Title:Acute lymphoblastic leukemia presenting with abnormal uterine bleeding: an uncommon cause of a common complaint — case report and literature reviewKey Clinical MessageIn women presenting with abnormal uterine bleeding, hematologic malignancies such as acute lymphoblastic leukemia, though rare, should be considered—particularly in the presence of cytopenias or atypical laboratory findings. Early suspicion and diagnostic workup are crucial to avoid delays in life-saving treatment.Keywords:Acute Lymphoblastic Leukemia; Female Genital Neoplasms; Uterine Hemorrhage; Immunophenotyping; Flow CytometryAbbreviationsALL – Acute lymphoblastic leukemiaAUB – Abnormal uterine bleedingCNS – Central nervous systemFISH – Fluorescence in situ hybridizationPET/CT – Positron emission tomography/computed tomographyTdT – Terminal deoxynucleotidyl transferaseHb – HemoglobinWBC – White blood cell countG2P2 – Gravida 2, Para 2SummaryUterine involvement as the initial manifestation of acute lymphoblastic leukemia (ALL) is extremely rare and may mimic common gynecologic disorders.Persistent heavy uterine bleeding accompanied by anemia and thrombocytopenia should prompt evaluation for underlying hematologic malignancy.Histopathologic and immunophenotypic confirmation of blasts in endometrial or cervical tissue is essential for definitive diagnosis.Early recognition and timely initiation of systemic therapy are critical to improve outcomes in this atypical presentation.IntroductionAcute lymphoblastic leukemia (ALL) is a malignant proliferation of lymphoid precursors, most commonly of B-cell lineage in adults, accounting for approximately 75% of cases [1]. Although relatively uncommon in adults, with an incidence of 1–2 per 100,000 per year, adult ALL is typically more aggressive and carries a poorer prognosis compared with childhood ALL [1,2]. Clinical presentation most often reflects bone marrow failure—manifesting as anemia, infections, or bleeding—or organomegaly, including hepatosplenomegaly and lymphadenopathy [3].Extramedullary involvement in ALL most frequently affects the central nervous system and testes, whereas infiltration of other organs is rare [3,4]. Involvement of the female genital tract, including the uterus, cervix, and ovaries, is exceptionally uncommon and is more often reported at relapse rather than at initial diagnosis [4–6]. Abnormal uterine bleeding (AUB) in patients with hematologic malignancies is typically secondary to cytopenias, such as thrombocytopenia, rather than direct leukemic infiltration [3]. One series estimated that only 3.6 per 1000 women with hematologic cancers present initially with AUB [3].Here, we describe a rare case of precursor B-cell ALL in which recurrent heavy uterine bleeding was the first manifestation of disease. We also review the relevant literature and highlight the diagnostic challenges of this unusual presentation.Case PresentationInitial presentation and investigationsA 40-year-old G2P2 woman was referred to gynecology for evaluation of several months of worsening abnormal uterine bleeding. She described heavy, irregular menses with intermenstrual spotting, unresponsive to over-the-counter hemostatic therapy. She denied weight loss, fever, or history of malignancy. Her past medical history was notable only for two prior vaginal deliveries, and she was not using hormonal therapy.On examination, she appeared pale. Pelvic examination revealed a slightly enlarged, non-tender uterus without adnexal masses. Pelvic ultrasound demonstrated a diffusely enlarged uterus with a thickened endometrium, but no focal fibroids or adnexal pathology.Laboratory evaluation showed normocytic anemia (hemoglobin 8.2 g/dL) and thrombocytopenia (platelets 60 × 10^9/L), with a normal white blood cell count (Table 1). Peripheral smear revealed circulating blasts, raising suspicion for hematologic malignancy (Figure 1).Histopathology and immunophenotypingEndometrial curettage performed to evaluate the source of bleeding demonstrated sheets of small blasts infiltrating the endometrium and myometrium (Figure 2). The blasts were positive for TdT and CD79a on immunohistochemistry.Bone marrow aspiration revealed diffuse infiltration by large lymphoblasts with basophilic cytoplasm containing occasional vacuoles, a “starry-sky” appearance, and large nuclei with occasional nucleolar vacuoles (Figure 3). Flow cytometry of the