In 2019, the estimate of new cases of acute myeloid leukemia (AML) in the United States is more than 21,000.1 There has been increased interest surrounding potential germline predisposition to myeloid neoplasms including AML, and the revised 2017 World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia includes a section dedicated to myeloid neoplasms with germline predisposition.2 These have likely been underrecognized because of both lack of awareness and limited availability testing outside specialized centers.3–5 However, a recent analysis of cases from The Cancer Genome Atlas revealed that approximately 4% of AML cases are associated with rare germline truncation mutations.6 The WHO divides this category into myeloid neoplasms with germline predisposition and without a preexisting disorder or organ dysfunction, those with preexisting platelet disorders, and those with other organ dysfunction.2,7 Some of the known implicated genes include CEBPA, DDX41, RUNX1, ANKRD26, ETV6, and GATA2.2
Usher syndrome is an autosomal recessive disorder characterized by hearing and vision loss of variable severity and onset and is the leading cause of deaf-blindness in the United States.8 The disease manifests because of defects in photoreceptor maintenance and inner ear hair cell development. Usher syndrome is categorized into types I, II, and III according to the severity of the clinical presentation, with type I being the most severe and presenting with congenital deafness, vestibular areflexia, and onset of retinitis pigmentosa prior to puberty.8 The abnormalities have been associated with at least 13 causative gene mutations including MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2, USH2A, GPR98, DFNB31, CLRN1, and PDZD7.8 However, 20% to 30% of patients with clinical Usher syndrome do not have a known associated genetic mutation.9 Studies have been conducted to help elucidate genotype-phenotype correlations and classification of Usher syndrome; however, an associated predisposition to malignancy in this patient population has not been reported.10,11
A 45-year-old woman with Usher syndrome and associated congenital deafness, progressive blindness due to retinitis pigmentosa, and latent autoimmune diabetes in adults presented to the emergency department with generalized malaise, dizziness, and lower pelvic pain. Two months prior to presentation, she had a routine exchange of her intrauterine device. One month prior to presentation, she began experiencing squeezing pelvic pain in the groin area and intermittent lower back pain with no vaginal discharge, bleeding, or dysuria. Over-the-counter analgesics provided little relief. One week prior to presentation, she had the intrauterine device removed, hoping the pain would be alleviated. She received a diagnosis of bacterial vaginosis after results of cultures obtained at that time were reviewed, and she began antibiotic treatment with metronidazole. Concurrently, she noted unusual difficulty controlling blood glucose, subjective fevers, night sweats, and an unintentional 4.5-kg weight loss. She was a nonsmoker in a monogamous relationship with her husband and had no history of sexually transmitted disease.
In the emergency department, she was hyperglycemic with a blood glucose of 435 mg/dL (reference range, 60–99 mg/dL) and β-hydroxybutyrate of 7.74 mmol/L (reference range, 0.02–0.27 mmol/L), consistent with diabetic ketoacidosis and was admitted to the critical care facility. She developed progressive anemia and thrombocytopenia with a white blood cell count elevated at 30,400/μL, initially attributed to infection, although she was on day 4 of metronidazole treatment. A firm, friable posterior vaginal wall mass, approximately 1 cm thick, was found on pelvic examination, inconsistent with an abscess. A computed tomography scan identified prominent internal iliac lymph nodes and was negative for intrapelvic abscesses. The gynecological team was concerned for malignancy including carcinoma and lymphoma.
