Histiocytoma is a common, benign, cutaneous neoplasm of the dog. Histiocytomas usually occur as solitary lesions which undergo spontaneous regression. The age specific incidence rate for histiocytomas drops precipitously after 3 years, although histiocytomas do occur in dogs of all ages. Reports of recurrence of histiocytomas at the same or other sites are rare; and the occurrence of multiple tumors is considered unusual. Epidermal invasion by cells of histiocytoma frequently occurs and intra-epidermal nests of histiocytes resemble Pautrier's aggregates, characteristically found in epidermotropic lymphoma (Mycosis Fungoides or MF). Epidermal invasion in histiocytoma, or presence of simultaneous multiple histiocytomas especially in aged dogs can present a diagnostic dilemma and distinction from MF and non-epidermotropic cutaneous lymphoma (NECL) is difficult on purely morphological grounds.

 




Histiocytomas on ear margins

  Histiocytomas on ear margins of Boxer


Histiocytoma Topography

  The infiltrate occupies the superficial dermis and extends to the subcutis. Epidermal invasion (individual cells or nests) are seen in about 60% of lesions.


Histiocytoma (20x)

  Histiocytes (20x) infiltrate the superficial dermis and invade the epidermis. Infiltrating lymphocytes herald the onset of regression.


Histiocytoma (100x)

  Histiocytes (100x) have abundant cytoplasm and round to ovoid or complexly folded nuclei; mitotic figures may be numerous.


Cutaneous T cell lymphoma

  T cells in this lesion have abundant clear cytoplasm and are easily confused with histiocytes seen in histiocytoma. A CD3 stain would clearly resolve this dilemma.

 




Multiple histiocytomas are also readily confused with cutaneous histiocytosis on clinical appearance, although morphologically, histiocytomas are consistently epidermotropic and commonly epidermally invasive, these are not features of cutaneous histiocytosis. Multiple histiocytomas appear to be more common in Shar Peis (Moore, unpublished data), but can occur in any breed. Delayed regression of multiple histiocytomas can occur
and lesions can persist for up to 10 months.


Multiple Histiocytomas

  Multiple Histiocytomas on the right hind limb of a 2 year old Shar Pei. The lesions regressed after a 10 month course - large ulcerated lesions were surgically removed; others were left undisturbed.

 




Metastatic histiocytoma

Recently, we have observed several cases of histiocytoma in which histiocytes had migrated to draining lymph nodes and completely obliterated them. Pathologists diagnosed histiocytic sarcoma in these instances and prognosis was reported as poor. In 3 instances regression of these lesions occurred spontaneously within 3 -4 weeks. In other instances the metastatic lesions of histiocytoma failed to regress and dogs were euthanized. The disease course in these cases extended over several months. Spread beyond lymph nodes to lung has also been observed in some of these cases. These complications are rare.





Histiocytoma Metastasis

  Histiocytoma metastasis to lymph node in a 12 week old Boxer. The lymph node was obliterated by tumor. Lesions spontaneously regressed in about 4 weeks.


Histiocytoma in lymph Node

  Afferent lymphatics and subcapsular sinuses are expanded by histiocytes; paracortical infiltrates were extensive and obliterated normal architecture (not shown).




 

Langerhans cell Histiocytosis
The presence of multiple histiocytomas is now a well recognized syndrome. However, there is yet another presentation in which widespread cutaneous lesions histologically identical to histiocytoma are observed. Clinically, the lesions are almost confluent in affected regions. Rapid internal spread is observed and the affected animals have all been euthanized. There is one published account of such a case, and we have data on 3 dogs with what appears to be an identical syndrome.





Canine LCH

  Dachshund; Note the discrete nodular lesions on the muzzle and the confluent masses along the mucocutaneous junctions - eyelids and lips.


Canine LCH

  West Highland White Terrier; Multiple discrete to coalescing nodular lesions on the ventral abdomen.


Canine LCH

  Pulmonary perivascular infiltrates.

 






Immunophenotypic Studies
Immunohistochemistry (IHC) is best performed on frozen sections of tumor (not formalin fixed material!). Histiocytoma is readily distinguished from other histiocytic disorders and cutaneous lymphoma with the aid of IHC. Our work has clearly shown that histiocytomas have the phenotype of epidermal Langerhans cells. They express CD1a, CD1b, CD1c, MHC class II, CD11c, and E-cadherin. Amongst leukocytes, E-cadherin expression is unique to Langerhans cells. Langerhans cells utilize E-cadherin to localize in the epidermis via homotypic interaction with E-cadherin expressed by keratinocytes. Histiocytomas lack expression of CD4 and Thy-1, which are consistently expressed by histiocytes in cutaneous and systemic histiocytosis. Hence cutaneous histiocytoma is a localized epidermal Langerhans cell tumor, and the rare examples of systemic spread of histiocytoma are best characterized as Langerhans cell histiocytosis (LCH) similar to that observed in humans.





Epidermal Langerhans Cell

  Distinctive surface markers and chemokine receptors.


Histiocytoma, CD1c

  Histiocytes diffusely express CD1c.


Histiocytoma, Thy1

  Histiocytes lack expression of Thy-1.


Histiocytoma, E-cadherin

  Histiocytes adjacent to epidermis express E-cadherin. Expression level falls in histiocytes deeper in the dermis.
 




Regression of Histiocytomas

The factors that determine the onset of regression in canine histiocytomas are unknown. Evidence of regression is usually observed in lesions that have been present for only a few weeks, although regression can be delayed for many months in problem cases. Regardless, regression is mediated by CD8+ alpha beta T cells; only scant numbers of CD4+ T cells are observed in histiocytoma lesions. By implication, the stringent co-stimulatory requirements of CD8+ cytotoxic, effector T cells must have been met for them to mediate regression. This could occur in several ways. Migration of tumor histiocytes and/or tumor infiltrating reactive DC to draining lymph nodes could activate CD4+ T cells, which would assist in CD8+ cytotoxic T cell recruitment and activation via exogenous IL-2. Alternatively, tumor histiocytes may undergo local differentiation and upregulate co-stimulatory molecules of the B7 family (CD80 and CD86), and thereby directly activate CD8+ cytotoxic T cells, and mediate their own destruction. Studies are currently underway to test the latter hypothesis.





Histiocytoma early regression

  Lymphoid infiltrate among histiocytes in superficial dermis.


Histiocytoma in advanced regression

  Intense lymphoid infiltrate among histiocytes in the deep dermis.


Histiocytoma in advanced regression, CD8

  Infiltrating lymphocytes are CD8+ (shown) and CD3+ (not shown)T cells.



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