Non-neoplastic histiocytic proliferations in bone marrow: a case series of uncommon morphologic findings

Introduction

Histiocytes are resident tissue macrophages that play a central role in immune surveillance, antigen presentation, and the clearance of cellular debris. In the bone marrow, histiocytes are normally present in small numbers and may become more prominent in a variety of reactive conditions. Non-neoplastic histiocytic proliferations represent a heterogeneous group of secondary processes that may be associated with infections, autoimmune disorders, hemophagocytic syndromes, metabolic disturbances, malignancies, or therapy-related changes. While these proliferations are benign and reactive, their morphologic features may be striking and occasionally raise concern for primary histiocytic or other hematologic neoplasms (1, 2).

The distinction between reactive and neoplastic histiocytic proliferations in bone marrow specimens can be challenging, particularly when histiocytes are markedly increased, form aggregates, exhibit cytologic atypia, or demonstrate hemophagocytosis (3). Such findings may mimic entities such as histiocytic sarcoma, Langerhans cell histiocytosis, metastatic malignancy, or marrow involvement by lymphoma or leukemia (4). In many of these settings, histiocytic proliferation represents a secondary response to cytokine-mediated immune activation or tissue injury rather than a clonal proliferation. Consequently, recognition of the underlying clinical context is often more informative than the degree of histiocytic expansion itself. In addition, prominent non-neoplastic histiocytic expansion may obscure the underlying disease process or represent a diagnostic red herring, potentially leading to misinterpretation, unnecessary ancillary testing, or delays in appropriate clinical management.

Recognition of reactive patterns such as hemophagocytosis, (9, 10) infection-associated histiocytosis, therapy-related changes, and storage-like appearances is essential to avoid overdiagnosis of a neoplastic histiocytic disorder. However, the spectrum of unusual morphologic presentations encountered in routine practice remains incompletely characterized in the literature, and awareness of these patterns is limited. In this case series, we present a collection of bone marrow specimens demonstrating non-neoplastic histiocytic proliferations which can lead to diagnostic challenges. We describe morphologic findings, clinical associations, and ancillary study results, and discuss potential diagnostic pitfalls. Increased recognition of these reactive patterns may facilitate accurate interpretation and help prevent overdiagnosis of histiocytic neoplasia.

Case 1

An elderly man in his seventies with a history of metastatic non–small cell lung cancer (NSCLC), previously treated with multiple lines of chemotherapy, immune checkpoint inhibitor therapy, and surgical resection, presented with newly developed pancytopenia (white blood cell count, 3.6 ×10⁹/L; hemoglobin, 9.2 g/dL; platelet count, 103 ×10⁹/L) and macrocytosis. Bone marrow examination demonstrated a hypercellular marrow for age (approximately 60% cellularity) with multilineage dysplasia involving erythroid and megakaryocytic lineages and increased ring sideroblasts (~18%). Blasts were not increased (~2%). These findings were consistent with a consistent with myelodysplastic neoplasm with low blasts (MDS-LB), post cytotoxic therapy in the appropriate clinical context.

Histologic evaluation of the bone marrow core biopsy revealed a focal aggregate of epithelioid cells characterized by enlarged pleomorphic nuclei, abundant clear to eosinophilic cytoplasm, and inconspicuous nucleoli (Figures 1A, B). Given the patient’s history of metastatic carcinoma, focal involvement of marrow with metastatic carcinoma was considered and a surgical pathology review of the case with multiple immunohistochemical stains confirmed absence of a metastatic carcinoma. Immunohistochemical studies demonstrated strong cytoplasmic positivity for pan-cytokeratin (AE1/AE3) with a characteristic dot-like (paranuclear) staining pattern (Figures 1C, D) and strong expression of the histiocytic marker CD163 (Figure 1E) in these cells. These cells were negative for myeloperoxidase (not shown), lysozyme (not shown), CD34 (not shown) and CD117 (not shown) and other carcinoma markers TTF-1 (not shown), CAM5.2 (Figure 1F) and Napsin A (not shown).

