Published online Jun 24, 2026. doi: 10.5306/wjco.121496
Revised: May 5, 2026
Accepted: June 4, 2026
Published online: June 24, 2026
Processing time: 85 Days and 5.5 Hours
Extramedullary hematopoiesis (EMH) in lymph nodes, particularly following neoadjuvant chemotherapy for breast cancer, is a rare phenomenon. Its occurrence in the context of combined immunochemotherapy remains underreported. Here, we present the first case of trilineage EMH in axillary lymph nodes following neoadjuvant immunochemotherapy for triple-negative breast cancer (TNBC).
A patient in her 50 years with newly diagnosed TNBC (cT1N1M0, stage IIA) underwent neoadjuvant therapy with epirubicin/cyclophosphamide and nab-paclitaxel, in combination with the PD-1 inhibitor toripalimab. Post-surgical pathological evaluation revealed a pathological complete response (ypT0N0) in both the breast and axillary lymph nodes, with undetectable circulating tumor DNA. However, histological examination of five axillary lymph nodes identified foci of trilineage EMH, com
This case highlights EMH as a rare benign finding after effective neoadjuvant chemoimmunotherapy. The deve
Core Tip: This is the first case report of trilineage extramedullary hematopoiesis (EMH) in axillary lymph nodes after neoadjuvant chemoimmunotherapy with a PD-1 inhibitor for triple-negative breast cancer. It highlights a benign mimic of malignancy, emphasizes granulocyte colony-stimulating factor as an initiator of EMH, and speculatively links PD-1 blockade to EMH persistence. Recognition prevents misdiagnosis and underscores systemic therapy effects.
- Citation: Xing P, Chen ZG, Jin HL, Luo HR, Gan MF, Huang J. Lymph node extramedullary hematopoiesis in breast cancer patients receiving neoadjuvant chemotherapy combined with immunotherapy: A case report. World J Clin Oncol 2026; 17(6): 121496
- URL: https://www.wjgnet.com/2218-4333/full/v17/i6/121496.htm
- DOI: https://dx.doi.org/10.5306/wjco.121496
Cancer treatment has undergone significant changes over the last hundred years. Initially, surgery and radiation therapy were the main methods used. The advent of cytotoxic chemotherapy in the mid-1900s marked a significant milestone, allowing for the treatment of metastatic cancers and increasing cure rates for various types of cancer. Later, the identification of cancer as a genetic disease led to the creation of molecularly targeted therapies, and a better understanding of the immune system’s role in controlling tumors paved the way for immune checkpoint inhibitors. A detailed review by Sonkin et al[1] in 2024 offers valuable insights into this historical development, summarizing key lessons from previous achievements and outlining the current challenges in oncology.
Among different cancer types, triple-negative breast cancer (TNBC) has traditionally been linked to a particularly poor outlook because of its aggressive nature and the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. The recent advent of immune checkpoint inhibitors has significantly transformed the treatment options for TNBC. Clinical studies have shown that combining PD-1/PD-L1 inhibitors with standard neoadjuvant chemotherapy markedly improves the rate of pathological complete response (pCR), resulting in the approval of these treatment protocols as standard care for early-stage and metastatic TNBC when suitable biomarkers like PD-L1 are detected. Consequently, chemoimmunotherapy combinations have become an integral part of current treatment strategies. However, the broad application of these powerful therapies has also revealed a range of unexpected host reactions, including extramedullary hematopoiesis (EMH) in regional lymph nodes, which is a rare but clinically significant occurrence. Hematopoietic stem and progenitor cells (HSPCs) typically differentiate into lymphoid and myeloid lineages, with little overlap between these pathways under normal conditions, maintaining a balanced blood system[2]. EMH refers to the production and maturation of HSPCs outside the bone marrow. In postnatal life, pathological EMH arises as a compensatory mechanism in response to ineffective bone marrow hematopoiesis, occurring in hematopoietic disorders and other stress conditions such as infections, advanced cancers, anemia, and metabolic stress[3]. Pathological EMH has been observed in various organs, and its locations may be linked to the reactivation of embryonic hematopoietic structures within these tissues[4]. While pathological EMH can support blood and immune cell production, it may also cause clinical complications, making it a double-edged sword. Recently, it has attracted significant research interest. Notably, EMH induced by advanced tumors contributes to tumor-related immunosuppression, with the tumor microenvironment promoting EMH[5]. Breast cancer is the most common cancer in women, and neoadjuvant chemotherapy combined with immune checkpoint inhibitors has become a standard treatment for high-risk TNBC[6]. Following adjuvant chemotherapy for breast cancer, EMH in lymph nodes has been rarely reported. However, EMH in axillary lymph nodes after neoadjuvant immuno-chemotherapy is extremely uncommon. Microscopically, it can be mistaken for lymphoma due to the presence of large, pleomorphic cells[7]. The current case is the only one reported following neoadjuvant chemotherapy combined with immune checkpoint inhibitors. In this report, we present our pathological findings and review the literature to enhance understanding of the profound effects this novel therapy has on the hematopoietic and immune systems, help prevent misdiagnosis, and provide new insights into the immune microenvironment changes induced by PD-1/PD-L1 blockade therapy.
