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Can Grey Zone Lymphoma Be Cured

author
Earl Hamilton
• Saturday, 31 October, 2020
• 20 min read

1 Hackensack Meridian Health Mountainside Medical Center, Department of Internal Medicine, 1 Bay Ave, Montclair, NJ 07042, USA There are no standardized guidelines; however, evidence strongly suggests that DLBCL-based regimens are effective in the treatment of GPL.

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Contents

We present a case of a patient initially diagnosed with CHL who underwent repeat biopsy which was revealed to be GPL. Based on PET scanning and immunohistochemical studies, she was classified as a stage ILIA CD20+/CD30+ GPL patient.

Given her strong CD30 expression, she underwent 6 cycles of R-BV-CHP (rituximab, rituximab Bedouin, cyclophosphamide, doxorubicin, and prednisone) chemotherapy and achieved complete response (CR) both clinically and radiographically. GPL often presents at an early stage with B symptoms and mediastinal mass in males aged 20-40 years .

Given the rarity of the condition and lack of clinicopathological prognostication, the management of GPL is particularly challenging as there is no standard of care . Rituximab Bedouin (BV) is an anti-CD30 antibody drug conjugate that has established efficacy in relapsed/refractory Hodgkin and some T-cell lymphomas.

We present a case of GPL that was initially diagnosed as CHL and then successfully treated with 6 cycles of BV with R-CHP (rituximab, cyclophosphamide, doxorubicin, and prednisone). Given concern for breast cancer, she underwent a core needle biopsy of the left axillary node and was diagnosed with classical Hodgkin’s lymphoma (CHL) with immunostaining showing large atypical cells that were CD30+, CD15+ (subset), CD20+ (strong), and PAX5+.

She underwent staging with a PET/CT scan and bone marrow biopsy of the right posterior superior Iliad crest. The patient was sent for a second opinion at a tertiary care referral center to confirm the diagnosis and advised on treatment options.

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The second opinion oncologist recommended excisional biopsy of the left axillary node for diagnostic clarity. This lymph node biopsy was read by the local pathologist as CHL against a background of extensive necrotizing granulators inflammation.

However, a second opinion by the pathology group at the tertiary care referral center rendered a diagnosis of B-cell lymphoma, unclassifiable, with features intermediate between DL BCL and CHL, also referred to as greyzonelymphoma (GPL) . This case was discussed at an interdisciplinary conference at the tertiary referral care center, and a final diagnosis of GPL was made.

Prior to beginning an anthracycline-based treatment regimen, she underwent cardiac echocardiography which revealed a normal ejection fraction of 60-65% with no valvular disease. She remained at the referral center for treatment of her stage ILIA CD20+/CD30+ GPL and underwent 6 cycles of R-BV-CHP (rituximab, rituximab Bedouin, cyclophosphamide, doxorubicin, and prednisone) therapy not as part of a clinical trial, with restaging PET scan after cycle 3 which showed complete response (CR).

Since June 2018, the patient remains in complete remission and retains an excellent performance status. In fact, the initial misdiagnosis of CHL was based on a core needle biopsy, which is inappropriate to diagnose GPL .

Typically, the diagnosis of GPL is obtained by a more invasive excisional or incisional biopsy that requires expert pathologic evaluation of the involved tissue . GPL can contain a variable level of fibrosis, and the neoplastic nuclei have a greater range in size and shape, with more infrequent eosinophilic nucleoli than the Reed-Sternberg cells seen in CHL disease .

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(Source: www.slideshare.net)

Typically, stage III CHL is treated with ABED (doxorubicin, Aureomycin, vinblastine, and dacarbazine) which has been the standard regimen for several decades . Alternative approaches to stage III CHL described by the National Comprehensive Cancer Network (CCN) also include Stanford V (doxorubicin, vinblastine, mechlorethamine, vincristine, Aureomycin, topside, and prednisone) with involved-site radiation therapy (SRT) in selected patients and escalated BEACON (Aureomycin, topside, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) with SRT in selected patients .

Alternatively, stage III DLBCL-like lymphomas are typically treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), DA-EPOCH-R (dose-adjusted topside, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), or more intensive anthracycline-based regimens for certain high-risk subtypes . Given the rarity of the condition and lack of clinicopathological prognostication, the management of GPL is particularly challenging as there is no standard of care .