marrow aspirate showed 85% blasts expressing B-lineage markers (CD19, CD10, weak CD22, CD79a, TdT), with co-expression of CD34 and HLA-DR. The blasts were negative for T-cell (CD3, CD7) and myeloid markers (Table 2).Cytogenetic analysis demonstrated a female karyotype with a translocation between chromosomes 6 and 9 in all examined cells (46,XX,t(6;9)(6q13;9p21), 100%) (Figure 4). This rearrangement involved the long arm of chromosome 6 (6q13) and the short arm of chromosome 9 (9p21). Fluorescence in situ hybridization (FISH) forBCR-ABL1 was negative, as were assays for other recurrent rearrangements including KMT2A and TCF3-PBX1 . These findings confirmed the diagnosis of Philadelphia-negative precursor B-cell acute lymphoblastic leukemia (ALL) with extramedullary uterine involvement.Treatment and outcomeThe patient was admitted for induction chemotherapy with the Hyper-CVAD regimen: hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (course A), alternating with high-dose methotrexate and cytarabine (course B). Intrathecal methotrexate was administered for central nervous system prophylaxis.On day 10 of induction, she developed febrile neutropenia with an absolute neutrophil count <0.1 × 10^9/L. Despite broad-spectrum antibiotics, granulocyte colony-stimulating factor, and escalation to meropenem for Gram-negative bacteremia, she progressed to septic shock with multi-organ failure. She died on hospital day 18, approximately two weeks after initiating therapy.DiscussionUterine infiltration by acute lymphoblastic leukemia (ALL) is exceptionally rare. Involvement of the uterus or cervix has been reported only sporadically, most often in the setting of relapse or pre-existing leukemia [1,2,5,9]. Robillard et al. described a 12-year-old with relapsed B-ALL presenting with heavy uterine bleeding, highlighting that abnormal uterine bleeding (AUB) in leukemic patients is frequently attributed to benign gynecologic causes or thrombocytopenia, yet leukemic relapse should be considered when bleeding remains unexplained [10]. In one series of 38 women with hematologic malignancies, only 0.36% presented with AUB as the primary symptom, typically associated with severe cytopenias [3]. The current case is unusual in that recurrent uterine bleeding was the initial and predominant manifestation of de novo precursor B-ALL.The pathophysiology of uterine involvement remains poorly understood, but likely reflects hematogenous dissemination, similar to the mechanism of myeloid sarcoma in acute myeloid leukemia. Imaging modalities may aid suspicion: for instance, MRI frequently reveals diffuse uterine enlargement with homogeneous signal intensity, as reported by Vanheule et al. in a patient with relapsed B-ALL [2]. Likewise, Kar et al. described polypoid uterine lesions with intense FDG uptake on PET/CT, findings that favor leukemic rather than primary gynecologic neoplasms [6]. In the present case, ultrasound findings were nonspecific and no MRI was performed.Histopathologic confirmation remains essential. Endometrial biopsy in our patient revealed sheets of blasts positive for TdT and CD79a. Flow cytometry confirmed a precursor B-cell immunophenotype (CD19+, CD10+, CD22 weak+, TdT+, CD34+), consistent with common B-ALL. This profile is typical of precursor B-ALL, which characteristically expresses CD19 and CD79a universally, and CD10 in the common subtype [4]. Differentiation from other hematologic malignancies, particularly mature B-cell lymphomas, is critical, as the latter express surface immunoglobulin but typically lack TdT. Rare reports also describe leukemic cell detection on cervical cytology [5].Cytogenetic evaluation provides additional prognostic information. Between 20% and 30% of adult B-ALL cases harbor the Philadelphia chromosome (BCR-ABL1), which is associated with adverse prognosis [12,13]. Other recurrent rearrangements include TCF3-PBX1, KMT2A fusions, and, less commonly in adults, ETV6-RUNX1 [14]. Our patient lacked these high-risk abnormalities but did harbor a t(6;9)(6q13;9p21) translocation. While the absence of BCR-ABL1 and other high-risk fusions might suggest a more favorable profile, adult ALL is generally aggressive and requires intensive treatment.Management follows standard adult ALL protocols. The patient received Hyper-CVAD induction with intrathecal methotrexate for CNS prophylaxis. Systemic therapy is