A woman in her 50 years presented with a newly detected 19-mm suspicious malignant lesion in the left breast.
A woman in her 50 years with no significant medical history, no family history of tumors, and no known hematologic disorders was admitted in June 2025 for a newly detected 19-mm lesion in her left breast, suspicious for malignancy on ultrasound (Figure 1A). Both the breast lesion and ipsilateral axillary nodes were clinically palpable.
Ultrasound-guided core needle biopsy confirmed grade III, ER-negative, HER2-negative invasive ductal carcinoma of no special type (Figure 1B). Axillary lymph nodes were enlarged on both clinical and imaging evaluation, and pathological examination confirmed lymph node metastasis (Figure 1C and D). Preoperative workup revealed a clinical stage IIA TNBC (cT1N1M0), with immunohistochemistry showing ER (< 1% weak positive), PR-negative, HER2 (4B5)-negative (0), and a high Ki-67 index of 80%.
Following multidisciplinary team discussion, neoadjuvant immunochemotherapy was planned to downstage the disease prior to breast-conserving surgery. The patient was admitted on June 19, 2025, and received sequential neoadjuvant therapy with the EC-nab-P protocol combined with toripalimab (anti-PD-1 inhibitor). Specifically, she received two cycles of epirubicin (90 mg/m2) plus cyclophosphamide (600 mg/m2), each with concurrent toripalimab (240 mg), administered every three weeks (June 23, 2025 and July 14, 2025; actual doses: Epirubicin 170 mg, cyclophosphamide 1.1 g, toripalimab 240 mg). Prophylactic long-acting granulocyte colony-stimulating factor (G-CSF; efbemalenograstim alfa, 20 mg) was given subcutaneously 24-48 hours after each cycle (June 25, 2025 and July 16, 2025). She then received two cycles of nab-paclitaxel (400 mg fixed dose) plus toripalimab (240 mg) every 3 weeks (August 4, 2025 and August 25, 2025), without additional G-CSF support. All chemotherapy doses were calculated based on body surface area. No treatment-related anemia was noted during therapy (Figure 2).
Imaging demonstrated an excellent response to neoadjuvant therapy, and the patient underwent breast-conserving surgery with axillary lymph node dissection on September 15, 2025.
Postoperative pathological examination of the breast specimen showed a 0.2 cm gray-white nodule without a distinct mass or prominent tumor bed, consistent with a pCR (ypT0N0M0). Twenty-four axillary lymph nodes were examined; none contained metastatic carcinoma, though two showed reactive changes related to chemotherapy. Notably, five lymph nodes exhibited prominent EMH. The EMH lesions were predominantly located in the paracortex and medulla, with scattered hematopoietic cells also seen in the subcapsular sinus, occupying approximately 70%-80% of the cross-sectional area of involved nodes. Microscopically, the lesions showed mixed trilineage hematopoietic cells, including myeloid precursors, erythroblasts, and megakaryocytes, associated with large areas of fatty vacuolation. Immunohistochemical studies confirmed the hematopoietic lineage: CD71-positive erythroid precursors (Figure 3A and B), scattered MPO-positive myeloid cells (Figure 3C and D), and CD61-positive megakaryocytes (Figure 3E and F). Ki-67 showed high expression (> 50%) within the EMH lesions. Markers for differential diagnosis of small B-cell lymphoma, including Bcl-2, CD10, cyclin D1, and SOX-11, were evaluated, with no evidence of lymphoma identified. The diagnosis of benign EMH was confirmed by a hematopathologist.
The patient had no significant prior medical history, including no chronic diseases, previous surgeries, or regular medication use. She had no known hematologic disorders or history of blood transfusion.
The patient had no history of smoking, alcohol consumption, or occupational exposure to carcinogens. There was no family history of breast cancer or other malignant tumors in first-degree relatives, and no known familial hematologic disorders.
Physical examination revealed a palpable, hard, non-tender mass measuring approximately 19 mm in the left breast. Enlarged, ipsilateral axillary lymph nodes were also palpable. There was no skin erythema, ulceration, or nipple discharge. The patient’s vital signs and general physical status were stable.
