Histiocytic Sarcoma

Roberto N. Miranda, MD

Key Facts

Terminology

Malignant neoplasm composed of mature histiocytes
Diagnosis based mainly on morphology and immunophenotype

Etiology/Pathogenesis

Transdifferentiation in subset of cases
- B-cell lymphoma and HS are clonally related
- Suggests that B cells can switch phenotype to histiocytic lineage

Clinical Issues

HS often presents as painless solitary mass
Clinical course can be indolent or aggressive
Bone marrow involvement is unusual
- Must exclude acute monocytic leukemia/monocytic sarcoma

Microscopic Pathology

Diffuse pattern
Large cells with abundant eosinophilic cytoplasm

Ancillary Tests

Immunophenotype
- CD163(+), CD68 (KP1 and PGM1)(+), and lysozyme(+)
- CD45(+), CD45RO(+), and HLA-DR(+)
- CD4(+/-), CD15(+/-)
- Ki-67(+): 5-50% (median: 15%)

Top Differential Diagnoses

Monocytic/myeloid sarcoma
Langerhans cell histiocytosis/sarcoma
Malignant histiocytic tumor, unclassified

CT of neck shows a 10 cm histiocytic sarcoma of soft tissue

, displaying extensive necrosis

. Calcified thyroid cartilage

is noted as a reference. (Courtesy P. Bhosale, MD.)

Histiocytic sarcoma. Low magnification shows diffuse effacement of the nodal architecture.

TERMINOLOGY

Abbreviations

Histiocytic sarcoma (HS)

Synonyms

True histiocytic lymphoma
Extramedullary monocytic tumor
Malignant histiocytosis is historical term
- Not a true synonym as this term encompassed a number of entities

Definitions

Malignant neoplasm composed of mature histiocytes
- Diagnosis mainly based on morphology and immunophenotype
  - Tumor cells are positive for histiocyte-associated markers, such as CD68, CD163, and lysozyme
  - Tumor cells are negative or show minor reactivity for dendritic or follicular dendritic cell markers
Monocytic/histiocytic neoplasms associated with acute myeloid leukemia, myeloproliferative neoplasms, or myelodysplastic syndromes are excluded
- Better considered as monocytic sarcoma

ETIOLOGY/PATHOGENESIS

Postulated Normal Cell Counterpart

Phagocytic histiocyte or macrophage derived from bone marrow monocytes

Etiology

Unknown

Pathogenesis

Histiocytic and monocytic tumors are closely related
Some cases arise as 2nd malignancy after chemotherapy

Concept of “Transdifferentiation”

Patient has both lymphoid and histiocytic tumors that are clonally related
- In most patients, histiocytic tumors follow or are synchronous with lymphoid neoplasms
  - Rare histiocytic tumors precede lymphoid neoplasms
- This occurrence suggests that mature lymphoid cells can switch phenotypes to histiocytic lineage
  - Process may require initial de-differentiation &/or subsequent re-differentiation
Examples in literature include
- HS and follicular lymphoma
- HS and splenic marginal zone lymphoma
- HS and B-lymphoblastic leukemia/lymphoma
- Interdigitating dendritic cell sarcoma (IDCS) and follicular lymphoma
- IDCS and chronic lymphocytic leukemia/small lymphocytic lymphoma
Histiocytic neoplasms associated with follicular lymphoma share
- t(14;18)(q32;q21)/IgH-BCL2 and IgH rearrangements
- Suggests common clonal origin of follicular lymphoma and histiocytic neoplasms
- Supports that lymphoid neoplasms can transform into histiocytic neoplasms
  - An example of lineage plasticity
- This concept also may encompass subset of sporadic histiocytic or dendritic cell sarcomas that
  - Bear monotypic IgH gene rearrangements
  - Show IgH/BCL2 translocation also identified in histiocytes
  - Express B-cell transcription factor Oct-2 but are negative for CD20, CD79a, and PAX-5
Possible mechanisms explaining monoclonal IgH gene rearrangements in HS
- Lineage infidelity of primitive cells, supported by association with germ cell tumors
- Dual genotype of histiocytes, which rearrange B- or T-cell antigen receptor genes
- Artifactual detection of pseudoclones by polymerase chain reaction (PCR)
  - False-positive clonal rearrangements detected when there are too few lymphocytes for analysis
  - Duplicate testing tends to eliminate this artifact
- True small clonal response by nonneoplastic lymphocytes to presence of tumor
- Analysis of microdissected histiocytes may help define origin of clonal gene rearrangements
- There is experimental evidence that immature or committed B cells can give rise to
  - Macrophages, natural killer cells, and T cells

