After Chemo, Breast Cancer Patient Develops Two Malignant Neoplasms

Derick Alison
Derick Alison
5 Min Read

A breast cancer patient in her 30s presented for assessment of disseminated erythematous papules and nodules 9 months after undergoing her final chemotherapy treatment.

Her medical history showed that she had been receiving adjuvant chemotherapy consisting of doxorubicin, cyclophosphamide, and paclitaxel for nonmetastatic hormone receptor-positive, BRCA-negative breast cancer, reported Yorick Sandberg, MD, PhD, of Maasstad Hospital in Rotterdam, the Netherlands, and colleagues in JAMA Dermatology.

The team ordered a skin biopsy, which showed infiltration of highly proliferative Langerhans cells. This finding was supported by results of immunohistochemical staining of skin lesions, which “revealed a proliferative histiocytic cell type with strong positivity for S100 and CD1a, supporting the diagnosis of Langerhans cell histiocytosis (LCH). Next-generation sequencing showed a previously undescribed variant of MAP2K1 (OMIM 176872) on exon 2 (c.166C>A; Gln56Lys) with a mutant allele frequency of 16%,” the authors noted. There was no evidence of variants in BRAF, KRAS, or NRAS.

Analysis of bone marrow at the same time showed 14% myeloid blasts and 9% promonocytes, and a balanced translocation (9;11) involving 11q23/KMT2A. Sandberg and colleagues noted that these findings confirmed the prospective diagnosis of therapy-related acute myeloid leukemia (AML). They found no evidence that LCH had infiltrated the bone marrow, and no MAP2K1 variant could be detected in the bone marrow.

The patient underwent fluorodeoxyglucose (FDG)-PET and CT, which showed FDG-avid lesions in the lymph nodes, muscle, skin, bone, and lung. Histopathologic and immunohistochemical assessment of biopsy specimens from the lymph nodes indicated that the LCH was localized.

No abnormalities were evident on examination of the peripheral blood smear.

The team treated the patient with two cycles of induction chemotherapy with cytarabine and daunorubicin. Subsequently, minimal residual disease negativity was achieved and all skin lesions were resolved. At the time of the report, she was receiving consolidation therapy with azacitidine.

Discussion

This case illustrates the importance of considering the possibility that a secondary malignant neoplasm may develop at any time point in relation to LCH diagnosis, Sandberg and team noted, and a thorough examination should be performed — as per current guidelines — after making such a diagnosis.

LCH is often associated with both solid and hematologic malignant neoplasms. AML has been reported in patients with LCH, often as a complication of treatment.

In particular, AML has been observed in the setting of chemotherapy with type II topoisomerase inhibitors, such as etoposide. In patients with histiocytic disorders who develop secondary myeloid or lymphoid neoplasms, a clonal relationship is often involved, the authors said.

“We present a unique case of concurrent — possibly — therapy-related systemic LCH and AML,” they wrote. Both diseases had different genetic alterations. “The LCH presented with a novel Gln56Lys variant in MAP2K1, a well-known activating gene mutated in LCH, and AML showed a balanced translocation involving the MLL (KMT2A) (OMIM 159555) gene,” they explained.

Treatment-related AML is often characterized by 11q23 translocations, particularly after use of chemotherapy regimens that contain anthracyclines or other type II topoisomerase inhibitors.

However, the two other patients reported to have developed both LCH and AML had not received chemotherapy, the authors added. One involved a “molecularly determined clonal relationship,” and the clonal relationship involved in the other remains undetermined.

“We unambiguously show that, in concurrent LCH and AML cases, their clonal relationship is not evident beforehand and should be determined at the DNA level,” they wrote.

Key factors recently reported to have a role in the concomitant development of LCH and malignant neoplasms include variants in the mitogen-activated protein-kinase pathway, tumor predisposition syndromes, and the existence of a common hematopoietic cell of origin, Sandberg and colleagues said.

That there was no evidence of a clonal relationship in their patient’s case raises the possibility that both diseases resulted from a different etiology, they noted; this points to the “possible existence of a fourth mechanism of therapy-related LCH and myeloid neoplasms (i.e., simultaneous therapy-induced different genetic alterations).”

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    Kate Kneisel is a freelance medical journalist based in Belleville, Ontario.

Disclosures

The authors reported no conflicts of interest.

Primary Source

JAMA Dermatology

Source Reference: Beckmann S, et al “Concurrent Langerhans cell histiocytosis and acute myeloid leukemia without clonal relationship” JAMA Dermatol 2023; DOI: 10.1001/jamadermatol.2023.4360.

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