Preoperative laboratory tests, including complete blood count, liver and renal function, and coagulation profile, were all within normal limits. No evidence of anemia or cytopenia was noted. Tumor markers including CA15-3 were within normal ranges prior to treatment. No significant laboratory abnormalities were observed during neoadjuvant therapy.
Breast ultrasound identified a 19-mm suspicious lesion in the left breast, with features highly suggestive of malignancy (BI-RADS 5). Ipsilateral axillary lymph nodes were enlarged and showed abnormal architecture, consistent with metastatic involvement (Figure 1A). Chest computed tomography and abdominal ultrasound were performed to rule out distant metastasis, with no evidence of metastatic disease detected.
The case was discussed at a multidisciplinary team meeting involving breast surgeons, medical oncologists, radiologists, and pathologists. Based on the diagnosis of TNBC (cT1N1M0, stage IIA), neoadjuvant immunochemotherapy with sequential EC-nab-P regimen combined with anti-PD-1 inhibitor was recommended to downstage the tumor, followed by breast-conserving surgery and axillary lymph node dissection.
Invasive ductal carcinoma of the left breast (ypT0N0M0, pCR), triple-negative subtype (ER-negative, PR-negative, HER2-negative) benign EMH in axillary lymph nodes.
The patient received neoadjuvant immunochemotherapy with the sequential EC-nab-P regimen combined with toripalimab (anti-PD-1 inhibitor), followed by breast-conserving surgery and axillary lymph node dissection. The patient tolerated treatment well without significant adverse events.
After surgery, the patient did not receive conventional adjuvant chemotherapy because a pCR had been achieved. Adjuvant radiotherapy was administered to the breast/chest wall and regional lymph nodes at a total dose of 50 Gy delivered in 25 fractions (2 Gy per fraction). Concurrently, the patient continued maintenance immunotherapy with toripalimab at a dosage of 240 mg every three weeks, with a planned total treatment duration of one year, inclusive of the neoadjuvant phase. At the most recent follow-up, conducted 7.5 months post-surgery, the patient remained alive without any evidence of disease recurrence. Complete blood count parameters were within normal ranges, including hemoglobin at 13.8 g/dL, white blood cell count at 6.07 × 109/L, and platelet count at 157 × 109/L. No cytopenias or abnormal peripheral blood cell morphologies were detected, and the radiotherapy course was completed without significant hematological toxicity. Ongoing long-term testing for circulating tumor DNA (ctDNA) using a customized next-generation sequencing panel targeting 63 cancer-related genes, with a detection limit of 0.5% variant allele frequency, showed negative results at 1 week, 6 months after surgery, surveillance is being maintained.
EMH has been observed in various solid tumors, such as breast cancer, renal cell carcinoma, lung cancer, colorectal cancer, hepatocellular carcinoma, endometrial cancer, adrenocortical carcinoma, skin cancer, ovarian cancer, and melanoma[8-10]. Seven prior studies have described a total of 10 EMH cases featuring megakaryocytes in breast axillary lymph nodes (Table 1). The initial case was discovered after surgery in the axillary lymph nodes of a patient who had not undergone neoadjuvant chemotherapy and was characterized by the abnormal presence of megakaryocytes[11]. All later cases were reported following neoadjuvant chemotherapy and mainly showed microscopic megakaryocyte heterotopia. To date, there are no reports of nucleated red blood cells appearing in axillary lymph nodes during immunotherapy. This case is the first known example of such a finding.
