Chapter 10: Histiocytic and Dendritic Cell
Neoplasms
·
Definition
o
Neoplasms derived
from phagocytes and dendritic cells
o
Neoplasms in WHO
classification
§
Histiocytic
sarcoma
§
Langerhans cell
histiocytosis
§
Langerhans cell
sarcoma
§
Interdigitating
dendritic cell sarcoma/tumor
§
Follicular
dendritic cell sarcoma/tumor
§
Dendritic cell
sarcoma, not otherwise specified
·
Incidence
o
< 1% of tumors
presenting in lymph nodes
o
True histiocytic
malignancy is a “vanishing diagnosis”
·
Epidemiology
o
Detailed data
difficult to obtain because of disease rarity
o
No significant
geographical or racial differences in incidence
·
Pathophysiology
o
Normal cellular
counterparts
§
Phagocytic cells
(antigen-processing)
§
Dendritic cells
(antigen-presenting)
§
Common cellular
origin (BM stem cell), except perhaps follicular dendritic cells
§
Independent lines
of differentiation
·
Histiocytes/Macrophages
o
Primary role:
removal of particulate antigen
o
Derived from the
circulating blood monocyte pool
o
Can demonstrate
phagocytosis
§
Usually not a
feature of histiocytic malignancies
§
More common in
benign proliferations of histiocytes (hemophagocytic syndrome)
o
Markers
§
CD68
§
Acid phosphatase
§
Nonspecific
esterases
§
Most prominent in
epithelioid histiocytes
·
Lysozyme
(decreases with increase in phagocytosis)
·
Alpha-1-antitrypsin
o
Less specific
markers
§
Antibodies to
cell surface receptors for the Fc portion of IgG:
·
CD16, CD32, CD64
§
Complement
receptors:
·
CD21, CD35
§
Cellular
activation and adhesion molecules:
·
CD11a, CD11b, CD11c, CD14, CD18
·
Langerhans
Cells/Interdigitating Dendritic Cells
o
Primary role:
presenting antigens to T lymphocytes
o
Langerhans cells
(LC)
§
Birbeck granules
§
Found primarily
in skin
§
Can migrate to PB
(veiled cells)
§
Enter LNs via
afferent lymphatics; reside in paracortex as interdigitating dendritic cells
o
Langerhans cell immunophenotype
§
MHC Class II
§
S-100
§
CD1a
§
CD4
o
Interdigitating
dendritic cells
§
MHC Class II
§
S-100
·
Follicular
Dendritic Cells (FDC)
o
Primary role:
present antigens to B lymphocytes
o
Most likely not
of hematopoietic origin
o
Found in
follicles where they form a meshwork to trap antigens
o
Contain
iccosomes: antigen-antibody complexes in organelles
o
Needed for B-cell
activation
o
Immunophenotype: CD21+,
CD23+, CD35+
·
Survival
o
Histiocytic
sarcoma and IDC sarcoma
§
Aggressive
§
Potential for
systemic spread
o
FDC tumors
§
Localized
§
Potential for
local invasion and recurrence
§
Distant
metastases are infrequent
o
LC histiocytosis
§
Wide spectrum of
clinical behavior; correlates with extent of organ system involvement and age
of the patient
Hemophagocytic Syndrome (HPS)
·
Recognized as a
clinical syndrome by Scott and Robb-Smith (1939)
·
Non-neoplastic,
proliferative disorder of macrophages
·
Important in DDX
of histiocytic neoplasms
·
More common than
histiocytic neoplasms
·
Immunodeficiency
or other hematopoietic malignancies
·
Fulminant
clinical course (often fatal)
·
Pathogenesis of
HPS
o
Infection with
EBV (or another virus) is a frequent precipitating event
o
Excessive
production of cytokines and chemokines (“cytokine storm”)
o
Profound and
uncontrolled macrophage activation with marked phagocytosis
o
Pancytopenia
Histiocytic Sarcoma
·
Definition
o
Malignant
proliferation of cells showing morphologic and immunophenotypic features
similar to those of mature tissue histiocytes
o
Expression of one