BV is an anti-CD30 antibody drug conjugate (ADC) that has established efficacy in relapsed/refractory Hodgkin and some T-cell lymphomas . A recent review paper also showed that BV had a positive response in NHL with a wide range of CD30 expressions .

While typically vincristine (Oncoming) is used in the standard R-CHOP regimen for DL BCL, it was replaced with BV in this patient since her GPL strongly expressed CD30 positivity. A recent trial explored the use of BV with R-CHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) as frontline treatment for CD30+ primary mediastinal large B-cell, DL BCL, and GPL .

There were two GPL patients in the trial; one remains in CR after the chemotherapy followed by an autologous stem cell transplant. Regimens incorporating BV in the management of GPL show promise and are being further explored in ongoing clinical trials .

lymphoma marginal zone stomach extranodal malt maltoma pathology webpathology type comments
(Source: webpathology.com)

Our patient had stage ILIA GPL with strong CD30+ expression, received 6 cycles of R-BV-CHP chemotherapy, and achieved CR both clinically and radiographically. Fortunately, through interdisciplinary collaboration between medical oncology and pathology at the tertiary care referral center, the patient was able to be diagnosed and subsequently properly managed for the rare condition of greyzonelymphoma.

References A. Richards, M. Pilichowska, and A. M. Evens, “How I manage patients with gray zone lymphoma, ” British Journal of Hematology, vol. Ferry et al., “Clinicopathologic consensus study of gray zone lymphoma with features intermediate between DL BCL and classical HL,” Blood Advances, vol.

View at: Google Scholar H. Sunday, L. E. Farad, M. J. Glenn et al., CCN Clinical Practice Guidelines for B-Cell Lymphomas Version 5.2018, 2018. View at: Publisher Site | Google Scholar D. Chiara, J. R. Weston, R. N. Miranda et al., “Dose adjusted-EPOCH-R and mediastinal disease may improve outcomes for patients with gray- zone lymphoma, ” British Journal of Hematology, vol.

View at: Publisher Site | Google Scholar E. Camp, S. H. Overflow, N. L. Harris, S. Pier, H. Stein, and E. S. Gaffe, “The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications,” Blood, vol. View at: Publisher Site | Google Scholar M. Pilichowska, A. Richards, and A. M. Evens, “Gray zone lymphoma : current diagnosis and treatment options,” Hematology/Oncology Clinics of North America, vol.

View at: Publisher Site | Google Scholar J. Stood, D. J. Lands burg, S. D. NASA et al., “Rituximab Bedouin with R-CHP chemotherapy as frontline treatment for patients with CD30 positive primary mediastinal large B-cell, diffuse large B-cell, and gray zone lymphomas: results of a phase I/II multisite trial,” Blood, vol. View at: Google Scholar R. Hope et al., CCN clinical practice guidelines for Hodgkin lymphoma 2018.

lymphoma marginal splenic zone radiopaedia radiology
(Source: radiopaedia.org)

J. M. Connors, W. Murcia, D. J. Strauss et al., “Rituximab Bedouin with chemotherapy for stage III or IV Hodgkin’s lymphoma, ” The New England Journal of Medicine, vol. Park, and A. Houses, “Five-year follow-up of rituximab Bedouin combined with ABED or AND for advanced-stage classical Hodgkin lymphoma, ” Blood, vol.

View at: Publisher Site | Google Scholar D. Ernst, Debris Plus Chemotherapy Approved for Peripheral T-Cell Lymphoma, MPR, 2018. E. D. Jacobsen, J. P. Sherman, Y. OK et al., “Rituximab Bedouin demonstrates objective responses in a phase 2 study of relapsed/refractory DL BCL with variable CD30 expression,” Blood, vol.

Title Gray zone lymphoma is a rare type of lymphoma, cancer of a part of the immune system called the lymph system. In many cases, the original diagnosis of gray zone lymphoma is later reclassified as a different type of lymphoma, such as nodular sclerosis classical Hodgkin lymphoma (Niche).

An accurate diagnosis of gray zone lymphoma is challenging, and the clinical characteristics, optimum therapy, and prognosis have not been well-defined. Because these lymphomas are treated differently, the optimal therapy for gray zone lymphoma is unclear.