Aberrant cytokeratin expression with a dot-like cytoplasmic pattern in the myeloblasts has been previously described in hematopoietic neoplasms like myelodysplastic syndrome (11), acute myeloid leukemia (12) and in myeloid sarcoma (13), where it represents a potential diagnostic pitfall. Contrastingly, in our case, the cytokeratin-positive cells demonstrated histiocytic differentiation based on strong CD163 expression, indicating that the aberrant cytokeratin reactivity was present in marrow macrophages rather than blasts or epithelial tumor cells. Similar findings of this aberrant cytokeratin expression in the tissue macrophages have been described in prior studies (14), however, has never been documented in bone marrow macrophages. This finding represents an important diagnostic pitfall, particularly in patients with a known history of metastatic carcinoma undergoing bone marrow evaluation for cytopenias. Reliance on a single cytokeratin stain may lead to overdiagnosis of metastatic disease. Careful morphologic assessment and confirmation with a comprehensive immunohistochemical panel, including histiocytic markers (e.g., CD163, CD68), lineage-specific epithelial markers, and hematopoietic markers are essential to avoid misinterpretation. Recognition of this phenomenon is especially relevant in the setting of myelodysplastic syndromes, where dysplastic changes and therapy-related alterations may further complicate interpretation.

Case 2

A young teen male with a history of a congenital neurodevelopmental disorder presented with acute hypoxemic respiratory failure, fever, and fatigue secondary to viral respiratory infection with superimposed bacterial pneumonia. Laboratory studies incidentally revealed pancytopenia (WBC 1.9 K/mm³, hemoglobin 7.6 g/dL, platelets 19 K/mm³, ANC 1.2 K/mm³). CT imaging showed massive splenomegaly (30.7 cm) with multiple hypoenhancing lesions and mild hepatomegaly without lymphadenopathy. Viral studies, including EBV, Parvovirus B19, HIV, and hepatitis B/C, were negative. Peripheral smear demonstrated dacrocytes. Given concern for a myelophthisic process, a bone marrow biopsy was performed.

The bone marrow was markedly hypercellular (~100%) with decreased trilineage hematopoiesis and prominent aggregates of large histiocytes (Figure 2A). Aspirate smears showed histiocytes with abundant cytoplasm displaying a characteristic “crinkled tissue paper” appearance and eccentric nuclei, morphologically consistent with Gaucher cells (Figures 2C, D). The cells were positive for PAS (Figure 2B) and PAS-diastase (diastase-resistant) and negative for AFB. Wade’s-AFB demonstrated characteristic lacunae and clefts within the cytoplasm. Immunohistochemistry demonstrated CD68 and CD163 positivity with negative S100. Mild reticulin fibrosis (MF-1) was present around histiocytic collections.

Rapid Trio whole genome sequencing (GeneDx, 2025) identified biallelic GBA1 pathogenic variants: paternal c.764T>A (p.F255Y) (reference sequence: NM_000157.4(GBA1):c.764T>A (p.Phe255Tyr)) and maternal c.701G>A (p.G234E) (reference sequence: NM_000157.4(GBA1):c.701G>A (p.Gly234Glu)). Revvity Lantern Gaucher’s Testing demonstrated elevated glucosylsphingosine (LysoGB1 >200 ng/mL) and deficient beta-glucocerebrosidase activity (0.26 μmol/L/hr; normal ≥1.6 μmol/L/hr). These findings confirmed the diagnosis of Gaucher disease, Type 1 (non-neuronopathic).

This case illustrates several important teaching points regarding the recognition and diagnosis of storage histiocytosis in bone marrow. Gaucher cells have a distinctive appearance that, once recognized, is highly suggestive of the diagnosis. The “crinkled tissue paper” cytoplasm results from the accumulation of glucocerebroside within lysosomes, which forms tubular structures visible as fine striations at light microscopy (15). This appearance differs from the foamy, vacuolated cytoplasm of Niemann-Pick cells or the crystalline inclusions of crystal-storing histiocytosis (16, 17). An important diagnostic pitfall is the pseudo-Gaucher cell, which can occur in various hematologic malignancies including chronic myeloid leukemia, myelodysplastic syndromes, Hodgkin lymphoma, and multiple myeloma (18–21). These cells arise from macrophage engulfment of cellular debris in states of increased cell turnover and can closely mimic true Gaucher cells at light microscopy. The distinction between pseudo-Gaucher cells and true Gaucher cells should not rely solely on enzyme assay findings. While demonstration of deficient beta-glucocerebrosidase activity confirms Gaucher disease (8, 22), ancillary studies may aid in the distinction; notably, iron staining is often positive in true Gaucher cells but is typically absent or much less prominent in pseudo-Gaucher cells (23). Notably, the clinical background is crucial for accurate interpretation, as the presence of an underlying lysosomal storage disorder versus a process associated with high cell turnover strongly supports the diagnosis of true Gaucher cells or pseudo-Gaucher cells, respectively.