or more histiocytic markers (without dendritic cell markers)
o
Exclusion of
extramyeloid manifestations of acute monocytic leukemia
·
Historical
annotation: virtually all “diffuse histiocytic lymphoma” cases are now DLBCL. Most
cases of “histiocytic medullary reticulosis” and “malignant histiocytosis” are
now considered systemic ALCL or hemophagocytic syndrome
·
Epidemiology
o
Rare (only few
series of bone fide neoplasms)
o
Wide age range
(median 46 years)
o
Male predilection
(in some studies)
o
Subset of cases
associated with prior mediastinal germ cell tumors
o
Other cases
associated with malignant lymphoma (preceding or subsequent), or with
myelodysplasia
·
Sites of
Involvement
o
1/3: Lymph nodes
o
1/3: Skin,
solitary or multiple lesions
o
1/3: Other
extranodal sites (mostly GI)
o
Some patients
present with “malignant histiocytosis” (systemic, multiple sites of
involvement)
·
Clinical Features
o
Systemic symptoms
(fever and weight loss), even in patients with solitary mass
o
Skin
manifestations vary widely
§
Benign-appearing
rash
§
Solitary lesions
§
Innumerable
tumors on trunk and extremities
o
GI lesions
§
Possible
intestinal obstruction
o
Hepatosplenomegaly
(relatively common)
o
Bone
§
Lytic lesions
o
Bone marrow
§
Pancytopenia
·
Etiology: unknown
·
Morphology
o
Effacement of
architecture by a diffuse, non-cohesive proliferation of neoplastic cells
·
Cells
o
Usually
polymorphic
o
Large
o
Round to oval
(spindling focally)
o
Cytoplasm
§
Abundant
§
Eosinophilic
§
May be foamy
o
Nuclei
§
Large
§
Round to oval
§
Eccentric
o
Large
multinucleated cells (common)
o
Vesicular
chromatin
o
Variable atypia
o
Variable number
of reactive cells
§
Small lymphocytes
§
Plasma cells
§
Benign
histiocytes
§
Eosinophils
o
May be
indistinguishable from DLBCL or ALCL
o
Markers necessary
·
Immunophenotype
o
By definition
§
Presence of
histiocytic markers
·
CD68
·
Lysozyme (Golgi pattern)
·
CD11c
·
CD14
§
Absence of
specific myeloid markers
·
MPO
·
CD33
·
CD34
o
Usually positive
§
CD45
§
CD45RO
§
HLA-DR
§
CD4
o
S-100 may be positive (weak or focal)
o
Ki67: variable
(10-90%; mean 20%)
o
Negative
§
B and T-cell
markers
§
LC and IDC
markers (CD1a, CD21, CD35)
§
CD30
§
HMB-45
§
EMA
§
CK
·
Genetics
o
By definition, no
clonal immunoglobulin or TCR genes
·
Postulated Cell
of Origin
o
Mature tissue
histiocyte
·
Prognosis
o
Aggressive
neoplasm
o
Poor response to
therapy
o
High clinical
stage (III/IV) at presentation (70%)
o
60% die of
progressive disease
Langerhans Cell Histiocytosis (LCH)
·
Definition
o
Neoplastic
proliferation of Langerhans cells
o
CD1a+
o
S-100+
o
Birbeck granules
on EM
·
Synonyms
o
Histiocytosis X
(Lichtenstein, 1953)
o
Langerhans cell
granulomatosis
o
Eosinophilic
granuloma
o
Hand-Schüller-Christian
disease
o
Letterer-Siwe
disease
·
Epidemiology
o
~5 per million
o
Childhood
o
Male:female ratio
3.7:1
o
Common in Whites
of Northern Europe descent
·
Sites of
Involvement
o
Unifocal disease
(solitary eosinophilic granuloma)
o
Usually in bones
(skull, femur, pelvis, ribs) and less often lymph nodes, skin, and lung
o
Multifocal,
unisystem disease (Hand-Schüller-Christian disease)
§
Several sites of
involvement in one organ system, usually bone
o
Multifocal,
multisystem disease (Letterer-Siwe disease)
§
Multiple organ
systems: bone, skin, liver, spleen, and LNs
·
Clinical Features
of Unifocal Disease
o
Older children,
adults
o
Lytic bone
lesions (diaphysis) with erosion into soft tissues
·
Clinical Features