In general, treatment usually involves chemotherapy (with the specific drugs depending upon each person's treatment plan), which may be followed by radiation therapy in some cases. Individual case reports have reported success with different PD-1 inhibitors (such as pembrolizumab and nivolumab), but larger studies are needed to determine if this might be an effective new strategy for treating gray zone lymphoma.

marginal splenic lymphoma zone radiopaedia radiology
(Source: radiopaedia.org)

The in-depth resources contain medical and scientific language that may be hard to understand. The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers.

Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. Dubbed is a searchable database of medical literature and lists journal articles that discuss Gray zone lymphoma.

Click on the link to view a sample search on this topic. Pilichowska M, Petaluma S, Ferry JA, et al. Clinicopathologic consensus study of gray zone lymphoma with features intermediate between DL BCL and classical HL.

Traverse-Glehen A, Petaluma S, Guard P, Barbara L, Alonso MA, Raffled M, Gaffe ES. Melanie C, Major A, Schowinsky J, et al. PD-1 Blockade in Mediastinal Gray- Zone Lymphoma.

However, there remains complexity in establishing diagnosis, delineating prognosis, and determining optimum therapy. Sixty-eight cases diagnosed as GPL across 15 North American academic centers were evaluated by central pathology review to achieve consensus.

marginal lymphoma zone splenic radiopaedia radiology
(Source: radiopaedia.org)

Morphology was critical to GPL consensus diagnosis (e.g., tumor cell richness); immunohistochemistry showed universal B-cell derivation, frequent CD30 expression, and rare Epstein-Barr virus (ABV) positivity (CD20 +, 83%; PAX5 +, 100%; BCL6 +, 20%; MUM1 +, 100%; CD30 +, 92%; ABV +, 4%). Forty-two cases were reclassified: nodular sclerosis (NS) CHL, n = 27 (including n = 10 NS grade 2); lymphocyte predominant HL, n = 4; DL BCL, n = 4; ABV + DL BCL, n = 3; primary mediastinal large BCL n = 2; lymphocyte-rich CHL and BCL–not otherwise specified, n = 1 each.

GPL consensus-confirmed vs reclassified cases, respectively, more often had mediastinal disease (69% vs 41%; P = .038) and less likely more than 1 extra nodal site (0% vs 25%; P = .019). Interestingly, NS grade 2 reclassified patients had similar PFS as GPL consensus-confirmed cases.

For prognostication of GPL cases, hypoalbuminemia was a negative factor (3-year PFS, 12% vs 64%; P = .01), whereas frontline cyclophosphamide, doxorubicin, vincristine, and prednisone ± rituximab (CHOIR) was associated with improved 3-year PFS (70% vs 20%; P = .03); both factors remained significant on multivariate analysis. Altogether, accurate diagnosis of GPL remains challenging, and improved therapeutic strategies are needed.

Antigens, cd30, Chile, chlorambucil, diffuse large b-cell lymphoma, lymphoma, neoplasms, cd20 antigens, mediastinal diseases, rituximab, immunohistochemistry Gray zone lymphoma (GPL) is an uncommon neoplasm initially described in 2005. Despite advances in immunophenotyping, molecular diagnostics, and more exact morphology-based discrimination, the diagnosis of GPL remains complex.

In addition, initially described as primarily involving the mediastinum, 1,3,4 further analyses have elucidated both primary mediastinal and mediastinal (systemic) clinical disease presentations. 5,7-10 Thus, accurate diagnosis is imperative, and development of new and improved therapies is critically needed.

lymphoma marginal zone nodal cell cells lymph node pathology histopathology pathpedia sll symptoms eatlas education
(Source: www.pathpedia.com)

A recent multi center retrospective study described 112 GPL cases diagnosed and treated in 19 North American academic centers. To better understand the diagnostic challenges and to delineate useful morphological and immunohistochemical features that may facilitate accurate diagnosis of GPL, a comprehensive study with detailed centralized pathologic review and associated analyses of clinical data was undertaken.

For the current study, we obtained 73 cases previously diagnosed as GPL across 15 US and Canadian academic medical centers for centralized pathologic review. Slides were identified from each center (i.e., full sections/tumor blocks) and submitted centrally.

All cases were subjected to central pathology review by a panel of 5 hematopathologists (M.P., S.P., J.A.F., J.H., and E.S.J.). Each case was reviewed at the multiheaded scope and discussed until consensus for morphological and immunohistochemical features and diagnosis was reached.

