Lymphoma & related disorders

• Indolent and rare mature B cell neoplasm associated with age related or iatrogenic immunosuppression
• Almost all Epstein-Barr virus positive mucocutaneous ulcer (EBVMCU) patients achieve remission with the reduction or discontinuation of immunosuppressants

• ICD-O: 9680/1 - EBV+ mucocutaneous ulcer

• Iatrogenic or age associated immunosuppression

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• Biopsy

Contributed by Sergio Pina-Oviedo, M.D.

• EBV+ DLBCL (Pathogens 2018;7:28):
  • Sheets of large B cells, nongerminal center immunophenotype (CD10-, variable BCL6, MUM1+)
  • More common nodal presentation
  • Rapidly progressive disease
• Classical Hodgkin lymphoma (Pathogens 2018;7:28):
  • Reed-Sternberg cells, CD15+, CD30+, CD45-, PAX5-, CD20-, variable EBV
  • B symptoms, lymphadenopathy, mediastinal mass
• Extranodal NK / T cell lymphoma (Curr Hematol Malig Rep 2016;11:514):
  • Angiocentric, angiodestructive growth pattern, NK or T cells CD2+, CD56+
  • Often involving the nasal cavity or skin
• Lymphomatoid granulomatosis (Am J Surg Pathol 2010;34:e35):
  • Angiocentric, angiodestructive lesion composed of B cells, CD30+
  • Pulmonary nodules, skin lesions, B symptoms

• EBV+ polymorphic lymphoproliferative disorder:
  • Often linked to immunosuppression, such as posttransplant
  • Systemic symptoms like fever, weight loss and lymphadenopathy
  • Involves multiple anatomical locations, mainly lymph nodes, spleen and liver
  • Heterogeneous lymphoid population, including B cells, T cells and plasma cells
  • Reed-Sternberg-like cells may be present but are not definitive
  • Immunophenotype similar to EBVMCU; B cells often express EBV latent membrane proteins (EBER, LMP1, EBNA2) in a range of cell sizes
  • Monoclonal or oligoclonal IG rearrangements

A 34 year old woman presents with a painful ulcer on her upper lip (as shown in the image above). The lesion has been present for ~4 weeks and has not responded to topical treatments. The lesion is about 1.5 cm in diameter, has a raised border and a yellowish base. She reports no history of trauma to the area but reports a recent onset of fatigue and malaise. The patient has a history of Hodgkin lymphoma, which was treated with chemotherapy and radiation therapy 2 years ago. A biopsy of the lesion shows diffuse infiltration of large atypical lymphoid cells, positive for CD20, CD30, PAX5 and Epstein-Barr virus (EBV) and negative for CD15 and CD56. There is a mixed inflammatory infiltrate, including lymphocytes and plasma cells. What is the most likely diagnosis?

1. Classic Hodgkin lymphoma
2. EBV+ mucocutaneous ulcer
3. Extranodal NK / T cell lymphoma
4. Lymphocyte predominant Hodgkin lymphoma
5. Posttransplant associated lymphoproliferative disorder (PTLD)

B. EBV+ mucocutaneous ulcer. EBV+ mucocutaneous ulcer (EBVMCU) is the most likely diagnosis for this patient due to the presence of a localized ulcer on her upper lip and the histological findings of a polymorphous infiltrate with large atypical cells, positive for CD20 and CD30 and negative for CD15, which align with the typical profile of EBVMCU. Additionally, the presence of Epstein-Barr virus (EBV) in the atypical cells, as well as the patient's history of immunosuppression following treatment for Hodgkin lymphoma, further support the diagnosis. EBVMCU is a self limited, often recurring disease that usually occurs in the setting of immune dysregulation or immunosuppression, fitting well with the patient's clinical context.

Answer A is incorrect because the clinical presentation and the immunophenotypic profile of the cells are not typical for classic Hodgkin lymphoma (CHL). CHL usually presents as lymphadenopathy rather than a mucocutaneous ulcer. Furthermore, CHL is characterized by the presence of Reed-Sternberg cells, which are typically CD30 positive, CD15 positive and CD20 negative, in contrast to the cells in this case, which are CD15 negative and CD20 positive.

Answer C is incorrect because extranodal NK / T cell lymphoma is typically associated with Epstein-Barr virus (EBV) infection but the neoplastic cells are typically T cells or NK cells, not B cells. The cells in this case are positive for CD20, a B cell marker, which makes NK / T cell lymphoma unlikely. Additionally, extranodal NK/T cell lymphoma frequently involves sites such as the nasal cavity, whereas this lesion is on the lip.

Answer D is incorrect because lymphocyte predominant Hodgkin lymphoma (LPHL) is characterized by the presence of LP cells, which are variants of Reed-Sternberg cells. LP cells typically express CD20 but not CD30. This case presents cells that are both CD20 and CD30 positive, which is not characteristic of LPHL. Furthermore, LPHL typically presents as lymphadenopathy, not as a mucocutaneous ulcer.

Answer E is incorrect because despite the patient's history of immunosuppression, the findings do not match those of a posttransplant lymphoproliferative disorder (PTLD). Polymorphic LPDs can appear in multiple settings of immune deficiency, not just posttransplant. They usually manifest as mass forming lesions composed of heterogeneous infiltrate of cells, including those similar to Hodgkin / Reed-Sternberg cells. While they share some immunophenotypic similarities with EBV+ mucocutaneous ulcers, polymorphic LPDs more often show monoclonal or oligoclonal IG rearrangements and have a broader range of potential sites of involvement, more commonly lymph nodes and various organs. The solitary painful lip ulcer in this case is more consistent with an EBV+ mucocutaneous ulcer.

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Reference: EBV+ mucocutaneous ulcer