Histiocytic Diseases: A Mystery Unraveled

February 24, 2016

Brooke Fowler, DVM, DACVIM
Oncology Specialist

For oncologists and general practitioners alike, proliferative histiocytic diseases are some of the most frustrating and complicated cases out there. The frustration lies in the diagnosis of this disease process, prediction of outcomes, but also in our ability to effectively treat these diseases. The development of histiocytic markers has better enabled us to figure out the pathophysiology of these diseases and occasionally to better diagnose these diseases and predict outcomes.

Histiocytes differentiate from bone marrow cell precursors and eventually terminate in dendritic cell or macrophage lineages. The general responsibility of these cells is antigen presentation and phagocytosis. This integral physiologic function that these cells maintain is relevant, however one can see where these “talents” can be used for ultimate harm when these cells turn neoplastic. There are 4 distinct syndromes that occur in the canine patient. These 4 syndromes (not all cancer) are all different depending on the type of dendritic cell or macrophage that has undergone a reactive or neoplastic process. IHC can differentiate which of the cell lineages has caused the problem to help differentiate neoplastic processes from more benign and treatable processes.


Most of you know histiocytomas as a benign tumors of younger dogs. This single lesion often occurs in dogs < 3 years of age.   These lesions often occur on the cranial aspect of the body. Multiple tumors and metastatic histiocytomas have been reported (just to keep this confusing!). Cytology can often provide the answer, but definitive answers can be provided by biopsy and IHC (immunohistochemical staining).  The tumor typically manifests in the skin and regresses on its own. The regression can take weeks or even months.  Contrary to popular belief stimulation of the immune system may make regression of these tumors slower ( not faster) since it may interfere with cytotoxic T cell action. Keep this as a differential if your patient is young, although these tumors may arise at an older age.

Cutaneous langerhaans cell histiocytosis:

Cutaneous histiocytosis is a process that is limited to the skin and draining lymph nodes. The cells that cause this disease are langerhaans cells. Breeds most commonly represented are Shar-pei dogs but any breed can be represented. Lesions can take up to 10 months for regression and because of the significant cutaneous involvement dogs are commonly euthanized due to lack of regression and complications in management of the ulcerative lesions. Lymph node metastasis has a poorer prognosis since spontaneous regression is les s likely. Anecdotal responses to Tyrosine kinase inhibitors or lomustine have been reported.


This disease process can be separated into cutaneous histiocytosis (not to be confused with the above-mentioned cutaneous langerhaans histiocytosis) and systemic histiocytosis. Cutaneous histiocytosis is limited to skin and subcutis. Lesions can be seen on the nasal planum and mucosa. This can often manifest as swelling of the nose and sturturous breathing. Small studies have been completed but those studies reveal that breed predilections may include Bouvier De Flanders, Golden retrievers, and Great Danes. Cutaneous histiocytosis follows a benign course and often is responsive to immunosuppressive therapies. Long term survival is possible with treatment with steroids, leflunomide, tetracyclines, niacinamide, safflower oil, vitamin E, azathioprine and a few other anecdotal remedies. Again, look for the nasal inflammation and biopsy to determine direct cause.


Systemic histiocytosis is a non-neoplastic disease of circulating histiocytes. Presentation can be similar to cutaneous histiocytosis but systemic spread to visceral organs, lymph nodes, and ocular involvement will tip off the fact that this is a systemic disorder. Genetic predisposition is throught to occur in Rottweilers, Bernese mountain dogs, Golden retrievers, and Irish wolfhounds. Hypercalcemis is a possible finding on routine bloodtests. Cytologically this disease is similar to cutaneous histiocytosis. These lesion will express alternative markers on histopathology indicating that the cell of origin is different. Lesions have a waxing and waning appearance but do not resolve spontaneously. The clinical course of this disease is long and usually requires long-term immunosuppressive therapies centered around modulating T lymphocytes. Remember, many of the breeds involved in this disease process are also have genetic predispositions to neoplastic conditions so make sure the disease process is not more benign before assigning a fatal or poor prognosis.


Malignant proliferations of histiocytic cells comprise this disease. This disease can manifest as a solitary mass (similar to a sarcoma)—often around a joint– or can be a disseminated disease process. A subset of this disease called, hemophagocytic syndrome, can arise. These cells are macrophages and not dendritic cells and often manifest by phagocytisizing host red blood cells or platelets. The clinical course of disseminated histiocytic sarcoma is rapid and fatal. Survival times surrounding amputation of an affected limbs for solitary masses is around 6 months with metastatic rates of 91%. The periarticular form of this disease may have a slightly better prognosis with median survival times of around 1 yr. Lomustine ( CCNU) appears to be the most affective chemotherapy in dogs. Studies have reported a 46% response rate. Some studies report lengthy survival times associated with solitary histiocytic sarcomas.