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Diagnosis and Discussion: Case 1149

Final Diagnosis

Myeloid Sarcoma with concurrent low level bone marrow involvement

Pathology reports from the orchiectomy specimens (reviewed at an outside institution) also revealed testicular involvement by myeloid sarcoma.

Discussion

Myeloid sarcomas are extramedullary (outside the bone marrow) masses composed of myeloid blasts, which may involve any body part including the skin, soft tissues, lymph nodes, gastrointestinal tract, testicles etc. and are considered equivalent to a diagnosis of acute myeloid leukemia (AML).

Such collections of myeloid blasts in tissues can occur concurrently with bone marrow involvement by acute myeloid leukemia or precede the disease in other cases. Just like AML, myeloid sarcoma can occur as an evolution of other myeloid neoplasms. Isolated myeloid sarcoma, without morphologic involvement of the bone marrow, is extremely rare.

Morphologically, myeloid sarcomas can be a challenging diagnosis to make and may have a broad differential diagnosis on H&E evaluation. CD43 immunohistochemical staining is often helpful in identifying myeloid sarcomas. CD45 is expressed in only about 60% cases. Further, negativity for B-cell and T-cell markers can help exclude most lymphomas. CD34 and CD117 are positive in tumors with an immature granulocytic profile, whereas others with immature monocytic cells express CD11b, CD11c, CD15, CD64, lysozyme and IRF8. CD61 and glycophorin-A may serve as indicators of rarer megakaryocytic and erythroid differentiation. Mutation specific IHC markers, such as NPM1 and IDH2 p.R132H, may also be helpful. Besides lymphomas, differential diagnoses of small blue round cells tumors and histiocytic/dendritic cell neoplasms like blastic plasmacytoid dendritic cell neoplasm (BPDCN) may also be considered.

Cytogenetic and molecular findings in myeloid sarcoma cases tend to recapitulate those noted in acute myeloid leukemia. NPM1 mutations are identified in 20-30% of total cases and are typically a 4-bp insertion in exon 12 of the gene (>99% cases). The protein encoded by NPM1 gene has chaperone and nuclear shuttling features and is hence predominantly localized within the nucleus. Aberrant cytoplasmic localization, as detected by immunohistochemical staining for the NPM1 protein, indicates the presence of a mutation. Other immunohistochemical stains, such as the one utilized at our institution, are capable of selectively identifying the mutant NPM1 protein and may be interpreted simply as positive or negative. Blasts usually show myelomonocytic or monocytic differentiation in AML and myeloid sarcoma cases with NPM1 mutations. The presence of NPM1 mutations is an AML-defining event and a blast cut-off of 20% is not required for the diagnosis per WHO 5th Edition classification. Per ICC (International Consensus Classification), a blast cut-off of 10% within the bone marrow is still required to be met to classify the disease as AML. NPM1 mutations confer a good prognosis. However, in the presence of FLT3 internal tandem duplications, the prognosis is less favorable (intermediate).

Typing of NPM1 mutations is based on the specific 4-bp insertion noted in the mutant gene. The most common mutations involve insertions of the following nucleotides: TCTG (Type A mutation; ~70% cases), CATG (Type B mutation; ~10% cases) and CCTG (Type D mutation; <10% cases). Insertions of other nucleotide combinations is much less common. However, knowledge of the exact genetic change is important in the follow-up monitoring of NPM1 mutated cases using Real time polymerase chain reaction (RT-PCR) and next-generation sequencing (NGS) technologies.

The current case has several interesting features. The myeloid sarcoma is accompanied by a very low-level bone marrow involvement that was only detectable by immunohistochemical analysis using NPM1 immunostain (due to lower sensitivity of the routine molecular and cytogenetic tests employed for bone marrow and peripheral blood analysis). Molecular testing of the right chest/shoulder lesion revealed a rare NPM1 mutation with a TAAA insertion (non - A, B or D mutation). This was accompanied by a FLT3 tyrosine kinase domain mutation. Tyrosine kinase domain mutations in FLT3 gene are targetable by FLT3 inhibitors but do not have the same prognostic significance as FLT3-ITD mutations.

References

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