The remaining 68 cases were evaluated on the basis of hematoxylin and rosin sections of routinely fixed and paraffin-embedded material. Immunostained slides from the referring institutions were available for review; additional stains were performed in selected cases at Tufts Medical Center and at Massachusetts General Hospital.

The recommended immunohistochemical panel considered adequate to diagnose GPL was performed in all cases and included CD20, CD79a, PAX5, MUM1, CD30, CD15, CD3, and Epstein-Barr virus (ABV) (EBV-encoded small RNA) in situ hybridization. Immunohistochemical staining intensity was scored on a semi quantitative basis by comparing staining intensity of neoplastic cells with reactive cells on the scale 1 to 3 (weak, moderate, strong).

marginal lymphoma zone survival stage radiation figure therapy impacts underutilization negatively overall early
(Source: www.practicalradonc.org)

Staining was considered satisfactory if background T and/or B cells were deemed positive. In addition, response was defined according to revised and current criteria (e.g., including fluorodeoxyglucose–positron emission tomography).

Characteristics were compared using 2 test for categorical variables and Wilcox on rank-sum for medians. Patients without PFS or OS events were censored at the time of last clinical follow-up.

Survival analyses were performed regardless of the amount or length of therapy received. Three-year PFS and OS rates were estimated through Kaplan-Meier method, 14 whereas survival differences were assessed using the log-rank test.

Univariate associations between clinical and laboratory factors and survival were derived using the Cox proportional hazards model. 15 Variables with a P .10 in univariate analyses were entered into the multivariate Cox proportional hazards model in a stepwise fashion.

16 Hazard ratios (Hrs) and their 95% confidence intervals (CIs) were reported. Clinical descriptions of these bona fide GPL cases are detailed in Table 1.

(Source: service-med.com)

Sheetlike proliferation of tumor cells resembling PBL is seen in the top left panel. © Reclassified case: primary mediastinal large B cell lymphoma.

Diffuse proliferation of large neoplastic cells is seen (top left). The neoplastic cells have abundant clear cytoplasm and vesicular nuclei with basophilic nucleoli (top right).

They are strongly, uniformly positive for CD20, with dim expression of CD30, and are negative for CD15 (bottom). (D) Synopsis of the immunohistochemical staining results from consensus confirmed GPL cases.

The bar graph illustrates immunohistochemical staining for markers CD20, CD79a, PAX5, MUM1, CD30, CD15, CD3, and in situ hybridization for ABV (EBV-encoded small RNA ). For immunohistochemical studies, staining was considered to be positive if it had intensity of 2 or more (on +1 to +3 scale) and was distributed in more than 25% of neoplastic cells.

Sheetlike proliferation of tumor cells resembling PBL is seen in the top left panel. © Reclassified case: primary mediastinal large B cell lymphoma.

Diffuse proliferation of large neoplastic cells is seen (top left). The neoplastic cells have abundant clear cytoplasm and vesicular nuclei with basophilic nucleoli (top right).

They are strongly, uniformly positive for CD20, with dim expression of CD30, and are negative for CD15 (bottom). (D) Synopsis of the immunohistochemical staining results from consensus confirmed GPL cases.

The bar graph illustrates immunohistochemical staining for markers CD20, CD79a, PAX5, MUM1, CD30, CD15, CD3, and in situ hybridization for ABV (EBV-encoded small RNA ). For immunohistochemical studies, staining was considered to be positive if it had intensity of 2 or more (on +1 to +3 scale) and was distributed in more than 25% of neoplastic cells.

In general, neoplastic cells in the confirmed GPL cases were abundant, often occurring in sheets, with tumor cells usually being large with centralistic or immunoblastic appearance and a high degree of allomorphism. These 4 latter cases did not qualify for the diagnosis of CHL, in part based on a lack of morphological criteria characteristic for CHL; most notably, absence of a more extensive inflammatory background and geomorphology resembling primary mediastinal large B-cell lymphoma (PBL) with strong PAX5 staining.

There was no morphological and/or immunophenotypic difference between GPL primarily occurring in the mediastinum or involving peripheral sites (data not shown). In contrast to CHL and GPL, neoplastic cells of nodular lymphocyte predominant Hodgkin lymphoma had a germinal center cell immunophenotype (i.e., were BCL-6 positive) and arose in altered follicles with admixed small CD20 + B-cells.

