Bone marrow nonneoplastic
Storage type histiocytosis
Sea blue histiocytosis (syndrome)
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PubMed Search: Sea blue histiocytosis (syndrome)
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Practice question #1 | Practice answer #1Cite this page: Nguyen PN, Tran N. Sea blue histiocytosis (syndrome). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bonemarrowseablue.html. Accessed April 29th, 2025.
Definition / general
- Sea blue histiocytes containing phospholipids and glycosphingolipids appear blue-green on Wright-Giemsa stain, hence the name sea blue
Essential features
- First described by Silverstein in 1970 as the syndrome of the sea blue histiocyte; the term syndrome should be reserved exclusively for this entity (N Engl J Med 1970;282:1)
- These histiocytes accumulate extensively in the spleen but are also seen in other etiologies
- Morphological features: histiocytes with variably sized cytoplasmic granules
- Blue / blue-green on Romanowsky / Wright-Giemsa stain
- Yellow-brown on H&E
- PAS positive, diastase resistant and lipid positive
- Primary condition: sea blue histiocytosis syndrome / inherited lipemic splenomegaly
- Familial autosomal disease associated with apolipoprotein E (APOE) p.Leu167del mutation
- Main symptoms: splenomegaly, thrombocytopenia, hypertriglyceridemia, hepatosteatosis with abnormal liver function
- Secondary associations
- Lipid storage diseases: Niemann-Pick and Gaucher diseases
- Myeloproliferative disorders: acute / chronic myeloid leukemia, myelodysplastic neoplasms
- Longterm parenteral nutrition for short bowel syndrome with malnutrition
- Autoimmune thrombocytopenia
- Beta thalassemia (Indian J Hematol Blood Transfus 2016;32:262)
Terminology
- Ceroid histiocytosis
- Inherited lipemic splenomegaly (sea blue histiocytosis syndrome)
ICD coding
- ICD-10: D76.3 - other histiocytosis syndromes
Epidemiology
- Inherited lipemic splenomegaly is an extremely rare autosomal condition
- Secondary sea blue histiocytosis can occur in patients of any age or demographic, depending on the underlying etiology
Sites
- Primary involvement: spleen, often leading to splenomegaly in sea blue histiocytosis syndrome
- Other sites: bone marrow, liver, lymph node
Pathophysiology
- In inherited lipemic splenomegaly, the p.Leu167del mutation in APOE disrupts lipid metabolism, causing systemic lipid accumulation (J Clin Endocrinol Metab 2000;85:4354, J Clin Lipidol 2013;7:566)
- Secondary causes like Niemann-Pick and Gaucher diseases arise from lysosomal enzyme deficiencies, leading to ceroid and lipid buildup
Etiology
- APOE (p.Leu167del) mutation (primary condition)
Clinical features
- Inherited lipemic splenomegaly: splenomegaly, thrombocytopenia, hypertriglyceridemia, hepatosteatosis with abnormal liver function, cardiovascular disease, diabetes mellitus
- Secondary causes: symptoms reflect the underlying disorder
Diagnosis
- Bone marrow aspirate smear: large cells with deep blue cytoplasmic granules on Wright-Giemsa stain
- Formalin fixed paraffin embedded tissue: large cells with small central or eccentric nuclei with abundant cytoplasm and cytoplasmic granules
- These cells are positive for histiocytic markers, such as CD63 and CD163
- PAS with or without diastase stains cytoplasmic granules
- Reference: N Engl J Med 1970;282:1
Laboratory
- Primary condition: with or without hypertriglyceridemia, hyperglycemia, thrombocytopenia
Case reports
- 29 and 49 year old men with splenomegaly (J Clin Endocrinol Metab 2000;85:4354)
- 32 year old woman with splenomegaly and small splenic rupture, hepatic steatosis and hypertriglyceridemia (Hum Pathol Case Rep 2017;9:46)
- 44 year old man with splenomegaly and mild thrombocytopenia (Haematologica 2001;86:896)
- 47 year old man with immune thrombocytopenic purpura (Cureus 2020;12:e10396)
- 70 year old man on longterm parenteral nutrition (Am J Hematol 2024;99:971)
- 80 year old man with a history of treated non-Hodgkin lymphoma (Case Rep Oncol 2020;13:849)
Treatment
- Manage hyperlipidemia and hyperglycemia in inherited lipemic splenomegaly
- Address secondary causes with disease specific treatments
Microscopic (histologic) description
Microscopic (histologic) images
Contributed by Ngoc Tran, M.D., M.S.