Automated peripheral blood count results prompted a peripheral blood smear review, which showed 60% monocytic blasts. The atypical cells had large nuclei, fine chromatin, prominent nucleoli, and a moderate amount of pale cytoplasm with fine vacuoles and nuclear convolutions, consistent with immature monocytes (Fig. 1). Flow cytometry showed an atypical monocytic population, which expressed CD56, CD15, CD64, and CD33 (Fig. 2). The bone marrow biopsy showed a hypercellular marrow (cellularity of 95%) replaced by sheets of blasts with marked suppression of normal hematopoiesis (Fig. 3). The findings were consistent with acute monocytic leukemia. Concurrent biopsy of the vaginal mass displayed a diffuse, atypical monocytic infiltrate extensively involving the submucosa, with frequent apoptotic bodies and sparing of the overlying mucosal epithelium (Fig. 4). The lesional cells were diffusely positive for lysozyme, CD56, and CD68, and a diagnosis of myeloid sarcoma was rendered. Molecular studies demonstrated an NPM1 exon 12 mutation (c.863_864insCCGG), and cytogenetics revealed a complex karyotype (+del(5)(q12q33), +8, der(18)t(1;18)(q11;p11.2)/49, idem, −del(5)(q12q33), +9, t(9;19)(q13;q13.3), +19) with evidence of clonal evolution. CEBPA and FLT3 were unmutated, and no FLT3 internal tandem repeat was identified. Fluorescence in situ hybridization studies revealed a copy number gain of RUNX1T1 in 81.5% of cells, while negative for rearrangements of RUNX1T1/RUNX1, MLL, PML/RARA, CBFB, or RARA. Based on the complex karyotype, a diagnosis of AML with myelodysplasia-related changes was rendered based on 2017 WHO guidelines.2
The patient received induction chemotherapy with cytarabine and daunorubicin followed by consolidation chemotherapy with cytarabine. She achieved first clinical remission and proceeded with peripheral blood stem cell transplant from a 10/10 matched unrelated donor. Posttransplant, she received supportive treatment including immunosuppression to prevent graft-versus-host disease with methotrexate, tacrolimus, and fludrocortisone, and antimicrobial prophylaxis with acyclovir, fluconazole, and pentamidine. Her blood counts were suppressed with signs of improvement. Her most recent bone marrow biopsy, performed 100 days posttransplant, remained hypocellular but had no evidence of AML. Molecular studies for bone marrow chimerism were stable at 2% recipient. She is currently in remission for AML and continues to be monitored regularly. She has declined germline molecular testing.
This patient's scenario presented several challenges in diagnosis and treatment. Her presentation with pelvic pain, a vaginal mass, and potential complications of an intrauterine device raised concern for potential sepsis. This was further fueled by findings of a rising white blood cell count and worsening control of her underlying diabetes with diabetic ketoacidosis. Fortunately, a review of the peripheral smear was triggered by her automated blood count results and was quickly brought to the attention of the hematopathology team.
While the diagnosis of AML quickly became apparent, the precise classification of this process according to 2017 WHO criteria was challenging and had significant import for patient management. Given the patient's history of Usher syndrome, which is typically autosomal recessive in nature, the question arose as to whether her leukemia may represent a myeloid neoplasm with germline predisposition. While Usher syndrome has not previously been associated with an increased risk of hematolymphoid or other malignancies, the precise mutation resulting in her symptoms was not known. Of the approximately 13 genes that have been associated with this disorder, at least 2 have also been linked to AML and/or acute lymphoblastic leukemias: CDH23 (cadherin 23) and USH2A.12,13 Another preliminary study focusing on potential susceptibility to myeloid neoplasia in genetic syndromes found 15 mutations within 6 genes associated with Usher syndrome, including MYO7A, USH1C, CDH23, PCDH15, USH2A, and GPR98.14 Mutations in CDH23 were the most common, present in 2 cases of de novo AML, 1 case of secondary AML, and 1 case of myelodysplastic syndrome. CDH23 codes for a transmembrane protein with a long extracellular region harboring various cell adhesion domains that may bind cell surface proteins or extracellular matrix proteins. Six isoforms with various splice sites have been identified.15 Nonsense, splice-site, and frameshift mutations in CDH23 have been linked to Usher syndrome.8
A second question was whether this process could fulfill criteria for diagnosis within the category of AML with mutated NPM1. This AML subtype is typically associated with a more favorable outcome, particularly in the absence of an FLT3 mutation, and younger patients may be exempted from allogeneic hematopoietic stem cell/bone marrow transplant in first remission.2 Acute myeloid leukemia with mutated NPM1 is generally associated with a normal karyotype in this setting, but chromosomal aberrations have been reported such as trisomy 8 or 21, del(9q), or loss of Y without adverse prognostic implications.16 However, in this study of 631 patients with AML and an associated NPM1 mutation, 93 had an AML with an abnormal karyotype. Of these, only 4 patients had an AML with a complex karyotype similar to our patient. As such, how a complex karyotype would affect prognosis is less clear, and the 2017 WHO specifically states that a diagnosis of AML with myelodysplasia-related changes should be made in this setting.2 Further confirming this, a recent pooled analysis of 2426 patients with mutated NPM1, low or negative FLT3 mutation burden, and AML demonstrated worse outcome in patients with adverse-risk chromosomal abnormalities.17 This included lower rates of complete remission, inferior 5-year survival, and higher rates of relapse.
