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Lymphocyte Depleted Hodgkin Lymphoma
Introduction
Lymphocyte-depleted classic Hodgkin lymphoma is the rarest subtype of classic Hodgkin lymphoma globally, although it may be more common in developing countries.[1][2][3] The diagnosis of lymphocyte-depleted classic Hodgkin lymphoma could be challenging, and the disease might be misdiagnosed as more aggressive B-cell or T-cell lymphomas.[4] Patients with this disease present more often with unfavorable risk factors and have poorer survival rates than those with other subtypes of classic Hodgkin lymphoma.[5][6]
Etiology
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Etiology
Although certain viral infections such as Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV) have been associated with this disease, no specific causal link has been identified.[6][7][8]
Epidemiology
Lymphocyte-depleted classic Hodgkin lymphoma is regarded as the rarest subtype of classic Hodgkin lymphoma, accounting for 1% to 1.5% of classic Hodgkin lymphoma cases in Western countries.[5][9] However, it may be more common in the developing world.[3] Approximately 40% of cases are diagnosed in patients aged 60 years and older.[9] Younger patients aged 18 to 39 years are also affected by the disease seen in 28% of cases.[9] It is twice as common in men as in women.[6] At the time of presentation, 64% of patients have an advanced-stage disease (stage III-IV).[6]
Pathophysiology
The etiology of lymphocyte-depleted classic Hodgkin lymphoma has not been established. However, genetic factors and viral infections such as EBV and HIV may play a role in the pathogenesis of this disease.[6][7][8][10]
1. Genetic Disorders
Various gene mutations and chromosomal abnormalities in classic Hodgkin lymphoma affect transcription factors, signaling molecules, tumor suppressor genes, and immune regulators. These result in the transformation of germinal center B-cells to characteristic Hodgkin/Reed-Sternberg (HRS) cells.[11]
1.1. Genetic Abnormality
A genetic amplification or copy number gain of chromosome 9p24.1 leads to overexpression of programmed death-ligand 1 and 2 (PD-L1 and PD-L2).[10] Moreover, amplification of Janus activated kinase 2 (JAK2) locus induces Janus activated kinase - signal transducers and activators of transcription (JAK-STAT) signaling, leading to increased transcription of PD-L1.[10] The signaling between PD-L1 on HRS cells and programmed cell death-1 (PD-1) receptors on T-cells results in T-cell dysfunction, exhaustion, and subsequent apoptosis.[12] The resultant immunosuppressive tumor microenvironment allows HRS cells to evade an effective anti-tumor immune response.[13]
1.2. Aberrant Signaling
Constitutive activation of nuclear factor-kappa B (NF-kappaB) in HRS cells is hypothesized to stimulate proliferation, encourage migration, and inhibit apoptosis of malignant cells.[14] Cooperation of NF-kappaB with activator protein 1 complex (AP-1) causes increased expression of cyclin D2, c-met, and chemokine receptor 7 (CCR7), thus promoting HRS cell proliferation.[15] Additionally, loss-of-function mutations of suppressors of cytokine signaling-1 (SOCS-1) are associated with constitutive activation of JAK-STAT signaling and nuclear phospho-STAT5 accumulation.[16]
2. Viral Infections
2.1. Epstein-Barr Virus
EBV infection is present in 60% to 72% of patients with lymphocyte-depleted classic Hodgkin lymphoma, which is relatively more common than other subtypes of classic Hodgkin lymphoma.[6][7] Besides, EBV has been shown to play a significant role in the pathogenesis of this disease. Latent membrane protein 1 (LMP 1) of EBV induces PD-L1 expression on EBV-infected B-cells through several survival pathways such as the JAK-STAT signaling pathway, NF-kappaB, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathways.[17][18][19][20]
Moreover, LMP 1 acts as a functional homolog of CD40.[21] CD40 ligand on activated T-cells typically interacts with CD40 on antigen-presenting cells, leading to a T-cell-dependent immune response.[22] However, in EBV infection, LMP 1 imitates helper T-cell function and allows EBV-infected B-cells to undergo activation, proliferation, and differentiation in the absence of T-cells.[23]
2.2. Human Immunodeficiency Virus
Approximately 15% of patients with lymphocyte-depleted classic Hodgkin lymphoma have HIV infection that induces chronic B-cell activation via interacting with CD40-ligand-bearing virions, HIV-associated proteins such as gp120, p17, and nef, and altering cytokine production and release.[8][24][25][26] Failure to recognize and eradicate EBV-infected B-cells, caused by HIV infection with associated immune dysfunction, also contributes to malignant transformation.[27] Moreover, the HIV p17 protein variant induces EBV oncoprotein, which then leads to the uncontrolled proliferation of B-cells infected with EBV.[27]
Histopathology
The lymphocyte-depleted classic Hodgkin lymphoma diagnosis requires a histopathologic finding of characteristic HRS cells with abundant basophilic cytoplasm and a distinctive bi-nucleate morphology resembling owl's eyes appearance.[28] Lymphocyte infiltration is minimally seen in this subtype. The two morphological variants are diffuse fibrosis and reticular variant. The former has abundant HRS cells in a hypocellular background with disordered fibrosis, abundant histiocytes, and few plasma cells or eosinophils, while the latter has numerous HRS cells frequently associated with anaplastic and pleomorphic features.