Sea blue histiocytes (bone marrow core biopsy)
Sea blue histiocytes (bone marrow core biopsy)
Sea blue histiocyte (bone marrow aspirate smear)
Cluster of sea blue histiocytes (bone marrow aspirate smear)
Coarse cytoplasmic granules
Coarse cytoplasmic granules
Ruptured cell membrane and CD68+ histiocytes
Cytology description
Cytology images
Positive stains
Negative stains
Electron microscopy description
- Granules are electron dense and exhibit a myelin-like or fingerprint pattern, indicative of phospholipids
Electron microscopy images
Images hosted on other servers:
Cytoplasmic electron dense granules in hyperlipidemia
Fingerprint inclusion within histiocyte
Molecular / cytogenetics description
- Hallmark mutation in inherited lipemic splenomegaly is APOE (p.Leu167del), characterized by a 3 base pair deletion that results in the loss of leucine at position 167
- Detected by sequencing or polymerase chain reaction (PCR)
Sample pathology report
- Bone marrow aspirate, clot section, and left posterior iliac crest core biopsy:
- Normal cellular marrow with trilineage hematopoiesis
- Sea blue histiocytosis (see comment)
- Comment: Sea blue histiocytes have been described in the setting of hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, parenteral nutrition, high rates of intramedullary cell death due to lipid storage diseases (e.g., Niemann-Pick disease, Gaucher disease), myelodysplastic syndromes, lymphomas, chronic myeloid leukemia, idiopathic thrombocytopenic purpura, autoimmune neutropenia and beta thalassemia major. Clinical correlation is recommended.
- Bone marrow aspirate: The bone marrow aspirate smears exhibit clusters of sea blue histiocytes that have smooth, agranular, blue-green cytoplasm and scattered sea blue histiocytes with large, coarse, deep blue granules. Blasts are not increased. No significant dysplasia is observed in the erythroid and myeloid precursors or megakaryocytes.
- Bone marrow core biopsy: Marrow cellularity is appropriate for age. Myeloid and erythroid precursors show a full spectrum of maturation. Megakaryocytes are unremarkable. There are multiple large histiocytes with abundant granular cytoplasm. These histiocytes are positive for CD68. PAS highlights cytoplasmic particles of these sea blue histiocytes. Grocott methenamine silver (GMS) and Fite stains are negative for fungal forms and acid fast bacilli, respectively.
Differential diagnosis
- Niemann-Pick disease:
- Predominant foam cells with occasional sea blue histiocytes (Ann Hematol 2001;80:620)
- Diagnosis is confirmed by enzyme activity studies (sphingomyelinase deficiency) and genetic testing
- Gaucher disease:
- Presence of Gaucher cells with a characteristic wrinkled tissue paper appearance (ASH: Gaucher's Cells in Bone Marrow Aspirate Smears [Accessed 17 March 2025])
- Confirmatory tests include glucocerebrosidase enzyme activity assay and GBA gene mutation analysis
- Whipple disease:
- Clusters of PAS positive histiocytes primarily in the gastrointestinal tract
- Unlike sea blue histiocytes, these do not stain blue or bright blue on Wright-Giemsa stain (Clin Microbiol Rev 2001;14:561)
- Iron accumulation:
- Distinguished by Prussian blue positivity, indicating hemosiderin laden macrophages rather than lipid containing histiocytes
Additional references
Practice question #1
Aside from PAS, the cell in this bone marrow aspirate image is positive for which of the following?
- Acid fast bacilli (AFB) or Fite
- CD117
- Histiocytic markers
- Mucicarmine
- Tryptase
Practice answer #1
C. Histiocytic markers. The cell in the image is a sea blue histiocyte; therefore, it is positive for histiocytic markers, such as CD68 or CD163. Answer A is incorrect because acid fast bacilli (AFB) or Fite stains for mycobacteria, not histiocytes. Answer B is incorrect because CD117 is a marker for mast cells and early myeloid cells, not histiocytes. Answer D is incorrect because mucicarmine stains mucin, not lipid laden macrophages. Answer E is incorrect because tryptase is a marker for mast cells, not histiocytes.
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Reference: Sea blue histiocytosis (syndrome)
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Reference: Sea blue histiocytosis (syndrome)
