22 December 2021: Articles
Challenging differential diagnosis, Rare disease, Rare coexistence of disease or pathologyTinera Buckley12ABCDEFG*, Arati Inamdar12ABCDEFG, Nagyl H. Mikhail23AEFG, Abraham Loo23AEFG, Seth Cohen4ABCDEFG
Am J Case Rep 2021; 22:e932904
BACKGROUND: Richter transformation (RT) is an uncommon clinicopathological condition referring to the development of aggressive lymphoma from chronic lymphocytic lymphoma/small lymphocytic lymphoma (CLL/SLL) and characterized by sudden clinical deterioration with marked multifocal lymphadenopathy. Transformation of CLL/SLL to diffuse large B-cell lymphoma is the most common (2-9%), but T-cell and Hodgkin transformation (HL) (0.4%) occur, although less frequently.
CASE REPORT: A 68-year-old woman initially diagnosed with CLL/SLL presented to the hospital with fever, weakness, abdominal pain, and vomiting. The physical examination showed hepatosplenomegaly and extensive abdominal lymphadenopathy on radiological imaging. The laboratory work-up revealed pancytopenia and a markedly increased alkaline phosphatase. In the setting of extensive granulomatous hepatitis, the development of aggressive Hodgkin lymphoma Richter transformation with multi-organ involvement within a few months led to the patient’s sudden death. Autopsy findings led to the post-mortem diagnosis of Richter’s transformation of CLL.
CONCLUSIONS: Here, we describe a rare case of Hodgkin lymphoma RT from progressive CLL, with transformation occurring at approximately 12 years after initial diagnosis, despite treatment. Our case report underscores the diagnostic challenges and pitfalls associated with the granulomatous presentation masking RT transformation of CLL to Hodgkin lymphoma. The purpose of this report is to raise suspicion for the clinicopathological signs of Richter transformation in the presence of an atypical granulomatous presentation.
Keywords: Hodgkin Disease, Leukemia, B-Cell, Lymphoma, Aged, Cell Transformation, Neoplastic, Female, Hepatomegaly, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Large B-Cell, Diffuse
Chronic lymphocytic leukemia/small lymphocytic lymphoma constitutes 25% to 30% of leukemia cases in the United States and is considered an indolent hematological malignancy. It usually affects adults with an average age of 70 years but can also be seen in adults as young as age 30. CLL/SLL is a monoclonal lymphoproliferative disease characterized by the increased production of mature but immunologically dys-functional B-cell lymphocytes . In CLL, the abnormal B cells are present in the blood, while in SLL they are primarily found in the lymph nodes. Other disease sites include bone marrow, spleen, skin, and other lymphoid tissues. Although the exact cause of CLL is unknown, multiple factors such as genetic mutations, cytogenetic abnormalities, environmental agents, and antigenic stimulation alone or in combination lead to the clonal replication of abnormal B lymphocytes .
The diagnostic laboratory findings include lymphocytosis with an absolute lymphocyte count greater than 5000/µL with peripheral smear showing abnormal mature B cells with a darkly stained nucleus, condensed chromatin, and non-prominent nucleoli with a narrow rim of basophilic cytoplasm commonly known as soccer ball cells. CLL immunophenotype shows expression of B-cell-associated antigens (CD19, CD20, CD21, CD23, and/or CD24); and expression of CD5, which is a T-cell-associated antigen. The co-expression of CD5, CD19, and CD23 by neoplastic B cells is one of the diagnostic features of CLL/ SLL. The prognostic genetic findings used for risk stratification include 17p deletion and/or TP53 mutations (very high risk) whereas the absence of 17p deletion and TP53 mutations with immunoglobulin heavy chain (IGHV) unmutated and IGHV mutated status indicate high and standard risk, respectively .
Richter transformation is an uncommon clinicopathological condition referring to development of aggressive lymphoma from CLL and characterized by sudden clinical deterioration with marked multifocal lymphadenopathy. Other indications include elevated lactate dehydrogenase with worsening “B” symptoms (50–80%), anemia (50%) and thrombocytopenia (43%) . Although the definitive risk factors for the development of RT in a patient with a history of CLL have not been identified, TP53 disruption, c-myc abnormalities, unmutated IGHV, and CD38 gene polymorphisms have been reported to predispose to RT . Parikh et al found a 6.2-year median period from diagnosis of CLL to Hodgkin’s Richter transformation and a median survival of 3.9 years after Hodgkin’s diagnosis, with worse outcomes for treated CLL patients (2.8 years) and even shorter survival (1.8 years) with prior purine analog therapy . Tsimberidou et al reported slight improvement using combination chemotherapy and allogeneic stem cell transplantation in patients with RT to HL (75% at 3 years), but found the overall prognosis was dismal, with survival ranging from 6 to 10 months among biopsy-proven RS patients on chemo-therapy or immunotherapy alone .