of Multifocal, Unisystem Disease
o
Young children
o
Multiple
destructive bone lesions, adjacent soft tissue masses
o
Skull often
involved with exophthalmos, diabetes insipidus, and tooth loss
·
Clinical Features
of Multifocal, Multisystem Disease
o
Infants
o
Fever, skin
manifestations, hepatosplenomegaly, lymphadenopathy, bone lesions, pancytopenia
o LCH
of the lung in adults generally presents as innumerable bilateral nodules, usually
less than 2.0 cm in diameter
·
Etiology
o
Unknown
o
No convincing
evidence for viruses
·
Morphology
o
Langerhans cells
in appropriate milieu
o
Longitudinal
nuclear grooves (twisted, whelk-shaped), inconspicuous nucleoli
o
Inflammatory
background of histiocytes, eosinophils, neutrophils, and lymphocytes
o
Necrotic foci
(eosinophilic abscesses), occasionally
o
Preferential
involvement of the sinuses in lymph nodes, followed by paracortex
o
Red pulp in
spleen
·
Grading
o
Degree of atypia
does not correlate with outcome
·
Ultrastructure
o
Cytoplasmic birbeck
granule
·
Tennis racket-shaped
·
200-400 nm in
length; 33 nm in width
·
Can be absent in
25% of Langerhans cells
o
Lysosomes present
o
Cell junctions
absent
·
Immunophenotype
o
CD1a+ and S-100+
o
Vimentin+ and
CD4+
o
Placental
alkaline phosphatase+ (only neoplastic LCs; normal LCs are negative)
o
Variable stain
for CD45, CD68, and lysozyme
o
(CD34, CD30, MPO,
and EMA negative)
o
Surface adhesion
molecules different in neoplastic and non-neoplastic LCs
o Ki-67
usually stains between 2% to 25% of the LCs with a mean of approximately 10%
·
Enzyme
Cytochemistry
o
Positive for
adenosine triphosphase, α-D-mannosidase, α-naphthyl acetate esterase,
α-naphthyl butyrate esterase, and acid phosphatase
o
Negative for
TRAP, peroxidase, 5'-nucleotidase, and β-glucuronidase, and chloroacetate
esterase
·
Genetics
o
Monoclonal
o
IgH gene, and
beta, gamma, and delta chain genes of the TCR are germline
·
Prognosis
o
Related to organs
involved
o
Absence of bone
lesions with multiorgan involvement is poor prognostic sign
o
Progression of
unifocal to multisystem disease ~10%
o
Unifocal disease
>95% survival
o
75% survival when
2 organs involved
o
Prompt response
to therapy better prognosis
o
LCH of lung can
regress after cessation of smoking
Langerhans Cell Sarcoma
·
Definition
o
Neoplastic
proliferation of Langerhans cells
o
Overtly malignant
cytologic features
o
Can present de
novo or progress from antecedent LCH
·
Epidemiology
o
Rare
o
Adults and
children (median age 41 years)
o
Female
predominance (in contrast to LCH)
·
Sites of
Involvement
o
Multiorgan
involvement
o
Lymph nodes,
liver, spleen, lung and bone
·
Morphology
o
Large malignant
cells
o
Nuclei with
occasional grooves, prominent nucleoli
o
Mitoses high
(>50/10 HPF)
o
Rare eosinophils
(prominent inflammatory infiltrate absent)
o
Sinusoidal
pattern in lymph nodes
·
Ultrastructure
o
Birbeck granules
can be identified
·
Immunophenotype
o
CD1a+ and S100+
o
CD1a may be focal
o
Some expression
of CD68, CD45 and lysozyme
o
Ki-67 ranges from
10% to 60% with a median of 22%
·
Prognosis
o
Aggressive
o
Overall survival
~50%
Interdigitating Dendritic Cell
Sarcoma/Tumor
·
Definition
o
Neoplastic
proliferation of spindle to ovoid cells with phenotypic features of IDCs
o
Term
tumor/sarcoma is used because of the variable cytological grade and clinical
behavior encountered in these neoplasms
·
Synonyms
o
Reticulum cell
sarcoma/tumor.
o
Interdigitating
cell sarcoma/tumor.