| Ref. | Neoadjuvant chemotherapy | Immunotherapy | Node procedure | pCR |
| Hoda et al[23], 2002 | No therapy | No | Sentinel lymphadenectomy | No |
| Wang and Darvishian[24], 2006 | Yes (cyclophosphamide and doxorubicin followed by paclitaxel) | No | EMH was seen in mastectomy specimens, not dissected lymph nodes | No |
| Millar et al[7], 2009 | Yes (cyclophosphamide, doxorubicin followed by docetaxel with G-CSF) | No | Axillary node dissection | No |
| Prieto-Granada et al[16], 2013 | Yes (chemotherapy regimen was not mentioned) | No | 1 patient with sentinel lymph node; 1 patient with axillary node dissection; 1 patient with a core biopsy of an enlarged axillary lymph node | Yes |
| Takhar et al[18], 2013 | Yes (chemotherapy regimen was not mentioned) | No | Sentinel lymphadenectomy/sentinel lymphadenectomy | Yes |
| Badr et al[25], 2019 | Yes (docetaxel-FEC concurrent trastuzumab) | No | The sentinel lymph node | No |
The precise pathogenesis of EMH remains elusive, with several hypotheses proposed to elucidate its development. Fundamentally, when the normal hematopoietic function of the bone marrow is compromised or suppressed due to myeloid malignancies, hematological disorders, or other etiologies that fail to meet the body’s demands, a compensatory response is initiated. This response involves reactivating tissues that were previously active in hematopoiesis during embryonic development—such as the liver, spleen, and kidneys—to restore blood cell production outside of the bone marrow[12]. In factor-induced EMH, research has demonstrated that cytokines associated with hematopoiesis and pathogen-associated molecular patterns contribute to promoting EMH. Key factors include G-CSF, granulocyte-macrophage colony-stimulating factor, interleukin-3, interleukin-6 (IL-6), soluble IL-6 receptor complexes, lipopolysaccharide, and Pam3CSK4[13]. Studies indicate that hematopoietic stem/progenitor cells (HSPCs) home to and circulate within both bone marrow and peripheral tissues by binding CXCL12 through their surface receptor CXCR4[14]. Under stress conditions such as infection, malignancy, anemia, or metabolic distress, alterations occur within the bone marrow microenvironment. Induced by specific cytokines and soluble factors, numerous HSPCs are mobilized from the bone marrow into peripheral circulation where they migrate to other organs—a process referred to as “mobilization”.
G-CSF is widely recognized as a potent mobilizer of HSPCs. It plays a critical role in the initiation of EMH by disrupting the CXCL12/CXCR4 axis, thereby releasing HSPCs from the bone marrow into the circulation[15]. Several case reports have documented EMH following G-CSF administration, including trilineage EMH in breast cancer patients receiving neoadjuvant chemotherapy with G-CSF support[16]. In some instances, EMH has been shown to be G-CSF-dependent, regressing after G-CSF withdrawal[17]. In our patient, G-CSF (efbemalenograstim alfa) was administered only after the first two cycles of EC chemotherapy and was discontinued approximately two months before surgery. Despite this prolonged G-CSF-free interval, trilineage EMH was unequivocally present in the resected axillary lymph nodes. This temporal dissociation indicates that, in contrast to the G-CSF-dependent cases reported in the literature, G-CSF is not required for the maintenance of EMH in this patient. Consequently, we propose that the role of G-CSF in this case was primarily initiating, promoting HSPC mobilization and seeding of the lymph nodes, rather than sustaining the EMH foci over time.
What then could account for the persistence of EMH after G-CSF withdrawal? Several non-mutually exclusive possibilities exist. First, chemotherapy-induced bone marrow suppression may have created a persistent “demand” for compensatory hematopoiesis, allowing EMH to continue without ongoing G-CSF stimulation. Second, some HSPCs mobilized by G-CSF might have homed to the lymph nodes and acquired a long-term residence, proliferating and differentiating in response to local microenvironmental cues. Third, the concurrent PD-1 blockade (toripalimab) may have contributed to the maintenance or trilineage differentiation of EMH by reshaping the nodal immune microenvironment - for example, by altering the cytokine network (e.g., IFN-γ, IL-6) that supports HSPC proliferation and lineage commitment. However, direct evidence for this hypothesis is lacking. We emphasize that the contribution of PD-1 blockade is speculative and should not be interpreted as a decisive or determinant factor. Other untested variables, such as individual variations in nodal stromal function or residual effects of chemotherapy, could equally explain the observed EMH persistence. In summary, we conclude that G-CSF was an important initiator but not a sustainer of EMH in this patient. The maintenance of EMH after G-CSF withdrawal likely involves multiple factors, with immunotherapy representing one potential, but unproven, contributor.
To provide a deeper contextualization, we systematically compared our case with the most relevant prior reports. Prieto-Granada et al[16] described three breast cancer patients who developed axillary trilineage EMH after neoadjuvant chemotherapy with G-CSF support; all achieved pCR and none received immunotherapy. Takhar et al[18] reported a similar case of axillary EMH following neoadjuvant chemotherapy with G-CSF, also without immunotherapy. Dagdas et al[17] reported a patient with myelodysplastic syndrome who developed trilineage EMH after G-CSF therapy, which regressed upon G-CSF withdrawal, demonstrating G-CSF dependency. Our case shares trilineage EMH and pCR with the study of Prieto-Granada et al[18], but uniquely includes a PD-1 inhibitor (toripalimab) throughout all cycles. Moreover, unlike the G-CSF-dependent EMH in Dagdas et al’s case[17], ours persisted after G-CSF withdrawal. This comparison suggests that while G-CSF combined with chemotherapy can induce trilineage EMH, the addition of PD-1 blockade did not fundamentally alter the histological phenotype, but might have contributed to the prolonged persistence of EMH (a hypothesis that requires further testing).
