Page 815 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 34 Miscellaneous Tumors 793

interstitial DCs. 484 Cytokines and growth factors that influence DC performed in unfixed cytologic smears or snap frozen tissues, or by
development include FLT3 ligand, granulocyte-macrophage colony flow cytometry. Important markers for the dissection of the histio-
cytic lineage that are only detectable in fresh smears or snap frozen
stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-
VetBooks.ir α), interleukin-4 (IL-4), and transforming growth factor-beta tissues include CD1a, CD11b, CD11c, CD80, and CD86. It is
possible to presumptively identify histiocytes in formalin fixed par-
Macrophage development from CD34 precursors
(TGF-β).
484,485
+
is influenced by GM-CSF and macrophage colony stimulating fac- affin embedded (FFPE) tissues by using combinations of lymphoid
tor (M-CSF). Blood monocytes can differentiate into either mac- markers coupled with CD18 and CD11d staining (Table 34.4) in
rophages under the influence of M-CSF, or into DCs under the an appropriate morphological context. Additional useful markers of
influence of GM-CSF and IL-4. 484,486,487 histiocytic lineage in FFPE tissues include Iba-1 (ionized calcium
Dendritic cells are the most potent antigen presenting cells binding molecule-1), the macrophage class A scavenger receptors
(APC) for induction of immune responses in naïve T cells. The (CD163 and CD204), and E-cadherin. Iba-1 identifies macro-
development of canine specific monoclonal antibodies for func- phages and DCs, whereas the class A scavenger receptors are largely
tionally important molecules of DCs and macrophages has expressed by macrophages in normal tissues. 499 However, the scav-
enabled their identification in canine tissues, especially skin. 481,488 enger receptors, CD163 and CD204, are also expressed by DC sub-
Dendritic cells occur in two major locations: within the epidermis sets in some species. 500,501 The potential exists for coexpression of
(LCs), and within the dermis, especially adjacent to postcapillary class A scavenger receptors on DCs in diseased tissue. Alternatively,
venules (dermal interstitial DCs). 489 Canine DCs abundantly there is some evidence for mixed lineages in HS, particularly in the
express CD1a molecules which, together with MHC class I and central nervous system of dogs. 502
MHC class II molecules, are responsible for presentation of pep-
tides, lipids, and glycolipids to T cells. 481,482,490 Hence, DCs are Cutaneous Histiocytoma
best defined by their abundant expression of molecules essential
to their function as APC. Of these, the family of CD1 proteins is Cutaneous histiocytoma is a benign tumor of Langerhans cells
largely restricted in expression to DCs in skin, whereas MHC class that often occurs as a single lesion in young dogs (<3 years of
I and II are more broadly expressed. age), although histiocytomas do occur in dogs of all ages. In a
The beta-2 integrins (CD11/CD18) are critically important retrospective review from the United Kingdom of histopathologic
adhesion molecules, which are differentially expressed by all leu- diagnoses of neoplasia in dogs less than 1 year, CH was the most
kocytes. CD11/CD18 expression is highly regulated in normal common diagnosis, representing 89% of 20,280 submissions. 503
canine macrophages and DCs. CD11c is expressed by LCs and These tumors typically present as a solitary raised pink skin mass,
interstitial DCs, whereas macrophages predominately express often in the cranial portion of the body. The growth of the lesion
CD11b (or CD11d in the splenic red pulp and bone marrow). can be quite rapid (1–4 weeks), but tumors usually spontane-
A subset of dermal interstitial DCs also express CD11b. 491–493 ously regress within 1 to 2 months of presentation. 503–509 IHC is
In diseased tissues, these beta-2 integrin expression patterns may rarely necessary to diagnose histiocytomas; however, expression of
be broadened. Langerhans cells and dermal interstitial DCs are E-cadherin is unique to histiocytomas and can help differentiate
also distinguishable by their differential expression of E-cadherin histiocytomas from reactive histiocytosis (CH, SH). 479,482,510,511
(LCs+) and Thy-1 (CD90) (dermal interstitial DCs+). Langerhans When necessary, this differentiation can be made based on IHC or
cells localize within epithelial tissue via E-cadherin homotypic flow cytometry. The factors that determine the onset of regression
adhesion with E-cadherin expressed by epithelial cells. 485 in canine histiocytomas are unknown. Regression may be rapid or
+
Migration of DCs (as veiled cells) beyond the skin to the paracor- delayed for many months. Regression is mediated by CD8 αβT
tex of LNs, where they join forces with interdigitating DCs, occurs lymphocytes. 478,482 Migration of tumor histiocytes and/or tumor
after contact with antigen. Successful interaction of DCs and T cells infiltrating reactive interstitial DC to draining LNs likely activates
in response to antigenic challenge also involves the orderly appear- CD4 T cells, which would assist in CD8 cytotoxic T-cell recruit-
+
+
ance of costimulatory molecules (B7 family—CD80 and CD86) ment. Because massive CD8 T-cell infiltration is observed with
+
on DCs and their ligands (CD28 and CTLA-4) on T cells. 494–496 histiocytoma regression, immunosuppression should be avoided
In situ DCs have low expression of MHC class II and costimulatory once a definitive diagnosis of histiocytoma has been reached to
molecules and are more receptive to antigen uptake. Migratory DCs avoid interference with cytotoxic T-cell function. E-cadherin
upregulate MHC class II and B7 family members and become more expression has been found to be associated with lymphoid infil-
adept at antigen presentation to T cells. 495,496 trate and stage of regression of histiocytomas. 512 Cases of multiple
Aspects of the developmental and migratory program of DCs or metastatic histiocytomas are rare and may require IHC to dif-
are recapitulated in canine histiocytic diseases. Defective interac- ferentiate from lymphoma or other round cell tumors if cells are
tion of DCs and T cells appears to contribute to the development poorly differentiated. These cases are usually classified as cutane-
of reactive histiocytoses (cutaneous histiocytosis [CH] and sys- ous Langerhans cell histiocytosis (LCH). 478
temic histiocytosis [SH]), which are related interstitial DC dis-
orders arising out of disordered immune regulation. The distant Cutaneous Langerhans Cell Histiocytosis
migratory potential of DCs is of immense clinical significance in
the adverse prognosis of histiocytic sarcomas (HSs), which largely Cutaneous LCH is a disease comprising multiple or diffuse cuta-
originate in interstitial DCs and rapidly disseminate. neous tumors of LC origin with or without metastasis to LNs or
internal organs. 478,513,514 Lesions are identical morphologically
Immunophenotyping and immunohistochemically to histiocytomas, but may have
more cytologic atypia. Cutaneous LCH limited to skin appears to
To classify hematopoietic neoplasia according to the WHO sys- be more common in Shar Pei dogs, but can occur in any breed.
tem as applied to the dog, it is important to have access to mark- Delayed regression of cutaneous LCH can occur, even in cases
ers for IHC analysis. 497,498 Determination of lineages of histiocytes with widespread disease, and may be delayed for up to 10 months
(macrophages, interstitial type DCs, and Langerhans cells) is best before onset of regression. In the authors’ experience, lesions do