In this case report, we describe a rare case of Hodgkin RT in a patient with relapse/recurrent CLL and transformation occurring at approximately 12 years after initial diagnosis. The unique presentation of the case includes the presence of massive hepatosplenomegaly with ascites, isolated persistent elevation in alkaline phosphatase (up to 961 U/L) without increase in lactate dehydrogenase, and histological diagnosis of acute granulomatous hepatitis on liver biopsy. The sampled ascitic fluid was also negative for any malignant cells. The diagnosis of Hodgkin RT was rendered at autopsy, thereby emphasizing this unusual presentation of Hodgkin RT.
A 68-year-old woman was initially diagnosed in 2008 with CLL/SLL by inguinal lymph node biopsy, which was confirmed by a subsequent bone marrow biopsy. The patient was started on FCR (fludrocortisone cyclophosphamide-rituximab) therapy and completed 6 cycles. She underwent a total thyroidectomy for chronic lymphocytic thyroiditis and Hurthle cell adenoma and excision of basal cell carcinoma nodular and superficial type involving the chest wall in 2011 and 2015, respectively. In 2015, the patient was lost to follow-up. Three years later (2018), she presented with cervical lymphadenopathy and her treatment was modified to include Rituxan and Bendamustine for 6 cycles. Fluorescence in situ hybridization (FISH) performed on the peripheral blood showed mono-allelic deletion of 13q14.3 locus, which is associated with a more favorable clinical outcome. The follow-up imaging demonstrated regression of the cervical lymphadenopathy and thus complete remission. In June 2020, she again presented with left axillary lymphadenopathy. The CT imaging demonstrated a 3.5 cm left axillary lymph node as well as enlarged retroperitoneal and mesenteric lymph nodes (Figure 1A). The patient was planned to start on Gazyva (obinutuzumab) and Venetoclax. However, Venetoclax was held and only Gazyva was given. She completed 3 doses of Gazyva in August 2020 and showed clinical improvement with regression of her mesenteric lymphadenopathy (Figure 1B). Again, the dose of Venetoclax was held due to clinical improvement on Gazyva. The fludarabine-containing regimen was never administered.
One month later, she presented to the Emergency Department with recurrent fever (39.2°C), weakness, abdominal pain, and vomiting for 1 day. The laboratory work revealed elevated alkaline phosphatase 961 (N: 42–119 U/L); AST 10 (N: 10–43U/L); ALT 26 (N: 10–43 U/L), and total bilirubin 1.4 (N: 0.2–1.2 mg/dl). The serological studies were negative for hepatitis A, B, and C, antinuclear antibody (ANA), and anti-smooth muscle antibody (ASMA). No duct dilatation, gallbladder thickening, or peripancreatic ascites was identified on MRI imaging. Extensive splenomegaly with splenic varicosities, ascites, and porta hepatis lymphadenopathy were appreciated. The CT of abdomen and chest confirmed hepatosplenomegaly, enlarged intra-abdominal lymph nodes (largest: 4.5×1.9×2.8 cm), ascites and pleural effusion (Figure 2A, 2B). A liver biopsy was performed, and microscopy showed periportal fibrosis with marked expansion of the majority of the portal tracts by a histiocytic-predominant inflammation (Figure 3A–3D). A diagnosis of acute granulomatous hepatitis with hemophagocytosis was rendered. No evidence of steatosis, cholestasis, malignancy, or infectious agents (AFB and fungus) was identified. The peritoneal fluid showed sparse normal-appearing small lymphocytes but was negative for carcinoma. A bone marrow biopsy was suggested but was declined by the patient as she became progressively weaker. The patient received a blood transfusion as well as consultations by gastroenterology, infectious disease, and hematology/oncology specialists and was treated for neutropenic fever. Fifteen days after admission, a rapid response was called for hypotension (BP 85/57 mmHg). She was transferred to the Intensive Care Unit for septic shock, where she remained on vasopressors for low blood pressure, increasing respiratory distress and hypoxia. She died 3 days later.