The literature has established that EMH can generate immunosuppressive cell subsets (e.g., erythroidderived myeloid cells) that promote tumor progression, correlate with poor prognosis, and may even undermine the efficacy of anti-PD-1/PD-L1 therapy[19,20]. In stark contrast, our patient achieved a pCR and sustained negative ctDNA, yet exhibited trilineage EMH in axillary lymph nodes. This paradoxical observation raises the question: Is EMH in this setting a positive indicator of treatment response or merely an incidental finding? We offer several possible, non-exclusive interpretations. First, the biological role of EMH may vary greatly depending on the context. In patients with active, advancing tumors, EMH might contribute to an immunosuppressive environment. However, in cases where the tumor has been completely eliminated (pCR) and the immune system is activated by treatment, the same histological observation could instead indicate a harmless, reactive, and temporary process reflecting successful blood cell regeneration after intensive bone marrow-suppressing therapy. Second, in our patient, EMH was limited to the lymph nodes and was not linked to any clinical signs of immune suppression, such as opportunistic infections or rapid disease progression. Third, it is also possible that the EMH was an incidental finding without any effect on tumor immunity or the patient’s outcome. Currently, we cannot definitively determine which of these explanations is correct. Therefore, we propose that EMH observed after neoadjuvant chemoimmunotherapy resulting in pCR should not automatically be interpreted as a sign of poor prognosis. Instead, it might indicate the intensity of treatment and bone marrow stress, or simply be an incidental histological observation. Longer follow-up and studies with more patients are needed to clarify whether this type of EMH has any prognostic relevance.
The occurrence of EMH in cancer is both a major focus of research and an important factor affecting treatment outcomes. Previous research has shown that EMH contributes to tumor progression by directly or indirectly suppressing anti-tumor immune responses. EMH produces immunosuppressive hematopoietic cell populations, which create an immune environment that supports tumor growth and is linked to poorer patient survival[19]. Earlier studies have demonstrated that myeloid cells derived from erythroid precursors act as crucial immunosuppressive agents within the tumor immune microenvironment and also directly reduce the effectiveness of anti-PD-1/PD-L1 therapies[20]. Nevertheless, the mechanisms driving the functional changes of EMH in cancer patients are not yet fully understood. The relationship between EMH and immunotherapy remains in the early stages of investigation.
In this situation, in addition to the compensatory response triggered by chemotherapy-induced bone marrow damage, immunotherapy might contribute to the development of EMH in lymph nodes by influencing the local immune environment during an optimal treatment outcome to neoadjuvant chemoimmunotherapy, marked by pCR and undetectable ctDNA. However, this process may involve complex two-way interactions. The activation of EMH—linked to local low oxygen levels and systemic tumor-driven immune responses—acts as a compensatory mechanism for bone marrow blood cell production, aiming to restore blood cell levels and boost anti-tumor immunity. In this context, the presence of EMH offers valuable insights into understanding this biological interaction.
Combining chemotherapy with immunotherapy can further enhance the immune microenvironment and encourage the redistribution of immune cells within tumor tissues and nearby lymphoid tissues, such as axillary lymph nodes. For example, chemotherapy can eliminate immature precursor cells by disrupting DNA replication and cell division. As the number of these immature precursor cells decreases, the secretion of immunosuppressive cytokines they produce, like transforming growth factor-β, may also reduce. At the same time, in the context of immunotherapy, some mature dendritic cells that were previously suppressed by immature precursor cells can become reactivated. These dendritic cells can then more effectively present tumor antigens to T cells, triggering a stronger T cell immune response against tumor cells. This process may lead to an increased proportion of cytotoxic T cells, thereby improving the destruction of tumor cells.
This phenomenon indicates that our comprehension of the tumor immune microenvironment requires deeper exploration. While immature precursor cells in the axillary lymph nodes are typically thought to have immune-suppressive roles, the effectiveness of combining immunotherapy with chemotherapy suggests that the immune microenvironment is not solely governed by immune-suppressive cells. Other immune-activating elements might be involved. For instance, immunotherapy drugs can stimulate tumor-specific T cells, and chemotherapy can release tumor antigens as it kills tumor cells, providing additional targets for the immune system. This process enables the immune system to modify the immune surveillance environment of immature precursor cells in the lymph nodes, leading to tumor destruction. It also encourages a reassessment of the functional status of immune-suppressive cells, as their roles may be adaptable under certain therapeutic conditions. Combined treatments might alter the phenotype or function of these immune-suppressive cells, diminishing their inhibitory effects or even converting them into immune-activating cells.
