Case 282

Submitting Author: Paessler, Michele E, DO
Institution: The Children's Hospital of Philadelphia
Additional authors:Gerald Wertheim, MD PhD, Rebecca L. King, MD
Session: Therapy-related myeloid neoplasms

HISTORY

The patient is a 19 year old female diagnosed in December 2010 with classical Hodgkin lymphoma, nodular sclerosis type, stage IIA E in a right cervical lymph node. At presentation there was a bulky mediastinal mass and extension into the pericardium. The patient was treated for intermediate risk HL with modified (Stanford V) therapy. She was symptom free and off therapy as of May 2011. Routine follow-up scans from November 2012 showed large mediastinal nodes adjacent to a mediastinal mass and a biopsy of a mediastinal node was performed. CBC and physical exam were normal at this time.

DETAILS

December 2010:

Lymph node, cervical (fixed in formalin):

H&E sections of the lymph node shows a nodular pattern. The nodules are composed of a mixed cellular infiltrate (lymphocytes, plasma cells, histiocytes and eosinophils) and scattered prototypic Reed-Sternberg cells. Large bands of fibrosis separate the nodules.

November 2012:

Mediastinal lymph node (fixed in formalin):

H&E sections show regions with cellular nodules surrounded by bands of sclerosis. The cellular nodules are composed of scattered Reed-Sternberg cells surrounded by mixed inflammatory background consisting of small mature lymphocytes, eosinophils, plasma cells, and histiocytes. The cellular nodules are morphologically consistent with Hodgkin lymphoma. In many areas, the surrounding sclerosis is infiltrated by medium sized mononuclear cells with scant cytoplasm and fine chromatin that form sheets and dissect between collagen bundles.

Bone marrow, biopsy and aspirate (biopsy decalcified/fixed in AZF)

Normocellular marrow with trilineage hematopoiesis. No morphologic features of acute leukemia or Hodgkin lymphoma seen.

IMMUNOHISTOCHEMISTRY AND FLOW CYTOMETRY

December 2010:

Paraffin immunohistochemistry was performed to confirm the diagnosis of Hodgkin lymphoma. The scattered Reed-Sternberg cells are positive for CD30, and PAX5(dim) while negative for CD45, CD79a, CD20, CD3, and CD5.

November 2012:

Paraffin immunohistochemistry was performed on block A4 to better characterized the mononuclear infiltrate and to confirm the diagnosis of recurrent/residual Hodgkin lymphoma. The scattered Reed-Sternberg cells are positive for CD30, PAX5 (dim) while negative for CD45, CD79a, CD20, CD3, CD5. The mononuclear cell infiltrate is positive for CD33, MPO, lysozyme, CD45(dim) while negative for CD30, CD3, CD5, PAX5, CD20, CD79a, TdT, CD34, CD30 and EBER.

CYTOGENETIC FINDINGS

Mediastinal mass:

MLL FISH testing was performed on paraffin embedded, formalin fixed tissue revealing an MLL rearrangement.

Bone marrow:

RT-PCR for MLL breakpoints was positive (<1% t(9;11)).

INTERESTING FEATURES

This is an interesting case of a 19 year old female with classical Hodgkin lymphoma (cHL), nodular sclerosis type, that relapsed approximately 2 years following therapy and was incidentally found to have a therapy-related myeloid sarcoma with an 11q23 MLL rearrangement occurring in the same mediastinal mass (collision tumor).

Therapy-related myeloid neoplasms have been a long recognized complication of cHL, especially in patients exposed to alkylating agents and topoisomerase II inhibitors, and are associated with a poor prognosis. Alkylating agent-related leukemias peak in the first 5 years after therapy and are usually associated with dysplastic bone marrow changes and chromosomal aberrations involving chromosomes 5 and 7. In contrast, epipodophyllotoxin-related leukemias occur ~2-3 years after therapy and are not usually preceded by myelodysplasia. These leukemias are frequently associated with balanced translocations involving 11q23 (MLL) and 21q22 (RUNX1). Extended field radiation therapy is also a risk factor for therapy related myeloid neoplasms.

Current cHL therapy has been modified significantly from older regimens, and now typically offers minimal exposure to alkylating agents and less extended field radiation exposure. These modifications have led to a dramatic decrease in therapy-related MDS and AML in cHL. Based on the modified treatment strategies, the cumulative risk of developing therapy-related MDS or AML in cHL is low (<1%) (1). The majority of these cases occur in the first year after completion of initial therapy, and the outcome of these patients is typically very poor.

This case is interesting in that the patient had modified (Stanford V) therapy, and approximately one year after therapy completion developed a recurrence and concomitant myeloid sarcoma. The myeloid sarcoma contained an MLL rearrangement based on FISH studies. The patient had a normal CBC and no morphologic evidence of therapy-related MDS or AML in the bone marrow. However, RT-PCR for MLL, t(9;11), was positive in <1% of the cells in the bone marrow.

Therapy-related AML with t(9;11) is generally associated with a short latency period, and presents with overt AML without a preceding MDS as was the case with this patient. To our knowledge, concomitant therapy-related myeloid sarcoma in the same site as recurrent cHL has not been described. Although the prognosis for therapy-related MDS and AML is generally poor, the prognosis of a myeloid sarcoma with minimal involvement of the bone marrow is unclear. This patient is currently being conditioned for bone marrow transplant.

PROPOSED DIAGNOSIS

Therapy related myeloid sarcoma with an 11q23 (MLL) rearrangement occurring in a collision tumor with relapsed classical Hodgkin lymphoma.

CONSENSUS DIAGNOSIS

Therapy-related myeloid neoplasm, myeloid sarcoma with MLL rearrangement, occurring in a collision tumor with relapsed classical Hodgkin lymphoma