Autopsy showed diffuse lymphadenopathy and multi-organ involvement by large, atypical cells, including Reed-Sternberg cells (positive for CD30, CD15, Pax 5, Bcl-2 and EBV (EBER) and negative for CD20, ALK, CD138, and kappa/lambda in situ hybridization) in a background of Pax 5-positive CLL-specific abnormal B lymphocytes (Figure 4A–4I). Interestingly, multiple CD 68 predominant granulomatous areas in the liver were found in the vicinity of the CD30/CD15 atypical Reed-Sternberg-rich area (Figure 3A–3D). The negative immunostaining for CD30 and T cell markers (CD5) ruled out anaplastic large T cell (ALCL) and histiocyte-rich T-cell lymphomas. In addition to being seen in the liver, these CD 30/CD15 abnormal large neoplastic cells were identified in multiple organs, including abdominal, para-aortic, mesenteric, and perihilar lymph nodes, as well as bilateral lungs, liver, spleen, pancreatic surface, fallopian tubes, and bone marrow (Figure 5A–5F). The final diagnosis and cause of death rendered was CLL with transformation to Hodgkin’s lymphoma, involving multiple organs and leading to sepsis.
Our case highlights the Richter transformation of CLL to HL, which is reported to occur in about 0.4% of cases of CLL. Although DLBCL is the most common form of RT of CLL, hairy cell leukemia, lymphoblastic lymphoma, and high-grade T-cell and NSHL have also been documented [4,12]. Due to the aggressive nature of RT Hodgkin lymphoma, treatment options are limited, but the signs that transformation has occurred may not be obvious. Increased relapses on multiple therapies is a common indication that transformation has occurred. However, there is little agreement regarding the risk factors that predispose a patient to RT.
The clinicopathological findings of RT from CLL include sudden clinical deterioration with marked increase in lymphadenopathy, splenomegaly, and worsening “B” symptoms (ie, fever, night sweats, and weight loss). The serum level of LDH is elevated in 50–80% of cases . However, this constellation of symptoms does not occur in every case. Multiple prior therapies, young age, elevated LDH, and anemia are a few suggested risk factors. Immune suppression with fludarabine has been specifically implicated as a promoter of RT [8,9].
Other important clinical indicators to be aware of include noncaseating granulomatous liver disease and elevated alkaline phosphatase and LDH levels. Elevated LDH is often seen in HLRT, but it is nonspecific and can be seen in other conditions as well, so it must be considered in the proper context. Granulomatous liver disease is seen in 2–10% of liver samples with periportal and lobular involvement and varying degrees of inflammation. The causes of this range from infection to autoimmune cholangitis, sarcoidosis, drug toxicity, carcinoma, and lymphoma, specifically HL . It is important to consider HL in the differentials of such cases because, as demonstrated in our case, the HL Reed-Sternberg cells are not clustered in every granuloma and may be missed due to sampling. Perhaps a more suitable biopsy location may have yielded more diagnostic tissue, such as an enlarged mesenteric or intrabdominal lymph node; however, given the presence of markedly elevated alkaline phosphatase levels, the sampling choice was within the reasonable standard of care. Although the liver biopsy did not show CD15+CD30+, CD20- cells, autopsy sampling confirmed the presence of these cells in numerous granulomatous nodules throughout the liver. A recently published case report also describes extensive granulomatous reaction masking the CD30/CD15-positive RS cells in the cervical lymph node of a young male . The exact etiology of a background granulomatous process in HL is unknown, but a few studies suggest the role of T cell-mediated nonspecific inflammatory response especially neoplastic cells induced T-helper cell-mediated immune response as well as delayed hypersensitivity reaction in conjunction with cytokines against antigen produced by neo-plastic cells, which subsequently result in fibrosis and granuloma formation [12,13].