While morphology is highly suggestive, confirmatory biochemical and/or genetic testing is essential. Enzyme assay demonstrating deficient beta-glucocerebrosidase activity is the gold standard for diagnosis, and molecular testing identifies the specific GBA1 variants (22). In this case, both enzyme deficiency and biallelic pathogenic variants were confirmed. This case also highlights that Gaucher disease may be diagnosed incidentally during workup for other conditions. The patient presented with respiratory infection and pancytopenia, and the bone marrow biopsy was performed to exclude malignancy given the concerning imaging findings. The massive splenomegaly with hypoenhancing lesions, initially raising concern for lymphoma or other malignancy, is in fact characteristic of Gaucher disease with “Gaucheroma” formation.

Notably, this patient has a concurrent undiagnosed congenital neurodevelopmental syndrome that is distinct from Gaucher disease. The neurological findings (congenital hypotonia, developmental delay, pyramidal signs) are not attributable to type 1 Gaucher disease and represent a separate genetic condition that remains unresolved despite trio whole genome sequencing. This illustrates the importance of not attributing all clinical findings to a single diagnosis, particularly when features are inconsistent with the established condition.

Case 3

A man in his sixties with several years of progressive fatigue presented with worsening hip pain and was found to have a right femoral neck stress fracture. Laboratory evaluation demonstrated monoclonal gammopathy of undetermined significance (MGUS) with a serum monoclonal IgG lambda protein (0.4 g/dL) and elevated lambda free light chains (2.90 mg/dL; kappa:lambda ratio 0.39). Bone marrow biopsy revealed a hypocellular marrow (~20% cellularity) with approximately 5% plasma cells by aspirate and small clusters comprising ~10% by CD138 immunohistochemistry. Numerous histiocytes contained irregular, non-polarizing crystalline cytoplasmic inclusions were noted in the aspirate smears (Figure 3A). Also, similar crystalline inclusions were noted in the plasma cells (Figure 3B). Hematoxylin and eosin staining shows the crystalline inclusions in macrophages (Figure 3C) and plasma cells (Figure 3D). Additional IHC staining on a bone marrow clot section demonstrated that the cytoplasmic crystals were positive for IgG and lambda in histiocytes (Figures 3E, F), confirming the diagnosis of IgG lambda immunoglobulin crystal-storing histiocytosis associated with a lambda-restricted MGUS. Of note, for the purpose of ruling out non-specific crystal staining, IgD and kappa IHC stains were negative in the crystals with a few scattered plasma cells showing positivity. A Congo red stain was also negative for amyloid deposition.

Crystal-storing histiocytosis (CSH) is a rare condition characterized by intralysosomal accumulation of crystallized material within histiocytes, most commonly immunoglobulins produced in association with lymphoplasmacytic or plasma cell disorders (24). The cytoplasmic inclusions should not be confused with the globular Russell body inclusions commonly seen in plasma cells. The immunoglobulin light chain staining pattern is typically concordant with that of the underlying neoplasm although polyclonal staining can also be observed, and IgM, IgG, and IgA heavy chains have all been reported (25). In rare cases, this phenomenon is observed in the setting of rheumatoid arthritis (26, 27) or secondary to a reactive polyclonal plasma cell proliferation (28). Alternatively, CSH can result from accumulation of crystallized clofazimine (29–31), Charcot-Leyden crystals (32, 33), or cystine (34). CSH often occurs as a localized lesion which can occur at a variety of anatomic sites although in a minority of cases this phenomenon is generalized (involving at least two distant sites). The CD68+ histiocytes of interest frequently comprise most infiltrating cells, which can complicate diagnostic evaluation of the underlying neoplasm.