CLINICAL ISSUES

Epidemiology

Incidence
- HS is rare, with only a few cases reported
- Most cases of “malignant histiocytosis” were described before immunohistochemical or molecular studies
  - Most of these cases are now recognized as other neoplasms
  - Most are diffuse large B-cell lymphoma and anaplastic large cell lymphoma
- Cases diagnosed as “histiocytic lymphoma” in Rappaport classification are, in fact, large cell lymphoma
Age
- Wide age range: 1-89 years
  - Median age: 51 years
  - Most cases occur in adults
Gender
- Male to female ratio is 1.2 to 1

Site

Most cases arise in extranodal sites
- Most common: Gastrointestinal tract, soft tissue, skin, spleen, and liver
- Lymphadenopathy is less common

Presentation

Usually presents as painless solitary mass
- Lesions usually present for < 1 year
- Most patients have stage I disease
Systemic symptoms, such as fever and weight loss, in subset of cases
Soft tissue masses may reach up to 12 cm in diameter
Skin manifestations are variable
- Rash is common
- Solitary or numerous lesions
Intestinal involvement may lead to abdominal pain, obstruction, or hematochezia
Bone marrow (BM) involvement is rare
- Association with diffuse BM involvement is better considered as acute monocytic leukemia
  - Subset of cases with patchy BM involvement are considered as HS

Laboratory Tests

There are no diagnostic studies available
- Pancytopenia or 1 or more cytopenias in some patients

Natural History

Clinical course can be indolent or aggressive

Treatment

Patients reported have not been uniformly treated
Surgical excision with wide margins was attempted when feasible
Combined chemotherapy and radiation therapy in subset of patients
- Chemotherapy regimens used have been variable
  - CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)
  - Regimens designed to treat acute leukemia

Prognosis

HS is often aggressive with poor response to therapy
60-80% of patients may die of progressive disease
- Worst prognosis in patients with high-stage disease
Patients with clinically localized disease and small primary tumors have more favorable long-term outcome
- Recurrences in subset of these patients (˜ 20%)

MACROSCOPIC FEATURES

General Features

Solitary mass is most common
Infiltrative margins
Median size: 7 cm (range: 1.8-12 cm)

MICROSCOPIC PATHOLOGY

Histologic Features

Focal or diffuse effacement of nodal or extranodal architecture
- Focal nodal involvement is often paracortical
- Sinusoidal distribution can occur but is uncommon
Soft tissue involvement displays infiltrative borders
- Necrosis is frequent, and its extent is variable
Neoplastic cells are large, noncohesive, and round to oval
- Cells are usually > 20 µm in largest dimension
  - Abundant cytoplasm, usually eosinophilic
- Spindle cells can be present focally
- Hemophagocytosis by neoplastic cells can be present
- Cytoplasmic vacuoles or xanthomatous appearance can be noted in some cases
- Emperipolesis can be present focally
Mitotic figures are conspicuous but variable in number
Nuclei are large; central or eccentric location
- Round to oval, or frequently with irregular folds and pleomorphic
- Chromatin is fine, and nucleoli may be prominent
- Few giant multinucleated cells are common
Usually prominent inflammatory background
- Small lymphocytes, plasma cells, neutrophils, eosinophils, and benign histiocytes
  - When neutrophils are abundant, tumor can mimic inflammatory lesion
  - HS of central nervous system is notorious for heavy neutrophilic infiltrate