This patient also had markedly elevated alkaline phosphatase levels (961 U/L), which is a poor prognostic factor in patients with HL. Saif (2005) found that overall survival in patients with elevated alkaline phosphatase level was associated with increased extranodal involvement, anemia, low albumin, and high LDH levels . Another interesting variable that may promote HLRT is the presence of EBV, which Fong et al (2005) found was more frequently present in patients with CLL that developed HLRT following treatment with fludarabine therapy, called EBV-associated HL. They found that there was a clonal relationship between the CLL cells and the post-transformation HL cells, and p53 expression was present in 43% of the EBV-associated classical Hodgkin’s Reed-Sternberg cells [9,10]. In our case, the patient was found to be positive for EBV, which was confirmed by positive immunohistochemical staining for EBER.
Treatment of Hodgkin RT has traditionally involved the use of combination Hodgkin-targeted chemotherapy including ABVD, MOPP, or CVPP. Research has implicated targeted therapy with Ibrutinib and Venetoclax in refractory patients in the promotion of RT, occurring in 8.3% of Ibrutinib patients at 26 months, with worse prognosis and overall median survival of 3.3 months after RT. The outcome of RT is generally poor and fatal if left untreated; therefore, the preferred treatment should be determined based on morphology and clinical context. The supplemental implementation of blood transfusion as well as bone marrow transplant are therapies that require further investigation. Currently, there is limited information on Hodgkin RT, but the use of combination chemotherapy in advanced-stage cases is recommended and ABVD has produced clinically significant complete remission outcomes . Further investigation of the risk factors and targeted therapies specific to this RT subtype are needed, but clinicians should always keep HLRT in the differential for CLL/SLL patients who present with classical clinical features as well as some unconventional manifestations such as granulomatous liver disease with elevated alkaline phosphatase. EBV testing should also be performed on initial diagnosis to prevent fludarabine therapy-induced EBV-associated HL, which has a higher incidence in this subpopulation. Another differential that bears consideration is hemophagocytic lymphohistiocytosis (HLH), which involves a constellation of symptoms, including fever, splenomegaly, histiocytic hemophagocytosis, hypertriglyceridemia/hyperfibrinogenemia, bicytopenia, hyperferritinemia, low NK activity, and high IL-2 receptor levels. HLH can be categorized as primary or secondary where primary HLH involves a specific genetic mutation, while secondary HLH can result from any process that promotes abnormal cytokine production and/or abnormal immune response. Although the criteria are nonspecific, meeting 5 criteria is sufficient to make the diagnosis . Our patient did not meet the minimum requirements for this diagnosis, as she only showed evidence of splenomegaly and fever, and she did not have a positive family history for consideration of primary HLH. Furthermore, the primary therapy for secondary HLH is treatment of the underlying disease process, which in our case would consist of chemotherapy for the patient’s EBV-associated HL.
In CLL patients, the follow-up visits are crucial. The indolent nature of CLL can be deceptive, giving rise to DLBCL, HL, or other clonal disease. Clinicians should be aware of rare Richter transformation of CLL to HL, especially in the setting of increasing lymphadenopathy and organomegaly or in despite the absence of abnormal blood parameters such as LDH. The sudden onset of hepatic and splenic enlargement is another clue to possible RT and may be masked by granulomatous conditions related or unrelated to RT. Hodgkin lymphoma is notoriously known to cause a granulomatous reaction. A similar extensive granulomatous feature has been previously reported in a cervical lymph node of a young male . Our report, to the best of our knowledge, is the first to demonstrate an extensive granulomatous reaction in the liver and other organs induced by RT Hodgkin lymphoma from CLL.
This report describes the rare case scenario of RT Hodgkin lymphoma from CLL. The diagnosis of HL in the background of extensive granulomatous reaction can be extremely challenging, especially in the absence of abnormal blood parameters indicative of HL. Our case report highlights the diagnostic issues associated with granulomatous presentation masking Hodgkin lymphoma. Although the prognosis for RT Hodgkin lymphoma is dismal, timely diagnosis is helpful in extending patient survival via combination chemotherapy, therapeutic transfusion, and/or bone marrow transplant.