essential from diagnosis, even when the presenting symptom is gynecologic bleeding, as ALL is a systemic disease. Nebgen et al. stressed that early chemotherapy is lifesaving in women with hematologic malignancies who present with AUB [3]. Unfortunately, our patient developed febrile neutropenia and Gram-negative sepsis during induction, progressing to septic shock and multi-organ failure before remission status could be assessed.Extramedullary ALL is associated with poorer outcomes, especially when diagnosis is delayed. This case emphasizes the importance of including hematologic malignancy in the differential diagnosis of unexplained AUB, particularly when cytopenias are present. A practical diagnostic approach should include prompt complete blood count and peripheral smear, followed by biopsy and immunophenotyping as indicated. Increased awareness of this rare presentation may facilitate timely recognition and treatment, potentially improving outcomes.ConclusionInitial presentation of acute lymphoblastic leukemia (ALL) with uterine involvement is exceedingly rare and may be mistaken for a primary gynecologic disorder. Recurrent heavy uterine bleeding in the setting of anemia and thrombocytopenia should raise suspicion for an underlying hematologic malignancy. Definitive diagnosis requires histopathologic and immunophenotypic confirmation of blasts in endometrial or cervical tissue. Early recognition and prompt initiation of systemic therapy are essential to optimize outcomes. This case underscores the importance of considering leukemia in the differential diagnosis of unexplained abnormal uterine bleeding and contributes to the limited literature on this atypical presentation.Figure Legends:Table 1. Lab Values on admittingFigure 1. Peripheral blood smear showing circulating blast.Figure 2. Uterine biopsy findings.(A) Diffuse infiltration of the endometrium and myometrium by immature lymphoid cells, consistent with precursor B-cell acute lymphoblastic leukemia (H&E).(B) Immature lymphoid infiltrate adjacent to endometrial glands (H&E).(C) Tumor cells showing nuclear positivity for TdT.(D) Tumor cells positive for CD79a.(E) Tumor cells negative for CD3.Figure 3. Bone marrow aspirate after Wright–Giemsa staining, highlighting nuclear details, cytoplasmic basophilia, and “starry sky” appearance due to scattered macrophages.Figure 4. Cytogenetic analysis of the patient’s bone marrow showing a female karyotype with a translocation between chromosome 6 and 9 [46,XX,t(6;9)(6q13-9p21)] present in 100% of analyzed cells.DeclarationsAuthor ContributionsA.A.H: Writing – original draft, Methodology, Investigation, ConceptualizationD.A.: Writing – review & editing, InvestigationS.M.: Writing – review & editingAB.A.: Writing – review & editing, SupervisionM.A.A.: Writing – review & editing, ValidationM.M.: Writing – review & editingAM.A.: Writing – review & editing, Supervision, ConceptualizationAcknowledgmentsThe authors would like to thank [Insert any institution, department, or individual who contributed but does not meet authorship criteria] for their support and contributions to this work.Ethics StatementThe authors confirm that the study was conducted in accordance with ethical standards and that no ethical issues are applicable beyond standard patient care.Consent for PublicationWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the consent is available upon request by the Editor-in-Chief.Conflict of InterestThe authors declare no conflicts of interest related to this manuscript.Declaration of Generative AI and AI-Assisted Technologies in the Writing ProcessDuring the preparation of this manuscript, the authors used ChatGPT (OpenAI) solely to improve language clarity and readability. All content was reviewed, edited, and approved by the authors, who take full responsibility for the accuracy and integrity of the work.References:1-Narang V, Dhiman A, Garg B, Sood N. Female Genital Tract Involvement in Acute Lymphoblastic Leukemia: A Rare Case Report. J Clin Diagn Res. 2016 Dec;10(12):ED09-ED10. doi: 10.7860/JCDR/2016/23832.9099. Epub 2016 Dec 1. PMID: 28208868; PMCID: PMC5296441.2- Nebgen DR, Rhodes HE, Hartman C, Munsell MF, Lu KH. Abnormal Uterine Bleeding as the Presenting Symptom of Hematologic Cancer. Obstet Gynecol. 2016 Aug;128(2):357-363. doi: 10.1097/AOG.0000000000001529. 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