EBV-driven lymphoid proliferations can morphologically and immunophenotypically overlap with CHL; 3 EBV-positive DL BCL cases were originally interpreted as GPL. Performance status was overall good, whereas a majority of patients presented with anemia, elevated lactate dehydrogenase, and hypoalbuminemia.

No patients had evidence or more than 1 site of extra nodal disease or bone marrow involvement, and nearly 70% had primary mediastinal presentation, with the remaining patients having no evidence of mediastinal disease. Clinical differences between primary mediastinal GPL vs mediastinal (systemic) GPL from the consensus-confirmed cases included age (i.e., 35 years vs 51 years, respectively; P = .05), anemia at diagnosis (44% vs 87%, respectively; P = .08), stage I/II disease at diagnosis (89% vs 46%, respectively; P = .03), and presence of bulk disease (44% vs 0, respectively; P = .06).

Clinical features of the cases reclassified on consensus review are depicted in supplemental Table 3. In addition, fewer patients among the reclassified cases had primary mediastinal disease (41% vs 69%; P = .038), whereas a higher proportion had involvement of more than 1 extra nodal site (25% vs 0; P = .019).

A majority of patients with reclassified lymphomas had advanced-stage disease (i.e., 56%) compared with GPL consensus cases; however, this was not significant (P = .12). Among GPL confirmed cases, the most common chemotherapy regimen given was cyclophosphamide, doxorubicin, vincristine, and prednisone ± rituximab (CHOIR) therapy, given to 17/25 (68%) of patients; 15 of these 17 patients received rituximab with CHOP.

Six of 25 patients with GPL received doxorubicin, Aureomycin, vinblastine, and dacarbazine (ABED), 2 with rituximab, and 2 patients received dose-adjusted topside, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R). Among 12 patients with GPL who had relapsed or refractory disease, 9 proceeded to salvage therapy followed by autologous hematopoietic stem cell transplant.

CHOP was also the most common therapeutic regimen for the reclassified cases given to 17/36 (47%) patients (16/17 with rituximab). Among 18 reclassified patients who had relapsed or refractory disease, 12 had salvage therapy and hematopoietic stem cell transplant (n = 9 autologous and n = 3 allergenic).

The 3-year (A) PFS of 25 patients with GPL compared with 36 reclassified lymphoma cases was 39% and 58%, respectively (P = .19), and corresponding 3-year (B) OS was 95% and 85%, respectively (P = .15). The 3-year (A) PFS of 25 patients with GPL compared with 36 reclassified lymphoma cases was 39% and 58%, respectively (P = .19), and corresponding 3-year (B) OS was 95% and 85%, respectively (P = .15).

We studied a multitude of pathologic and clinical variables for potential prognostication of outcome of patients with GPL. From the immunohistochemistry markers examined (i.e., CD20, CD79a, PAX5, BCL6, MUM1, CD30, and CD15) and analyzing across several cut-points among these markers, only strong PAX5 expression (i.e., 3 vs 2: HR, 4.25; 95% CI, 1.09-16.60; P = .037) and moderate to strong expression of CD30 (i.e., 2-3 vs 1: HR, 7.56; 95% CI, 1.000-58.83; P = .05) were associated with inferior PFS.

Among clinical variables on univariate analyses (Table 2), serum albumin was significantly associated with patient outcome, and sex was of borderline significance (i.e., male improved PFS). Examining the effect of treatment regimen on univariate analysis, use of CHOIR was associated with improved PFS and receipt of radiotherapy was borderline; use of ABDUL and DA-EPOCH-R predicted for inferior outcome, although only 2 patients with GPL were treated with the latter regimen in this series, and thus cannot be reliably assessed.