Beyond these mechanistic understandings, the clinical relevance of these findings is significant. Firstly, this case holds important clinical value, particularly in preventing diagnostic errors. The presence of immature hematopoietic cells in axillary lymph nodes is an uncommon pathological observation that presents diagnostic challenges. Focal sites of EMH contain a complex mix of cells. The proliferation of immature erythrocytes in EMH, which display uniform morphology, can be difficult to distinguish histologically from small B-cell lymphoma and may be mistakenly diagnosed as lymphoma or other cancers. These morphological characteristics are especially prone to misinterpretation as lymphoma-like infiltration during frozen section analysis or when sampling is limited. Therefore, immunohistochemical analysis is strongly advised to accurately identify EMH and exclude lymphoid or hematopoietic malignancies. Secondly, the presence of EMH in this scenario is not just a diagnostic observation but also holds significant biological meaning. It directly reflects the severe bone marrow suppression caused by chemotherapy and the vigorous activation of the systemic immune environment, including within lymph nodes, triggered by immunotherapy. EMH might indicate sufficient treatment intensity and a strong immune response, while also signaling that the patient’s bone marrow capacity has been heavily challenged. In this case, EMH found in the axillary lymph node represents a rare pathological event, likely resulting from the combined effects of chemotherapy and G-CSF, with a potential (though unconfirmed) role of PD-1 blockade. Importantly, the presence of EMH in our patient, who showed an excellent pathological response, contradicts the common belief that EMH could reduce the effectiveness of immunotherapy by attracting immunosuppressive cells. This unexpected finding underscores the unique and complex immune regulatory processes involved in EMH development during immune checkpoint inhibition. Instead of creating an immunosuppressive environment, EMH in the affected lymph node may reflect a strong, systemic immune activation or could be an incidental phenomenon without functional impact. When further adjuvant treatment is necessary, this highlights the need for clinicians to closely monitor blood counts and provide timely supportive care.
This case report is subject to several limitations. Primarily, it is derived from a single patient case without experimental corroboration, which renders the proposed mechanisms largely speculative. Additionally, there is a lack of direct evidence demonstrating a causal link between PD-1 inhibition and the development of EMH. The study also did not include analyses such as cytokine profiling or tracking of HSPCs, which could have provided more substantive mechanistic insights. As highlighted by recent research advocating for the integration of multi-omics approaches and artificial intelligence-driven methodologies[21,22], comprehensive mechanistic understanding in oncology increasingly relies on the synthesis of multidimensional datasets—including genomics, transcriptomics, and proteomics—rather than on single-modality pathological observations alone. Consequently, the interpretation that PD-1 blockade may influence remodeling of the nodal microenvironment should be considered a hypothesis-generating proposition that requires further investigation, rather than a definitive conclusion supported by the current data. Moreover, it remains unclear whether the observed EMH constitutes a causative factor, a consequence, or an incidental finding associated with the favorable therapeutic response. The follow-up period of 7.5 months post-surgery is relatively short, underscoring the need for extended monitoring to evaluate long-term hematological and oncological outcomes. Therefore, the present discussion should be regarded as exploratory, intended to generate hypotheses rather than establish conclusive evidence. Future research involving larger patient cohorts, longer follow-up durations, and functional assays—including cytokine profiling and immune cell characterization—is necessary to validate and expand upon these preliminary findings.
In this case, the EMH observed in axillary lymph nodes represents a rare pathological event likely resulting from the synergistic effects of chemotherapy, G-CSF, and PD-1 blockade. Chemotherapy-induced bone marrow suppression created a persistent demand for compensatory hematopoiesis, G-CSF mobilized HSPCs, and concurrent PD-1 inhibition may have reshaped the nodal microenvironment to permit trilineage differentiation and prolonged EMH persistence. This case documents a rare yet clinically critical phenomenon that highlights the complex interplay between modern cancer therapy and the host hematopoietic system. It alerts clinicians and pathologists to an unusual but benign histological finding that should not be mistaken for malignancy. Moreover, we propose a hypothesis that combination chemoimmunotherapy, together with G-CSF support, can unexpectedly remodel lymphoid tissues into sites of stressdriven EMH. Further mechanistic studies and accumulation of similar cases are needed to fully understand this intricate interplay and its potential implications for treatment efficacy and longterm patient outcomes.