History and Physical
Most patients experience B symptoms such as unexplained fever of more than 100.4 °F (38 °C), drenching night sweats, and unexplained loss of more than 10% of body weight over 6 months.[5] They typically present with an extensive symptomatic disease with a predilection for retroperitoneal lymph nodes, abdominal organs including subdiaphragmatic regions, and bone marrow.[28]
Evaluation
For a definitive diagnosis of lymphocyte-depleted classic Hodgkin lymphoma, an excisional lymph node biopsy is generally preferred over a core-needle biopsy.[29][30] However, a fine-needle aspiration biopsy (FNAB) is inadequate to establish the diagnosis.[31][32] Immunophenotyping is also required for a definitive diagnosis, and the HRS cells are positive for CD30 in almost all cases.[6][7] The neoplastic cells are also positive for CD15 and PAX5. A positive CD20 can be detected in 20% of cases. They are usually negative for CD3, CD45, and CD79a. Up to 60% to 72% of lymphocyte-depleted classic Hodgkin lymphoma cases may be positive in LMP 1 of EBV.
Proper staging is important to assess the extent of the disease and to guide therapy. Positron emission tomography (PET) and computed tomography (CT) scans are routinely done for staging evaluation in Hodgkin lymphoma, but contrast-enhanced CT scans can also be used.[33][34] A bone marrow biopsy is no longer mandatory for the routine staging of Hodgkin lymphoma.[35] The 2014 Lugano classification is described as follows:[36]
- Stage I: A single lymph node, a group of adjacent lymph nodes, or single extranodal lesions without nodal involvement
- Stage II: Two or more lymph node groups on the same side of the diaphragm or limited contiguous extranodal involvement
- Stage II bulky: Stage II as above with a bulky feature defined as a single nodal mass of 10 centimeters or greater than a third of the transthoracic diameter
- Stage III: Nodes on both sides of diaphragm or nodes above diaphragm with spleen involvement
- Stage IV: Additional noncontiguous extra lymphatic involvement
Treatment / Management
Clinical outcomes of classic Hodgkin lymphoma have been improving with the advancement of chemotherapy, radiation therapy, and targeted therapies.[37] The therapeutic approach is based on the age of patients, the extent of disease, high-risk features, comorbidities, potential toxicities, and survivorship.
1. Risk Stratification
Patients are generally classified into 3 groups: early-stage favorable (stage I–II without unfavorable factors), early-stage unfavorable (stage I–II with any of the unfavorable factors), and advanced-stage disease (stage III-IV). The National Comprehensive Cancer Network defines unfavorable factors for early-stage disease as the presence of B symptoms, erythrocyte sedimentation rate ≥ 50 millimeters per hour, bulky mediastinal disease (mediastinal mass ratio > 0.33, or adenopathy > 10 centimeters), and > 3 sites of disease.[38][39][40](A1)
The International Prognostic Score (IPS) helps determine the clinical management and predict prognosis for those with advanced-stage disease.[41] It is a seven-factor scoring system, which includes: serum albumin < 4 grams per deciliter, white-cell count ≥ 15,000/cubic millimeter, age ≥ 45 years, lymphocyte count < 600/cubic millimeter, or < 8% of white-cell count, hemoglobin < 10.5 grams per deciliter, male sex, and stage IV disease. Patients with high-risk scores (IPS ≥ 4) were found to have 5-year freedom from progression (FFP) of 65%, while those with low-risk scores (IPS 0 to 3) had a 5-year FFP of 81%.[42](B3)
2. Risk-Adapted Initial Therapy
2.1. Early-Stage Hodgkin Lymphoma
Two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy followed by 20 Gy of involved-field radiation therapy (IFRT) is generally considered as the standard therapy for early-stage favorable Hodgkin lymphoma.[43] For those with an unfavorable prognosis, ABVD for 4 cycles with a subsequent 30 Gy of IFRT is considered as the standard initial regimen.[44] The total number of chemotherapy cycles and the role of radiation therapy vary in both favorable and unfavorable patient groups depending on the initial response to chemotherapy and the therapeutic plan (chemotherapy alone versus combined modality therapy). Note that the omission of radiation therapy is associated with a slightly higher risk of disease relapse.[45][46] Cautions must be taken when using bleomycin in elderly patients due to a substantial risk of severe pulmonary toxicity.[47](A1)
2.2. Advanced-Stage Hodgkin Lymphoma
Six cycles of ABVD is a preferred therapeutic approach for adult patients with advanced-stage Hodgkin lymphoma.[48] Other regimens that may be considered include escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and brentuximab vedotin, an anti-CD30 antibody-drug conjugate, combined with AVD (doxorubicin, vinblastine, and dacarbazine).[49][50](A1)
3. Response-Adapted Therapy
After 2 cycles of ABVD, patients typically undergo the first interim response assessment using PET/CT scans.[51] The results are then interpreted using the Deauville criteria that utilize a 5-point scoring system.[52] The scale depends on the visual comparison of fluorodeoxyglucose (FDG) uptake in involved sites to that of mediastinum and liver. The interpretation is as follows:(B3)
