241 base pairs. These pathologic features were believed to be compatible with cutaneous T-cell lymphoma (mycosis fungoides).
The same molecular analysis was then performed on the lymph node biopsy, and an identical pattern was seen in the capillary gel electropherogram. Given this information, it was thought that the patient likely had a long history of undiagnosed mycosis fungoides with expressed in T-cell lymphomas. The histopathologic features in such cases may also mimic Hodgkin lymphoma.
The presented case was interpreted as a CD30-positive/CD15-positive T-cell lymphoma that most likely represents a transformation of an undiagnosed cutaneous T-cell lymphoma (mycosis fungoides). It illustrates several teaching points. First, expression of CD15 is not completely specific for classical Hodgkin lymphoma and can be misleading, particularly with the clinical history (albeit unconfirmed) of Hodgkin lymphoma. Second, CD30 expression is not specific for a lymphoma type and can be seen in a wide range of lymphomas, including Hodgkin lymphoma, anaplastic large cell lymphomas, cutaneous T-cell lymphomas, and even B-cell lymphomas. Finally, evaluation of the entire evolving clinical and pathologic findings combined can help resolve diagnostic difficulties. The combined pathologic findings, clinical features, and application of molecular genetic studies make it possible to render an appropriate diagnosis.
Dr Hsi has served as a consultant and speaker for Seattle Genetics and has received research funding from Allos Therapeutics, AbbVie, Cellerant Therapeutics, and Eli Lilly.
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Commentary: Diagnostic Dilemmas That Impact Treatment Decisions in Lymphoma Julie M. Vose, MD, MBA
Neumann M. and Mildred E. Harris Professor, Chief, Division of Hematology/Oncology, University of Nebraska Medical Center, Omaha, Nebraska
Dr Gascoyne described a young patient, age 35 years, who presented with diffuse lymphadenopathy.1 The patient underwent a biopsy at an outside institution and was diagnosed with PTCL-NOS based on the staining that was performed. In British Columbia, all suspected cases of lymphoid cancer are centrally reviewed. The central review at VCC involved additional staining and testing of T-cell clonality. Immunohistochemistry showed CD30 positivity, and ALK staining was positive. The diagnosis after central review was changed to ALCL, ALK-positive.
This case raises several important points. Expert hematopathology review, incorporating current immunohistochemistry, is often necessary to determine the subtype of lymphoma. Genetic analysis or fluorescent in situ hybridization (FISH) may be important for the diagnosis. In this case, it was important to identify that the patient was CD30-positive, as this status provided additional treatment options. The patient was enrolled in a clinical trial with brentuximab vedotin. Adequate testing can provide information not only on diagnosis but also prognosis and treatment. In this case, the correct diagnosis of ALCL has a much better prognosis than PTCL-NOS, and it also opened up additional treatment options. It is very important to diagnose the correct subtype of lymphoma in order to develop the optimal treatment plan.
Dr Hsi described a 42-year-old woman with a remote history of Hodgkin disease diagnosed in 1988. In 2003, the patient presented with lymphadenopathy, night sweats, and pruritus. Physical examination revealed diffuse lymphadenopathy present in many different areas. The patient underwent biopsy of a cervical lymph node. Results from H&E stains and immunostains suggested a diagnosis of classical Hodgkin lymphoma. The patient had a rash on her forearm; biopsy demonstrated a dermal infiltrate of lymphocytes, an unusual characteristic for Hodgkin lymphoma. Immunostains performed on the second biopsy, however, demonstrated some T-cell characteristics: CD3, CD4, and lack of CD8. PCR studies performed to test for T-cell gene arrangements were also positive.
Results of the skin biopsy were believed to be compatible with mycosis fungoides, a type of cutaneous T-cell lymphoma. In this case, a skin biopsy offered information that led to reevaluation of the original diagnosis. Reassessment of the lymph node biopsy suggested that the patient had experienced transformation of mycosis fungoides to a CD30-positive peripheral T-cell lymphoma. As Dr Hsi noted, this phenomenon is unusual. We know, however, that a variety of different clinical pathologic entities can occur in patients with CD30-positive lymphomas, including Hodgkin lymphoma, mycosis fungoides, and certain types of peripheral T-cell lymphoma. Some patients exhibit a spectrum of disease that can encompass different types of lymphoma, and they need to be treated differently from patients with a distinct diagnosis.
Transformed disease is often a much more aggressive type of lymphoma, and its treatment differs from that for mycosis fungoides or Hodgkin disease. This case again stresses the importance of having the pathology results reviewed by an expert hematopathologist.
Both of these cases illustrate the fact that it is very important to have the correct diagnosis. Oftentimes, it can be difficult to make the correct diagnosis without all of the necessary immunohistochemical stains and a central pathology review. Prognoses vary among the different types of lymphoma. Treatments used for Hodgkin disease are very different from those for peripheral T-cell lymphoma; there are different types of drugs and different types of regimens. For example, brentuximab vedotin is a targeted agent for CD30 that is used in the treatment of CD30-positive lymphomas.3,4 It should be noted that the correlation of response to brentuximab vedotin and the expression of CD30 is unclear, with a lack of a direct association in some studies.5
The hematopathologist and the clinicians must work closely together. For a correct diagnosis, the hemato-pathologist requires the clinical history, and the clinicians require the hematopathology review. It is important to work as a clinical team on these types of cases.
Dr Vose has received research grants from Allos Therapeutics/Spectrum; Bristol-Myers Squibb Company; Celgene Corporation; Genentech, Inc; GlaxoSmithKline; Incyte Corporation; Millennium Pharmaceuticals, Inc; Onyx, Pharmaceuticals, Inc; Pharmacyclics, Inc; sanofi-aventis; and US Biotest, Inc.
1. Gascoyne RD. Diagnosis of ALK-positive anaplastic large cell lymphoma based on CD30 testing. Clin Adv Hematol Oncol. 2014;12(1):3-6.
2. Hsi ED. Undiagnosed mycosis fungoides with transformation to large-cell peripheral T-cell lymphoma. Clin Adv Hematol Oncol. 2014;12(1):6-11.
3. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189.
4. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363(19):1812-1821.
5. Bartlett NL, Sharman JP, Oki Y, et al. A phase 2 study of brentuximab vedotin in patients with relapsed or refractory CD30-positive non-Hodgkin lymphomas: interim results in patients with DLBCL and other B-cell lymphomas [ASH abstract 848]. Blood. 2013;121(suppl 21).