The authors would like to thank the patient and her family for their participation in this case report. We also thank the pathologists and radiologists for their contributions to the diagnosis and management of this case.
| 1. | Sonkin D, Thomas A, Teicher BA. Cancer treatments: Past, present, and future. Cancer Genet. 2024;286-287:18-24. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 437] [Cited by in RCA: 415] [Article Influence: 207.5] [Reference Citation Analysis (0)] |
| 2. | Mazo IB, Massberg S, von Andrian UH. Hematopoietic stem and progenitor cell trafficking. Trends Immunol. 2011;32:493-503. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 119] [Cited by in RCA: 128] [Article Influence: 8.5] [Reference Citation Analysis (0)] |
| 3. | Yang X, Chen D, Long H, Zhu B. The mechanisms of pathological extramedullary hematopoiesis in diseases. Cell Mol Life Sci. 2020;77:2723-2738. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 51] [Cited by in RCA: 80] [Article Influence: 13.3] [Reference Citation Analysis (0)] |
| 4. | Musolino A, Guazzi A, Lazzaretti M, Pezzuolo D, Calzetti C, Degli Antoni A, Ardizzoni A. Intracranial hematopoiesis in a patient with AIDS-related central nervous system lymphoma and severe pancytopenia. Haematologica. 2007;92:e59-e61. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 7] [Cited by in RCA: 8] [Article Influence: 0.4] [Reference Citation Analysis (0)] |
| 5. | Xue Y, Lim S, Yang Y, Wang Z, Jensen LD, Hedlund EM, Andersson P, Sasahara M, Larsson O, Galter D, Cao R, Hosaka K, Cao Y. PDGF-BB modulates hematopoiesis and tumor angiogenesis by inducing erythropoietin production in stromal cells. Nat Med. 2011;18:100-110. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 144] [Cited by in RCA: 169] [Article Influence: 11.3] [Reference Citation Analysis (0)] |
| 6. | Schmid P, Cortes J, Dent R, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Untch M, Fasching PA, Cardoso F, Andersen J, Patt D, Danso M, Ferreira M, Mouret-Reynier MA, Im SA, Ahn JH, Gion M, Baron-Hay S, Boileau JF, Ding Y, Tryfonidis K, Aktan G, Karantza V, O'Shaughnessy J; KEYNOTE-522 Investigators. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. N Engl J Med. 2022;386:556-567. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 194] [Cited by in RCA: 910] [Article Influence: 227.5] [Reference Citation Analysis (0)] |
| 7. | Millar EK, Inder S, Lynch J. Extramedullary haematopoiesis in axillary lymph nodes following neoadjuvant chemotherapy for locally advanced breast cancer--a potential diagnostic pitfall. Histopathology. 2009;54:622-623. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 10] [Cited by in RCA: 11] [Article Influence: 0.6] [Reference Citation Analysis (0)] |
| 8. | Hsu FI, Filippa DA, Castro-Malaspina H, Downey RJ. Extramedullary hematopoiesis mimicking metastatic lung carcinoma. Ann Thorac Surg. 1998;66:1411-1413. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 10] [Cited by in RCA: 10] [Article Influence: 0.4] [Reference Citation Analysis (0)] |
| 9. | Vassiliou V, Papamichael D, Lutz S, Eracleous E, Kountourakis P, Polyviou P, Michaelides I, Shoukris M, Andreopoulos D. Presacral Extramedullary Hematopoiesis in a Patient with Rectal Adenocarcinoma: Report of a Case and Literature Review. J Gastrointest Cancer. 2012;43 Suppl 1:S131-S135. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 7] [Cited by in RCA: 9] [Article Influence: 0.9] [Reference Citation Analysis (0)] |
| 10. | Fan N, Lavu S, Hanson CA, Tefferi A. Extramedullary hematopoiesis in the absence of myeloproliferative neoplasm: Mayo Clinic case series of 309 patients. Blood Cancer J. 2018;8:119. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 30] [Cited by in RCA: 49] [Article Influence: 6.1] [Reference Citation Analysis (0)] |
| 11. | Hoda SA, Chiu A, Resetkova E, Harigopal M, Hoda RS, Osborne MP. Pathological examination of sentinel lymph node in breast cancer: potential problems and possible solutions. Microsc Res Tech. 2002;59:85-91. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 11] [Cited by in RCA: 10] [Article Influence: 0.4] [Reference Citation Analysis (0)] |
| 12. | Gallagher PG. Extramedullary hematopoietic stem cells. Blood. 2022;139:3353-3354. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 6] [Reference Citation Analysis (0)] |