ANCILLARY TESTS

Immunohistochemistry

1 or more histiocytic or histiocyte-associated markers are positive
- CD163(+), CD68 (KP1 and PGM1)(+), and lysozyme
  - CD68 and lysozyme: Cytoplasmic &/or Golgi/paranuclear pattern of staining
  - CD163: Membranous and cytoplasmic
- Usually (> 90%) CD45(+), CD45RO(+), and HLA-DR(+)
- CD4(+/-), CD15(+/- and dim)
- S100(+/-): When positive, S100 is expressed in < 25% of neoplastic cells
- Ki-67(+): 5-50% (median: 15%)
- α-1-antitrypsin(+/-), α-1-antichymotrypsin(+/-)
  - Less sensitive and less specific; not widely used
- CD1a(-), langerin/CD207(-)
- Follicular dendritic cell markers(-)
  - CD21, CD23, CD35, and CNA.42
- CD13(-), CD33(-), myeloperoxidase(-)
- Pan-T-cell antigens(-)
- B-cell markers(-)
- Melanoma and carcinoma markers(-)

Flow Cytometry

Commonly positive
- CD4, CD11c, CD45, CD45RO, CD68, CD163, and HLA-DR
Subset of cases positive
- CD11b, CD13, CD15, CDw32, CD36, CD43, Mac387, and factor XIIIa

Cytogenetics

No characteristic findings
Isochromosome 12p in cases associated with germ cell tumors

Molecular Genetics

Usually negative for monoclonal T- and B-cell antigen receptor gene rearrangements
Variable proportion of cases show monoclonal IgH gene rearrangements by PCR
- Histologic and immunophenotypic features are those of usual HS
- Similar gene rearrangements or translocations can occur in HS and preceding B-cell lymphoma
- Postulated to represent examples of “transdifferentiation”

Electron Microscopy

Cells show ample cytoplasm containing variable amounts of lysosomes and phagosomes
Negative for Birbeck granules, desmosomes, or cellular junctions

Enzyme Cytochemistry

Histiocytes are strongly positive for butyrate (nonspecific) esterase
Acid phosphatase(+/-)
Chloroacetate esterase(-)
Myeloperoxidase is usually negative, but it can be weakly positive in subset of cases

DIFFERENTIAL DIAGNOSIS

Monocytic/Myeloid Sarcoma

Neoplasm composed of monocytes
- Usually associated with acute myeloid leukemia, myeloproliferative neoplasm, or myelodysplastic syndrome
- Monocytic or myelomonocytic cell predominant represents approximately 40% of myeloid sarcomas
Small subset of these tumors is composed of large histiocytic rather than monocytic cells
- Some authorities acknowledge 2 subsets of cases with histiocytic cytology
  - HS: Neoplastic cells replace BM in patchy fashion and represent < 25% of cellularity
  - Acute monocytic leukemia: Neoplastic cells diffusely replace BM and represent ≥ 25% of cellularity
Commonly affected sites include lymph nodes, gastrointestinal tract, skin, and soft tissues
Histology and immunophenotype similar to HS
- Less pleomorphic than HS
- Ki-67 usually > 50%
- Myeloperoxidase positive in subset of cases
- Myelomonocytic marker MNDA(+) favors monocytic rather than histiocytic phenotype
- Variably CD56(+)

Langerhans Cell Histiocytosis/Sarcoma

Cytologically bland cells with grooved or twisted nuclei
- Pleomorphic cells in rare cases of Langerhans cell sarcoma
Eosinophils are commonly present
Immunophenotype
- S100 protein(+), CD1a(+), and langerin/CD207(+)
Birbeck granules present by electron microscopy