Baseline clinical factors Age (continuous) 0.99 0.96 1.03 .75 Sex (male vs female) 0.35 0.12 1.08 .06 B symptoms (yes vs no) 2.47 0.75 8.16 .13 BMI (median) 1.00 0.86 1.16 .99 ECG performance status (2-4 vs 0-1) 1.40 0.42 4.70 .58 Hemoglobin < 10.5 g/DL (no vs yes) 0.79 0.24 2.61 .70 LDH (creased vs normal) 1.71 0.48 6.16 .40 ESR (increased vs normal) 1.77 0.16 19.63 .63 Albumin < 4.0 g/DL (yes vs no) 5.061.1123.19.03 Primary mediastinal disease (yes vs no) 0.42 0.14 1.26 .12 Bulky disease (yes vs no) 0.33 0.07 1.53 .15 Stage at diagnosis (1-2 vs 3-4) 0.80 0.25 2.63 .72 Prognostic score, IPI (continuous) 1.28 0.63 2.61 .49 Prognostic score, IPS (continuous) 1.49 0.65 3.42 .34 Treatment factors Rituximab (yes vs no) 0.36 0.12 1.13 .08 ABED (yes vs no) 2.72 0.88 8.42 .08 CHOP (yes vs no) 0.220.020.53.008 EPOCH (yes vs no) 6.551.2833.45.02 Consolidate radiotherapy (yes vs no) 0.36 0.12 1.14 .08 On Cox regression multivariable analysis, PAX5 lost statistical significance while increased CD30 expression was borderline in predicting inferior PFS (HR, 7.08; 95% CI, 0.88-57.27; P = .06) (Figure 2E).

Among clinical variables, albumin was the only factor associated with patient survival (i.e., hypoalbuminemia: PFS HR, 5.54; 95% CI, 1.16-26.42; P = .03), and receipt with CHOIR for frontline therapy also remained significant when controlling for albumin and International Prognostic Index (PFS HR, 0.017; 95% CI, 0.001-0.319; P = .006), as also depicted via Kaplan-Meier curves in Figures 2F-G. 1-3,10,20 A retrospective analysis of 112 GPL cases diagnosed and treated across 19 North American academic centers described clinical features and outcomes of GPL treated in the contemporary era, including the majority of cases presenting with systemic disease without mediastinal disease and PFS rates comparatively inferior compared with CHL or DL BCL.

5 Further, there was a suggestion of improved outcomes with use of regimens typically used for DL BCL, rather than CHL. A critical limitation of this retrospective study, however, was the lack of centralized pathology review.

Slides from the majority of these previously reported GPL cases were obtained, and centralized pathologic consensus review was undertaken, together with analyses of all associated clinical data. To the best of our knowledge, this is the largest clinical-pathologic consensus study conducted to date on GPL.

Remarkably, less than 40% of the original cases diagnosed as GPL in the recent multi center retrospective study had this diagnosis confirmed on pathologic consensus review, with the majority of cases being reclassified to a different lymphoma diagnosis. Despite all original cases being diagnosed and treated at mostly large academic medical centers with excellent histopathology expertise, this result underscores the modest interobserver agreement and continued complexity of pathologic diagnosis of GPL.

Collectively, morphology remains a critical initial method in the diagnosis of GPL, with immunohistochemistry and in situ hybridization for ABV providing key diagnostic parameters. Other ancillary testing (e.g., flow cytometry or molecular studies) does not contribute substantially to the diagnosis at this time.

Nuclear geomorphology in GPL is an important feature because the neoplastic cell nuclei exhibit a broader range in size and shape, with more infrequent eosinophilic nucleoli, than the Hodgkin Reed Sternberg cells and variants of CHL. Similar to morphological findings, the immunophenotype of GPL is variable with transitional and divergent patterns (i.e., tumors with childlike morphology can exhibit classic DL BCL or PBL immunophenotype, and vice versa).

This feature, in conjunction with nuclear geomorphology, can be helpful in highlighting neoplastic cell nuclei within the inflammatory or fibrotic background. CD30 positivity was a common finding and, if seen in conjunction with CD15 and PBL morphology, should raise suspicion for GPL.

Altogether, based on consensus opinion, the minimum immunohistochemical panel considered adequate for diagnosis should include CD20, PAX5, MUM1, CD30, CD15, and ABV by in situ hybridization; these recommendations, along with an advocated diagnostic algorithm, are detailed in Figure 3. The minimum diagnostic panel for workup of GPL should include B-cell markers (CD20 and PAX5), MUM1, CD30, and CD15.

A broad panel of T-cell and cytotoxic markers is desirable to rule out anapestic large cell lymphoma. (Lower balloon) depicts potential pitfalls in the diagnostic evaluation of GPL to also consider.

The minimum diagnostic panel for workup of GPL should include B-cell markers (CD20 and PAX5), MUM1, CD30, and CD15. A broad panel of T-cell and cytotoxic markers is desirable to rule out anapestic large cell lymphoma.