| 13. | Barisas DAG, Kabir AU, Wu J, Krchma K, Kim M, Subramanian M, Zinselmeyer BH, Stewart CL, Choi K. Tumor-derived interleukin-1α and leukemia inhibitory factor promote extramedullary hematopoiesis. PLoS Biol. 2023;21:e3001746. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 2] [Cited by in RCA: 17] [Article Influence: 5.7] [Reference Citation Analysis (0)] |
| 14. | Schyrr F, Alonso-Calleja A, Vijaykumar A, Sordet-Dessimoz J, Gebhard S, Sarkis R, Bataclan C, Ferreira Lopes S, Oggier A, de Leval L, Nombela-Arrieta C, Naveiras O. Inducible CXCL12/CXCR4-dependent extramedullary hematopoietic niches in the adrenal gland. Blood. 2024;144:964-976. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 1] [Cited by in RCA: 6] [Article Influence: 3.0] [Reference Citation Analysis (0)] |
| 15. | Mendt M, Cardier JE. Role of SDF-1 (CXCL12) in regulating hematopoietic stem and progenitor cells traffic into the liver during extramedullary hematopoiesis induced by G-CSF, AMD3100 and PHZ. Cytokine. 2015;76:214-221. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 17] [Cited by in RCA: 26] [Article Influence: 2.4] [Reference Citation Analysis (0)] |
| 16. | Prieto-Granada C, Setia N, Otis CN. Lymph node extramedullary hematopoiesis in breast cancer patients receiving neoadjuvant therapy: a potential diagnostic pitfall. Int J Surg Pathol. 2013;21:264-266. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 9] [Cited by in RCA: 10] [Article Influence: 0.8] [Reference Citation Analysis (0)] |
| 17. | Dagdas S, Ozet G, Alanoglu G, Ayli M, Gokmen Akoz A, Erekul S. Unusual extramedullary hematopoiesis in a patient receiving granulocyte colony-stimulating factor. Acta Haematol. 2006;116:198-202. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 11] [Cited by in RCA: 11] [Article Influence: 0.6] [Reference Citation Analysis (0)] |
| 18. | Takhar AS, Ney A, Patel M, Sharma A. Extramedullary haematopoiesis in axillary lymph nodes following neoadjuvant chemotherapy for locally advanced breast cancer. BMJ Case Rep. 2013;2013:bcr2013008943. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 8] [Cited by in RCA: 11] [Article Influence: 0.8] [Reference Citation Analysis (0)] |
| 19. | De Cicco P, Ercolano G, Ianaro A. The New Era of Cancer Immunotherapy: Targeting Myeloid-Derived Suppressor Cells to Overcome Immune Evasion. Front Immunol. 2020;11:1680. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 284] [Cited by in RCA: 258] [Article Influence: 43.0] [Reference Citation Analysis (3)] |
| 20. | Long H, Jia Q, Wang L, Fang W, Wang Z, Jiang T, Zhou F, Jin Z, Huang J, Zhou L, Hu C, Wang X, Zhang J, Ba Y, Gong Y, Zeng X, Zeng D, Su X, Alexander PB, Wang L, Wang L, Wan YY, Wang XF, Zhang L, Li QJ, Zhu B. Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy. Cancer Cell. 2022;40:674-693.e7. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 32] [Cited by in RCA: 103] [Article Influence: 25.8] [Reference Citation Analysis (0)] |
| 21. | Ubaid S, Kushwaha R, Kashif M, Singh V. Comprehensive analysis of oncogenic determinants across tumor types via multi-omics integration. Cancer Genet. 2025;298-299:44-62. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 18] [Reference Citation Analysis (0)] |
| 22. | Liu HR. AI-driven integration of multi-omics and multimodal data for precision medicine. Med Data Min. 2026;9:1. [RCA] [DOI] [Full Text] [Cited by in RCA: 1] [Reference Citation Analysis (0)] |
| 23. | Hoda SA, Resetkova E, Yusuf Y, Cahan A, Rosen PP. Megakaryocytes mimicking metastatic breast carcinoma. Arch Pathol Lab Med. 2002;126:618-620. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 26] [Cited by in RCA: 21] [Article Influence: 0.9] [Reference Citation Analysis (0)] |
| 24. | Wang J, Darvishian F. Extramedullary hematopoiesis in breast after neoadjuvant chemotherapy for breast carcinoma. Ann Clin Lab Sci. 2006;36:475-478. |
| 25. | Badr NM, Roberts C, Shaaban AM. Extramedullary Haematopoiesis in Axillary Lymph Nodes of Breast Carcinoma Patients Receiving Neoadjuvant Chemotherapy: A Potential Diagnostic Pitfall. Pathobiology. 2019;86:167-172. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 7] [Cited by in RCA: 8] [Article Influence: 1.0] [Reference Citation Analysis (0)] |