FiguresFigure 1.. CT images of the abdomen. (A) Sagittal image showing mesenteric lymphadenopathy (yellow arrows) prior to treatment with Gazyva (in June 2020) (B) Sagittal CT image gradual reduction in the mesenteric lymphadenopathy after 3 doses of Gazyva (yellow arrows). Figure 2.. MRI images of the abdomen. (A) Axial MRI image showing extensive hepatic (blue arrow) and splenic (black arrow) enlargement (B) Axial CT image showing extensive hepatic lesions (blue arrow) and mesenteric lymphadenopathy (black arrow). Figure 3.. Biopsy of the liver. (A) Hepatic cells with periportal area (red circle) showing infiltration with inflammatory cells. (B) The immunostaining for CD68 highlights the histiocytic infiltration in the periportal area (red oval). (C, D) The reticulin and trichrome stains highlight the unremarkable hepatic parenchyma and extensive periportal fibrosis (arrow), respectively. Figure 4.. Richter transformation to classic Hodgkin lymphoma: (A) Low-power H&E-stained image showing the periportal area (blue oval) infiltrated by inflammatory cells and histiocytes causing granuloma, with adjacent area (red oval) showing the large, atypical cells infiltrating the liver parenchyma. (B) High-power H&E-stained image showing the large atypical binucleated to multinucleated Reed-Sternberg cells (arrow). (C) RS cells with no reactivity to ALK immunostaining (arrow). (D) RS cells (long arrow) with weak reactivity for Pax-5 but diffuse reactivity for background clonal/CLL-specific B cells (arrowhead). (E, F) The intense reactivity for CD 30 and CD 15 by RS (arrows) confirms the CLL transformation to CHL, respectively. (G) The background CLL cells showed weak CD 20 reactivity (arrow) and negative activity in RS cells (arrowhead). (H) Both RS cells (arrow) and CLL B cells (arrowhead) showed positive Bcl-2 reactivity and (I) positive reactivity for Eber-ISH was seen only in RS cells (arrow). Figure 5.. Multisystem involvement by HL. The atypical cells (arrows) identified in the spleen (A), bone marrow (B), pancreas (C), hilar lymph node (D), lung (E), and fallopian tube (F) suggest the extensive dissemination of RT HL to organs.
1.. Kipps TJ, Stevenson FK, Wu CJ, Chronic lymphocytic leukaemia: Nat Rev Dis Primers, 2017; 3; 16096
2.. Ghia P, Caligaris-Cappio F, Monoclonal B-cell lymphocytosis: Right track or red herring?: Blood, 2012; 119(19); 4358-62
3.. Bosch F, Dalla-Favera R, Chronic lymphocytic leukaemia: From genetics to treatment: Nat Rev Clin Oncol, 2019; 16(11); 684-701
4.. Janjetovic S, Bernd HW, Bokemeyer C, Fiedler W, Hodgkin’s lymphoma as a rare variant of Richter’s transformation in chronic lymphocytic leukemia: A case report and review of the literature: Mol Clin Oncol, 2016; 4(3); 390-92
5.. Fabbri G, Khiabanian H, Holmes AB, Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome: J Exp Med, 2013; 210(11); 2273-88
6.. Mocikova H, Markova J, Gaherova L, Outcome of patients with Hodgkin lymphoma transformed from chronic lymphocytic leukemia: Blood, 2015; 126(23); 5298
7.. Tsimberidou AM, O’Brien S, Khouri I, Clinical outcomes and prognostic factors in patients with Richter’s syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation: J Clin Oncol, 2006; 24(15); 2343-51
9.. Fong D, Kaiser A, Spizzo G, Hodgkin’s disease variant of Richter’s syndrome in chronic lymphocytic leukaemia patients previously treated with fludarabine: Br J Haematol, 2005; 129(2); 199-205
10.. Lewis J, Histopathology of granulomatous liver disease: Clin Liver Dis (Hoboken), 2018; 11(3); 77-80
11.. Du J, Zhang Y, Liu D, Hodgkin’s lymphoma with marked granulomatous reaction: A diagnostic pitfall: Int J Clin Exp Pathol, 2019; 12(7); 2772-74
12.. Dargent JL, Schandené L, Kornreich A, TH1-type immune response in lymphocyte-predominance Hodgkin’s disease: Br J Haematol, 1995; 91(3); 775-76
13.. Khan A, Hill JM, Maclellan A, Loeb E, Improvement in delayed hyper-sensitivity in Hodgkin’s disease with transfer factor: Lymphapheresis and cellular immune reactions of normal donors: Cancer, 1975; 36; 86-89
14.. Saif MW, Alexander D, Wilcox CM, Serum alkaline phosphatase level as a prognostic tool in colorectal cancer: A study of 105 patients: J Appl Res, 2005; 5(1); 88-95
15.. Swerdlow SH, Campo E, Harris NL: World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 2017, Lyon, IARC Press
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