Given that NPM1 functions as a driver mutation in de novo AML and is usually mutually exclusive to other driver mutations, another question is whether this type of AML could be associated with a potential germline predisposition. Of note, NPM1 mutations have also been seen as a later event in leukemogenesis, potentially secondary to mutations in TET2, DMNT3A, or other epigenetic modifiers.2,18 Even de novo AML with mutated NPM1 may arise from “preleukemic” hematopoietic stem cell clones, which lack the NPM1 mutation identified in concurrently isolated AML blasts,19 suggesting that a predisposing state could occur. In our patient, the presence of a complex karyotype with evidence of clonal evolution at diagnosis, combined with an NPM1 mutation, suggests that this process is unusual, and a potential relationship to her underlying genetic syndrome could not be entirely excluded. In particular, AML with mutated NPM1 appears to be associated with higher genomic stability when compared with other types of AML with defining genetic drivers including inv,16 t(15;17), t(8;21), or RUNX1 mutations.16,20
Finally, myeloid sarcoma is seen in 2% to 8% of patients with AML.21 Involvement of the female genital tract is somewhat unusual, although vaginal, uterine, or ovarian involvement at presentation has been reported.22–24 The first sign may be abnormal vaginal bleeding, although no abnormal bleeding or discharge was reported by our patient. The frequency of involvement may be increased during disease progression, with an older study finding that women with myeloid or monocytic leukemias had involvement of the uterus or ovary in 27% and 23% of cases, respectively, at autopsy.25 Vaginal involvement was not specifically reported. NPM1 mutations are frequently seen in the setting of monocytic differentiation (80%–90% of cases) and are also commonly associated with extramedullary disease.2 Based on immunohistochemical staining for NPM1 localization, NPM1 was estimated to be mutated in 15% of myeloid sarcomas. In this series, the positive cases most commonly involved the skin, gums, lymph nodes, and soft tissues, as well as other sites.26 No cases of vaginal involvement were evaluated; however, 2 cases involving the cervix in this series were negative for abnormal localization of the NPM1 protein. The patient's computed tomography scan was consistent with lymph node involvement, compatible with involvement of one of the most commonly involved sites.
The identification of genetic mutations in hematologic malignancies has proven valuable for diagnosis, prognosis, and treatment strategies. Only a small subset of AML appears to be related to germline predisposition, but this area is rapidly evolving with increased awareness as well as availability of advanced molecular testing. Guidelines have been laid out for consideration of germline testing including a personal history of multiple cancers, first- or second-degree relatives with a hematopoietic neoplasm or other malignancy suggestive of a germline predisposition syndrome, certain blood abnormalities preceding the diagnosis of the myeloid neoplasms, and other physical or immunologic abnormalities consistent with known predisposition syndromes.2,4,5,27 Our patient fell outside the current recommendations for germline testing and also declined germline evaluation. However, given the heterogeneity in the genetic causes of Usher syndrome and the reported mutation of multiple Usher-associated genes in patients with AML,12–14 the potential of a role for germline predisposition cannot be excluded. Fortunately, a matched unrelated donor was identified, obviating the need to screen potential related donors.
Overall, this case illustrates an unusual presentation of myeloid sarcoma involving the vaginal wall and a potential previously undescribed link between Usher syndrome and genetic predisposition to leukemia. A broader study will be required to investigate this potential association and to better understand the role of mutations of Usher-associated genes such as CDH23 in sporadic cases of AML.
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