(Lower balloon) depicts potential pitfalls in the diagnostic evaluation of GPL to also consider. Notably, expression of CD20 in a tumor otherwise typical of CHL should not lead to a diagnosis of GPL.

The NS2 variant of NHL, also known as CHL NS with lymphocyte depletion, tracks back several decades to original work at the National Cancer Institute, and subsequently at the British National Lymphoma Investigation, where it was identified as a subset with aggressive behavior and poor prognosis in several studies. 17,18,21,22 Although knowledge of various morphological subtypes of CHL and historical perspective on nomenclature development are helpful in understanding different entities, this became less relevant with improved treatment, 23 and the WHO does not currently mandate grading of CHL NS in routine clinical practice.

However, it is important to be aware of the morphological spectrum within CHL NS to avoid misinterpretation of these cases. Biopsies diagnosed as CHL NS2 showed fibrosis with at least a partially nodular growth pattern and a high content of Hodgkin Reed Sternberg cells, often palisade around areas of necrosis with frequent eosinophils and neutrophils.

It should be noted that the extent of necrosis often tends to correlate with burden of neoplastic cells. 24 CHL NS2 may resemble GPL in those cases showing confluent growth of lacuna cells in a relatively unicellular fibrotic stoma.

25-27 Further studies showed similar genetic aberrations in GPL, 10 although methylation profiling still revealed that CHL, GPL, and DL BCL clustered separately by principal component analysis. 20 Biologic analyses to compare the cases of CHL NS2 and GPL were beyond the scope of the current study, in part as samples were limited from this large retrospective series drawn from many centers.

Cases with consensus GPL without mediastinal disease were older both in the current study and prior published series. 10 Regardless of clinical presentation, however, PFS appears to be inferior compared with DL BCL or CHL patient populations.

Therapy was fairly heterogeneous among the consensus GPL cases; however, patients were primarily treated according to either a childlike (e.g., ABED) or DLBCL-like (e.g., CHOIR) paradigm. In addition, PFS was best for patients with GPL treated according to a DL BCL regimen.

A recent French series of GPL reported improved outcomes for patients treated with more intensive therapeutic regimens (i.e., methylprednisolone, doxorubicin, cyclophosphamide, procarbazine, topside, Aureomycin, vincristine (escBEACOPP) or doxorubicin, methylprednisolone, cyclophosphamide, Aureomycin, indexing. Nevertheless, the excellent OS in the current and other series, including good outcomes with second-line therapy for patients with GPL (with hematopoietic stem cell transplant in the majority of cases) suggests more intensive therapeutic platforms may play a role in the management of this disease.

Prognostically, increased PAX5 or moderate/strong CD30 expression was associated with inferior PFS in consensus patients with GPL. 31 In part, given that weak or absent CD30 staining was relatively uncommon in the current series, this observation warrants confirmation.

28 In addition, we did not test for the presence of tumor-infiltrating dendritic cells in this current analysis. 32-38 However, the small number of patients and relative heterogeneity of therapy limit conclusions regarding prognostication.

High tumor cell content is very helpful when differentiating between GPL and CHL, the most common alternative diagnosis in this series. Accurate diagnosis is a prerequisite for selection of optimal treatment because current therapeutic strategies for CHL NS, the entity most commonly misdiagnosed as GPL, are different.

The small number of patients and relative heterogeneity of therapy limit definitive delineation of optimal therapy for GPL; however, our results suggest that treatment with DLBCL-based regimens is most effective, including R-CHOP as well as DA-EPOCH-R, the latter as reported previously. Continued analysis of clinical and pathological features is required to better identify the most important prognostic and biologic factors of GPL.

In addition, rational targeted therapeutic agents should be studied in this disease. Presented in part at the 59th annual meeting of the American Society of Hematology, Atlanta, GA, 9-12 December 2017; the 58th annual meeting of the American Society of Hematology, San Diego, CA, 3-6 December 2016; and the 10th International Symposium on Hodgkin Lymphoma, Cologne, Germany, 22-25 October 2016.

The authors thank the institutional data managers and all local pathologists, treating physicians, and other providers. Correspondence: Elaine S. Gaffe, Histopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Building 10, Room 3s235, Bethesda, MD 20892-1500; e-mail: elainejaffe@nih.gov ; and Andrew M. Evens, Division of Hematology/Oncology, Tufts Medical Center, 800 Washington St, Boston, MA 02111; e-mail: dramevens@mac.com.

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