The pathogenesis is incompletely understood but is thought to involve overproduction and/or structural alterations of immunoglobulins that impair lysosomal degradation, leading to intracellular crystallization and accumulation. Interestingly, previous mass spectrometric analysis of the stored proteins in one case demonstrated amino acid substitutions hypothesized to affect hydrophobic packing within the kappa light chain, implying that conformational changes presumably affected downstream excretion or degradation, resulting in accumulation and aggregation of the protein product. Given the heterogenous nature of this entity (involving multiple subtypes of light and heavy chain immunoglobulins), it is likely that the causative mutations of CSH may be polymorphous but the mechanism of disease in each case is similar and result from dysfunctional degradation of immunoglobulin proteins secondary to structural changes, exacerbating pre-existing overproduction and ultimately leading to crystal aggregation in histiocytes (35).

Recognition of CSH is critical because while it may conceal the causative neoplasm, appropriate workup should include workup for clonal plasma cell or lymphoplasmacytic disorders. A high index of suspicion may be required in some cases since alterations in the protein structure may compromise staining. In rare cases, non-immunoglobulin crystals may be responsible for this phenomenon, therefore a broad differential diagnosis is appropriate.

Case 4

A male in his fifties with severe aplastic anemia and small (near 1%) paroxysmal nocturnal hemoglobinuria (PNH) clones who was being considered for an allogenic stem cell transplant due to poor response to ongoing immunosuppressive therapy (anti-thymocyte globulin (ATG) and cyclosporine), hematopoietic growth factors, and twice weekly supportive transfusions was admitted for gangrenous cholecystitis and underwent cholecystectomy. During this hospitalization, CMV viral load was markedly elevated at 2330 IU/mL but spontaneously resolved without treatment four weeks later.

Subsequently, the patient proceeded with his planned pre-transplant bone marrow biopsy. Histologic examination revealed an overall hypocellular marrow (ranging from 10-40% cellularity) with intact trilineage hematopoiesis, increased iron stores (5+/6), no increase in blasts, and no dysplasia. Unexpectedly, there were prominent hemophagocytic histiocytes observed on both the aspirate smear and core biopsy (Figures 4A–D), highlighted by CD163 and CD68 immunohistochemistry. The hemophagocytic histiocytes demonstrated ingestion of diverse nucleated hematopoietic cells, including granulocytes and nucleated erythroid precursors, with some histiocytes containing multiple ingested nucleated cells.

The bone marrow biopsy was also forwarded for expert review in which additional immunohistochemical studies showed no definite expression of CD1a, S100, and langerin (CD207), excluding Langerhans cell histiocytosis (LCH) and Rosai-Dorfman disease (RDD). Morphologic evaluation also did not demonstrate the foamy (xanthomatous) histiocytes or Touton giant cells characteristic of ECD. Both Factor XIIIa and BRAF V600E (VE1 clone) immunohistochemistry were negative, providing no support for ECD. The immunophenotypic profile (CD163+, CD68+, CD1a-, S100-, langerin-, Factor XIIIa-, BRAF V600E-) was more consistent with a reactive macrophage proliferation rather than a neoplastic histiocytic process.

Subsequent laboratory results showed ferritin 7,757 ng/mL, triglycerides 185-199 mg/dL, and elevated soluble CD25 1,550.3 pg/mL (reference range 175.3-858.2 pg/mL) which raises the clinical concern for hemophagocytic lymphohistiocytosis (HLH) per HLH-2004 and 2024 revised criteria (36, 37). However, no fever or organomegaly was documented, only changes suggestive of hepatosplenic iron deposition were noted on the most recent abdominal MRI. Two months after the initial marrow procurement, a repeat bone marrow biopsy was consistent with aplastic anemia (15% cellularity) showing no excess blasts and most notably, no hemophagocytosis. The patient then proceeded with an allogeneic stem cell transplantation.

Although hemophagocytosis is a hallmark morphologic feature of HLH, it is a nonspecific finding that may be encountered in infectious, inflammatory, autoimmune, and neoplastic conditions and does not independently establish a diagnosis of HLH. Indeed, isolated marrow hemophagocytosis lacks both sensitivity and specificity for HLH (80-83% and 60% respectively in isolated adult studies) (38). The North American Consortium for Histiocytosis (NACHO) guidelines further emphasize that hemophagocytosis is “not specific to HLH, or essential for the diagnosis, but helpful as a disease marker” (39). Still, there may be morphologic clues. Gars et al. demonstrated that certain morphologic hemophagocytic subtypes are more highly associated with HLH than erythrophagocytosis of non-nucleated red blood cells which are more likely to be a nonspecific finding (40). The hemophagocytes seen in this case displayed morphologically concerning features for HLH, including hemophagocytosis of multiple nucleated cells particularly granulocytes and nucleated erythrocytes.