- Score 1: no uptake
- Score 2: uptake is equal to or below mediastinum
- Score 3: uptake is above mediastinum but equal to or below the liver
- Score 4: uptake is moderately higher than liver
- Score 5: uptake is markedly higher than liver, any new lesions, or both
- Score X: new areas of uptake that are unlikely to be related to lymphoma
Depending on the Deauville score, further management is individualized for each patient.[52] Bleomycin can safely be omitted from ABVD regimen in patients who achieved a negative interim PET/CT scan.[47][53][54] In contrast, a biopsy is warranted for patients with a positive interim PET/CT scan, particularly Deauville score 5, to confirm a refractory disease or to establish the definitive diagnosis.[36](B3)
4. End-of-Treatment Assessment
At the end of treatment, PET/CT scans help establish remission status using the Deauville criteria.[36][52][55] A score of 1 to 3 represents a complete metabolic remission irrespective of the size of a residual mass. A residual PET-positivity could represent inflammatory changes or persistent disease, and these patients could undergo further evaluation by biopsy, subsequent radiation therapy, or can potentially be observed.[56](B3)
5. Relapsed or Refractory Hodgkin Lymphoma
A diagnosis of relapsed or refractory Hodgkin lymphoma must be confirmed histologically by biopsy.[36] Patients with a relapsed or refractory Hodgkin lymphoma are treated with an alternative chemotherapy regimen, such as ICE (ifosfamide, carboplatin, and etoposide).[57][58] High-dose chemotherapy and autologous stem cell rescue (HDT/ASCR) is the standard of care for patients with chemosensitive disease. Risk factors for relapse or progression after transplantation includes primary refractory disease, remission duration of <1 year following frontline therapy, and the presence of extranodal disease at relapse.[59] Consolidative brentuximab vedotin, with a duration of 1 year, is indicated for patients with high-risk features. Additional therapeutic options include brentuximab vedotin, PD-1 monoclonal antibodies such as nivolumab and pembrolizumab, and allogeneic stem cell transplantation.[60][61][62][63][64](A1)
Differential Diagnosis
Lymphadenopathy can be seen in various conditions such as infection, autoimmune disorders, and malignancies. Patients with lymphadenopathy should undergo proper workups. A definitive diagnosis requires a biopsy with histopathological and immunohistochemical examinations. It is prudent to obtain adequate tissue for histopathologic analysis, particularly for patients with suspected Hodgkin lymphoma, to yield a definitive diagnosis.[65]
Prognosis
Patients with lymphocyte-depleted classic Hodgkin lymphoma have more adverse risk factors than those with other subtypes of classic Hodgkin lymphoma. The 5-year progression-free survival and overall survival rates are significantly lower in these patients than those with other subtypes of classic Hodgkin lymphoma.[5]
Complications
In long-term survivors of Hodgkin lymphoma, the most serious late complications include secondary cancers, cardiovascular diseases especially in patients treated with mediastinal irradiation and/or anthracycline-based chemotherapy, hypothyroidism related to mediastinal irradiation, and infertility particularly associated with BEACOPP regimen.[66][67][68][69][70][71] Timely recognition and proper management of these potential long-term complications among survivors of lymphoma are crucial to mitigate treatment-related morbidity and mortality.
Deterrence and Patient Education
Being diagnosed with lymphocyte-depleted classic Hodgkin lymphoma and undergoing treatment can have significant psychosocial impacts on patients and their families. These can bring dramatic changes in their physical, spiritual, emotional, and interpersonal dimensions. Every clinic visit should include screening and assessing the emotional and social concerns of patients and their families. They should also be well-informed of the types of treatment, such as combined modality therapy versus chemotherapy alone, pros and cons of each treatment, side effects, supportive measures, regular follow-up, and long-term management plan.
Furthermore, as some chemotherapeutic agents are known to affect fertility, patients should be counseled for options such as sperm banking and egg freezing to preserve fertility. Regular follow-up with primary care physicians and oncologists is also important to monitor treatment response and treatment-related toxicities such as cardiotoxicity and pulmonary toxicity.
Enhancing Healthcare Team Outcomes
A patient-centered teamwork approach is of vital importance when managing patients with lymphocyte-depleted classic Hodgkin lymphoma. An interprofessional team comprising of primary care physicians, oncologists, nursing staff, radiologists, palliative services, social workers, and case managers should work together in every step of treatment to provide comprehensive care for patients and their families, in prevention and management of complications, regular follow-up, survivorship care, psychosocial support, and in end-of-life care.
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