·
Epidemiology
o
Extremely rare
neoplasm
o
Most studies
represent single cases or very small series
o Largest
series consisted of 4 cases
o
Mostly elderly
adults with no sex predilection
·
Sites of Involvement
o Wide
presentation
o Solitary
LN (most common)
o Skin,
intestinal, soft tissue, and hepatosplenomegaly been reported
·
Clinical features
o Usually
asymptomatic mass
o Systemic
symptoms: fatigue, fever, night sweats
o Complete
remission after localized treatment
·
Etiology
o Unknown
·
Morphology
o Paracortical
distribution with residual follicles
o Usually
forms fascicles, a storiform pattern, and whorls of spindled to ovoid cells
o Usually
abundant slightly eosinophilic cytoplasm, often indistinct border
o Vesicular
chromatin, small to large distinct
·
Immunophenotype
o S-100
+
o Negative
for vimentin and CD1a
o Variably,
weakly + for CD68, lysozyme, and CD45
o Negative
for FDCs (CD21 and CD35), MPO, CD34, specific B and T-cell antigens, CD30, CK,
EMA
·
Prognosis and predictive factors
o Range
from benign localized disease to widespread lethal disease
Follicular Dendritic Cell Sarcoma/Tumor
·
Definition
o
Neoplastic
proliferation of spindle to ovoid cells showing morphologic and phenotypic
features of follicular dendritic cells
o
Term
sarcoma/tumor is used because of the variable cytologic grade and indeterminate
clinical behavior in many cases
·
Synonyms
o
Reticulum cell
sarcoma/tumor
o
Dendritic
reticulum cell sarcoma/tumor.
·
Epidemiology
o
Rare neoplasm
o
Most studies are
single case reports or small series
o
The largest
series consisted of 13 and 17 cases
o
Wide age range,
with an adult predominance
o
Equal sex distribution
o
Association with
Castleman disease in 10-20% of the cases, usually hyaline vascular type
o
Castleman disease
may precede the tumor occur simultaneously
o
May be an
increased incidence in patients with treatment for longstanding schizophrenia
·
Sites of involvement
o In
LNs (between one-half to two-thirds of cases)
o Cervical
LNs most often affected
o Also
common LNs: maxillary, mediastinal, mesenteric and retroperitoneum
o Extranodal
sites: tonsil, spleen, oral cavity, GI tract, liver, soft tissue, skin, and breast
o Common
sties of metastasis: LNs, lung, and liver
·
Etiology
o Unknown
·
Morphology
o Spindle
to ovoid cell proliferation
o Forms
fascicles, storiform patterns, and whorls
o Uncommon,
fluid-filled cystic spaces, some in perivascular location resembling thymoma,
or amyloidal changes
o Cells
with plump slightly eosinophilic cytoplasm and indistinct cell borders
o Nuclei
elongated, with vesicular or granular finely dispersed chromatin, small but
distinct nucleoli
o Occasional
multinucleated cells, occasionally resembling Warthin-Finkeldy giant cells
o Pseudonuclear inclusions may be seen
·
Immunophenotype
o Generally
demonstrate the phenotype of non-neoplastic FDCs
o Positive
for one or more of the FD markers, including CD21, CD35, and CD23
o Usually
positive for desmoplakin, vimentin, fascin, HLA-DR, and often positive for EMA
o Variably
positive for S-100 and CD63
o CD45
and CD20 occasionally expressed
o Negative
for CD1a, lysozyme, MPO, CD34, CD3, CD79a, CD30, HMB-45, and CKs
o Ki-67
range from 1% to 25 % with a mean value of 13%
·
Prognosis and predictive factors
o Behavior
typically indolent
o Treatment
with complete surgical excision, with or without adjuvant radiotherapy or
chemotherapy
o Local
recurrences in about 40% to 50 % and metastasis in about 20% of pts often after
local recurrence
o Poorer
prognosis: intra-abdominal presentation, significant cytologic atypia,
extensive coagulative necrosis, high proliferation index, large tumor >6cm
o 10%
to 20% pts die of disease, often after a long time
Dendritic Cell Sarcoma, Not Otherwise
Specified
·
Definition
o
Occasional
dendritic cell neoplasms do not fall into well-defined categories, as defined
in the previous sections
o
Have been called
indeterminate cell sarcoma/tumor
o
Extremely rare
cases reported
o
Dx of exclusion,
not well characterized morphologically and immunophenotypically
o
Tumors positive
for CD1a and S-100 protein but without Birbeck granules have been called
indeterminate neoplasms said to derive from a cell in transition between a
Langerhans cell and an interdigitating dendritic cell
o
In a recent large
series with multiple markers and EM no cases of this category were found