Furthermore, the distinction between aplastic anemia and HLH can be particularly challenging, as both entities may present with profound cytopenias and bone marrow hypocellularity. Increasing evidence suggests that immune dysregulation and inflammatory cytokine signaling contribute to hematopoietic suppression in both disorders (41). In HLH, excessive cytokine production by activated T cells and macrophages can result in bone marrow failure and severe cytopenias, whereas aplastic anemia is characterized by immune-mediated destruction of hematopoietic stem and progenitor cells. Consequently, reactive hemophagocytosis may be observed in patients with marrow failure syndromes without fulfilling diagnostic criteria for HLH (42).

Case 5

A middle-aged man in forties with advanced HIV on antiretroviral therapy (emtricitabine/tenofovir alafenamide/bictegravir) presented with malnutrition and suspected malabsorption. He reported a prior history of night sweats, fevers, and weight loss, and currently experiences persistent back pain. His medical history was significant for Mycobacterium avium complex (MAC) infection on azithromycin/ethambutol/levofloxacin, neurosyphilis treated with IV penicillin, and biopsy proven Kaposi sarcoma involving the inguinal lymph node. Laboratory evaluation revealed normocytic anemia (hemoglobin 7.5 g/dL, MCV 88 fL) and CD4 count <20 cells/mm (3). Cross-sectional imaging revealed splenomegaly with a small splenic hypodensity, diffuse mesenteric lymphadenopathy, and a right lower lobe pulmonary opacity. A bone marrow biopsy was performed to evaluate for infectious involvement and to exclude a lymphoproliferative or Kaposi sarcoma-related process.

The bone marrow core biopsy revealed a markedly hypocellular marrow (~5% cellularity) with poorly formed granulomas (Figure 5A) involving approximately 10-15% of the marrow space. These aggregates consisted of loosely cohesive histiocytes lacking well-formed epithelioid features and without central necrosis. Scattered eosinophils were present. Reticulin staining demonstrated a mild increase in fibrosis (MF-1), predominantly surrounding the histiocytic collections. Periodic acid-Schiff (PAS) stain highlighted numerous intracellular, rod-shaped organisms within the histiocytes (Figure 5B). Ziehl–Neelsen (AFB) stain confirmed abundant intracellular acid-fast bacilli (Figure 5C). Grocott methenamine silver (GMS) stain was negative for fungal organisms. Immunohistochemistry showed CD68 and CD163 positivity within the histiocytic aggregates, supporting macrophage lineage. CD1a was negative, excluding Langerhans cell histiocytosis. HHV-8 immunostain was negative, arguing against bone marrow involvement by Kaposi sarcoma. Parvovirus B19 immunostain was negative, and spirochete stain did not demonstrate Treponema pallidum within the marrow. Giemsa-stained aspirate smears showed histiocytes filled with mycobacterial species casting a clear shadow of the organisms (Figure 5D).

This case highlights classic bone marrow findings of disseminated MAC infection in advanced HIV. The markedly hypocellular marrow (~5%) likely reflects a combination of HIV-associated myelosuppression, chronic infection, and treatment effects. Disseminated MAC typically occurs in patients with severe immunosuppression (CD4 <50 cells/mm³) (43). and commonly involves the liver, spleen, and bone marrow (44). Clinical features include fever, night sweats, weight loss, hepatosplenomegaly, lymphadenopathy, and anemia that is often disproportionate to the stage of HIV, all of which are present in this patient.

The histopathologic spectrum of MAC in bone marrow ranges from subtle histiocytic aggregates to florid granulomatous inflammation. In severely immunocompromised patients who typically lack the robust immune response, specifically reduced CD4+ T-cells, well-formed granulomas with epithelioid histiocytes are uncommon. Instead, the typical finding is poorly defined granulomas or distended macrophages packed with organisms and minimal inflammatory response (45, 46). The mild reticulin fibrosis (MF-1) observed in this case is a recognized reactive finding in granulomatous bone marrow disease and does not indicate a primary myelofibrotic process. MF-1 reticulin fibrosis can be secondary to infection, autoimmune disorder, or other chronic inflammatory conditions and should be distinguished from primary myelofibrosis. Fibrosis associated with granulomatous inflammation typically develops around granulomas through cytokine-mediated activation of mesenchymal cells (47).

The PAS-positive rod-shaped organisms within histiocytes are a characteristic finding in MAC infection. The organisms appear as intracellular bacilli that stain with both PAS and acid-fast stains, reflecting their mycobacterial cell wall composition. This dual staining pattern can be helpful in cases where AFB staining is equivocal.

This case illustrates the importance of bone marrow examination in HIV patients with unexplained cytopenias and suspected disseminated infection. The presence of poorly formed granulomas with numerous acid-fast organisms in a hypocellular marrow is diagnostic of disseminated mycobacterial disease, with MAC being the most common etiology in this clinical context.

Case 6

A 16 year old male presented with decreased appetite, 40 pounds of unintentional weight loss over one month, palpitations, and orthostatic visual changes. Initial laboratory evaluation demonstrated marked leukocytosis (white blood cell count, 425.4 × 10⁹/L) with a left-shifted myeloid differential characterized by neutrophilia, marked myelocytosis (122 × 10⁹/L), increased metamyelocytes (48 × 10⁹/L), and occasional promyelocytes (4 × 10⁹/L). Basophilia (18.8 × 10⁹/L) and eosinophilia (18.8 × 10⁹/L) were present, and circulating blasts accounted for approximately 2–3% of leukocytes. Concurrent severe normocytic anemia was noted (hemoglobin 6.6 g/dL), along with thrombocytosis (platelet count 499 × 10⁹/L). The peripheral blood smear demonstrated marked granulocytic proliferation with preservation of the full spectrum of myeloid maturation, without significant dysgranulopoiesis. Abdominal ultrasound revealed splenomegaly.

Bone marrow aspirate smears and core biopsy demonstrated a markedly hypercellular marrow (>95% cellularity) with left-shifted trilineage hematopoiesis and an increased myeloid-to-erythroid ratio of approximately 5:1. The myeloid lineage was expanded with full maturation to segmented forms, while erythroid precursors were relatively decreased but showed normoblastic maturation. Blasts were not increased, comprising ~3% of marrow cells by morphology and approximately 3–4% by CD34 immunohistochemistry. Megakaryocytes were adequate in number and included small, hypolobated (“dwarf”) forms (Figure 6A). Scattered sea-blue histiocytes were identified on the aspirate smear (Figure 6B). A pseudo-Gaucher cell for comparison is provided from the same aspirate smear (Figure 6C). Iron stores were decreased (1+/6+) without ring sideroblasts, and reticulin staining demonstrated only focal mild fibrosis (MF-1). Flow cytometric analysis showed no increase in blasts and no monotypic B-cell population. Bone marrow cytogenetic analysis identified t(9;22)(q34;q11), confirming chronic-phase chronic myeloid leukemia (CML), and therapy with imatinib was initiated.

Sea-blue histiocytes are bone marrow macrophages characterized by abundant cytoplasm containing coarse blue-green granular material, readily appreciable on routine aspirate smears. Although originally described in association with sea-blue histiocyte syndrome, in routine hematopathology practice they are more often encountered as a secondary phenomenon, reflecting acquired lipidosis related to increased cellular turnover rather than a primary disorder (48, 49). Chronic myeloid leukemia (CML) represents a well-recognized clinical context for this finding. Dosik et al. first described the presence of Gaucher-like cells and “blue cells” in chronic granulocytic leukemia, and Kelsey and Geary subsequently demonstrated in a retrospective analysis of 211 bone marrow specimens that both Gaucher-like cells and sea-blue histiocytes are frequent features in CML, likely related to sustained leukocyte turnover (49, 50). Howard and Kesteven similarly identified sea-blue histiocytes in 8 of 20 chronic-phase CML marrows in their comparative series, noting their occurrence predominantly in hypercellular marrow (51). In the present case, the sea-blue histiocytes are best interpreted as a secondary morphologic manifestation of increased myeloid turnover, rather than indicative of a primary storage disorder or a distinct histiocytic neoplasm (49–51). In CML, they reflect increased leukocyte and marrow cell turnover and may be seen alongside Gaucher-like (pseudo-Gaucher) cells. Their interpretation should be anchored in the overall marrow context, including hypercellularity, left-shifted myeloid maturation, basophilia, and dwarf megakaryocytes. The principal clinical significance of recognizing these cells is to avoid overdiagnosis of a lysosomal storage disorder or a distinct histiocytic proliferation in an otherwise typical CML marrow (50, 52).

Discussion

The morphologic interpretation of increased histiocytes in bone marrow biopsies remains challenging because morphology alone is commonly insufficient to distinguish reactive from clonal histiocytic proliferations. Unlike many hematologic malignancies, cytologic atypia is often subtle or absent in histiocytic disorders, including several chronic clonal histiocytoses. Accurate interpretation requires careful correlation with clinical history, laboratory findings, and morphologic features, along with judicious use of ancillary studies including immunohistochemistry, flow cytometry, microbiologic evaluation, and molecular testing. The presence of mitotic activity, destructive growth, or diffuse replacement of normal marrow architecture may support a neoplastic process but should always be interpreted in conjunction with the overall clinicopathologic picture.

The differential diagnosis is broad and includes reactive histiocytic proliferations, hemophagocytic syndromes, storage disorders, infections, therapy-related changes, and primary histiocytic neoplasms such as histiocytic sarcoma and Langerhans cell histiocytosis. An additional important diagnostic pitfall is chronic myelomonocytic leukemia (CMML), in which bone marrow may demonstrate prominent monocytes and macrophages with diverse morphologic appearances that can resemble reactive histiocytic proliferations (5). Furthermore, chronic non-Langerhans cell histiocytoses (6) including Erdheim-Chester disease (7), Rosai-Dorfman disease (4), reticulohistiocytosis, juvenile xanthogranuloma, and related entities may involve the bone marrow and often exhibit relatively bland cytologic features. In these disorders, diagnosis depends largely on the characteristic pattern of tissue involvement, clinical manifestations, immunophenotype, molecular alterations, and increasingly, the identification of MAPK pathway mutations, rather than cytologic appearance alone (6).

Another entity to keep into consideration is lysosomal storage disorders, which represent an important category of non-neoplastic histiocytic proliferations encountered in bone marrow. Gaucher disease (8), resulting from inherited deficiency of glucocerebrosidase, is characterized by accumulation of glucosylceramide within macrophages, producing the classic “wrinkled tissue paper” cytoplasm of Gaucher cells. Bone marrow involvement may be extensive, with large aggregates or diffuse sheets of histiocytes that can obscure the underlying hematopoietic elements and mimic histiocytic neoplasms or metastatic malignancy. Other lysosomal storage disorders, including Niemann-Pick disease and sea-blue histiocytosis, should also be considered in the differential diagnosis of prominent marrow histiocytosis, particularly in the appropriate clinical setting.

Recognition of the characteristic morphologic features, correlation with clinical findings such as splenomegaly and cytopenias, and confirmation by enzymatic and molecular testing are critical to establishing the correct diagnosis and avoiding unnecessary oncologic evaluation. Correlation with patient history, laboratory studies, radiologic findings, microbiologic evaluation, flow cytometry, immunohistochemistry, cytogenetic studies, and molecular testing is often necessary to establish the correct diagnosis and avoid inappropriate treatment.

Conclusion

Non-neoplastic histiocytic proliferations in the bone marrow are important diagnostic mimics that require careful evaluation to distinguish them from malignant processes. Their presence often reflects an underlying reactive or systemic condition rather than a primary histiocytic disorder. Accurate interpretation relies on comprehensive clinicopathologic correlation and judicious use of ancillary studies. Recognizing these entities and their varied presentations is crucial for pathologists to prevent misdiagnosis, guide appropriate further workup, and ensure optimal patient care.

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Footnotes

Edited by: Bianca Nowlan, The University of Queensland, Australia

Reviewed by: Arturo Bonometti, Humanitas University, Italy

Karen M. Chisholm, Seattle Children’s Hospital, United States