A mastocytoma in dogs (or mast cell tumor in dogs) is a neoplasm (neoplasia) originating from mast cells in the domestic dog, which occurs mainly in the skin and subcutis. Mastocytoma are not only extremely common in dogs, but also tend to be much more malignant in them than in other animal species. The average survival time for malignant tumors is only four months, whereas for benign tumors it is over two years.
Mast cells are cells of the immune system that play a role in the innate immune response. They produce a number of biologically active substances, including primarily histamine. Mastocytoma account for about one-fifth of all skin tumors in dogs. They present as nodules or raised patches, and about one-fifth of affected animals have ulcers and bleeding in the stomach and duodenum. Metastasis in malignant mastocytoma occur primarily in lymph nodes, liver, spleen, and bone marrow. Any lump in the skin or subcutaneous tissue can be a mastocytoma. Detection is only possible by taking tissue with a fine needle (fine needle biopsy) followed by staining and microscopic examination (cytopathology).
Although the classifications according to the clinical appearances and cell appearance in cytodiagnostics give indications of the biological behavior (benign or malignant) and thus the prospect of cure, this tumor disease is unpredictable and should be treated at an early stage. The treatment of choice is complete surgical removal, possibly combined with radiotherapy or chemotherapy. Tumors for which surgical removal is not possible or only incompletely possible can also be treated with tyrosine kinase inhibitors.
Mastocytoma are also more common in domestic horses, ferrets, and domestic cats, but usually behave benignly in these species. In other animal species and in humans, mastocytomas are very rare.
Mast cell
Mast cells (mastocytes) are cells of the immune system and represent an important link between the innate and acquired immune response. They arise from precursor cells in the bone marrow and migrate as immature cells to many tissues, especially those in close contact with the outside world, where they differentiate.
Mature mast cells are roundish cells in connective tissue whose cytoplasm contains granules with deviating staining behavior (metachromasia). The granules are stored histamine, heparin as well as cytokines such as tumor necrosis factor-a. On the cell surface, mast cells bear binding sites (receptors), two of which are functionally most important: The stem cell factor receptor (tyrosine kinase KIT) regulates mast cell differentiation, proliferation, activation and lifespan via stem cell factor binding. The immunoglobulin receptor FcεRI (high-affinity IgE receptor) binds immunoglobulin E (IgE) with high binding strength (affinity).R. J. Mayoral et al.: MiR-221 influences effector functions and actin cytoskeleton in mast cells. In: PloS one. Band 6, Nummer 10, 2011, p. e26133, . doi:10.1371/journal.pone.0026133. PMID 22022537. . Not only stem cell factor, but also a number of interleukinsC. P. Shelburne und J. J. Ryan: The role of Th2 cytokines in mast cell homeostasis. In: Immunological Reviews. Band 179, Februar 2001, pp. 82–93, . PMID 11292031. (Review). and ultraviolet radiationS. Ch'ng et al.: Mast cells and cutaneous malignancies. In: Modern Pathology. Band 19, Nummer 1, Januar 2006, pp. 149–159, . doi:10.1038/modpathol.3800474. PMID 16258517. (Review). lead to activation and proliferation of mast cells. When mast cells are activated, they either release inflammatory mediators, cytokines, and proteases from the granules or produce and release new ones in a short period of time.
The function of mast cells is best understood in allergies, and they are also involved in autoimmune diseases and in enhancing inflammatory responses in bacterial infections. On the other hand, mast cells may also have anti-inflammatory effects by protecting against damaging factors such as bacteria and parasites.S. J. Galli, M. Tsai: Mast cells in allergy and infection: versatile effector and regulatory cells in innate and adaptive immunity. In: European Journal of Immunology. Band 40, Nummer 7, Juli 2010, pp. 1843–1851, . doi:10.1002/eji.201040559. PMID 20583030. (Review). In addition, mast cells may contribute to the development and growth of other skin tumors due to their large repertoire of biologically active substances.
Occurrence and origin Mastocytomas in dogs occur mainly in the skin and subcutaneous tissue. Very rarely, they are found in internal organs such as the small intestine,Erwin Dahme und Eugen Weiss: Grundriss der speziellen pathologischen Anatomie der Haustiere. 6. Auflage, Parey Verlag, Stuttgart 2007, , p. 143. the mucosa of the mouth,L. A. Hillman, et al.: Biological behavior of oral and perioral mast cell tumors in dogs: 44 cases (1996–2006). In: Journal of the American Veterinary Medical Association. Band 237, Nummer 8, Oktober 2010, pp. 936–942, . doi:10.2460/javma.237.8.936. PMID 20946081. the nasal mucosaA. K. Patnaik et al.: Extracutaneous mast-cell tumor in the dog. In: Veterinary pathology. Band 19, Nummer 6, November 1982, pp. 608–615, . PMID 6815869. or the conjunctiva.M. Fife et al.: Canine conjunctival mast cell tumors: a retrospective study. In: Veterinary ophthalmology. Band 14, Nummer 3, Mai 2011, pp. 153–160, . doi:10.1111/j.1463-5224.2010.00857.x. PMID 21521438. About 20% of all skin tumorsMartin Kessler: Mastzelltumoren, Mastozytom (Mastzellsarkom). In: Hans Georg Niemand, Peter F. Suter (Hrsg.): Praktikum der Hundeklinik. 10. Auflage, Parey Verlag, Stuttgart 2006, , pp. 1135–1136. and 6% of all tumorsAnthony S. Stannard und L. Thoma Pulley: Mastocytoma of the dog. In: Jack E. Moulton (Hrsg.): Tumors in domestic animals. 2. Auflage, University of California Press, Berkeley [u. a.] 1978, , pp. 26–31. in dogs are mastocytomas. They occur more frequently in some breeds: German Boxer and related short-headed breeds, Golden Retriever, Beagle, Irish Setter, Dachshund and Bernese Mountain Dog. There is no dependence on the sex of the animal.F. Riva et al.: A study of mutations in the c-kit gene of 32 dogs with mastocytoma. In: Journal of veterinary diagnostic investigation. Band 17, Nummer 4, Juli 2005, pp. 385–388, . PMID 16131001. The median age of affected dogs is eight years, but a mastocytoma can develop in dogs as young as four months old or at a very advanced age.
In humans, a number of mutations and chromosomal alterations are known to lead to pathological proliferation of mast cells (mastocytoses). Mutations of the gene for the stem cell factor receptor (c-KIT) lead to prolonged cell life and increased formation of new mast cells. The D816V mutation is the most common of these c-KIT mutations and occurs in 80% of patients with mastocytosis. However, there are also mastocytosis patients without alterations in the stem cell factor receptor. In total, there are over 20 known chromosomal alterations in humans that can lead to mastocytosis, with chromosomes 2, 7, 12, 13, 14, and X being most commonly affected.H. Sadrzadeh, O. Abdel-Wahab, A. T. Fathi: Molecular alterations underlying eosinophilic and mast cell malignancies. In: Discovery medicine. Band 12, Nummer 67, Dezember 2011, pp. 481–493, . PMID 22204765.
In dogs, c-KIT alterations also appear to play a role. Both increased gene expression and a mutation with phosphorylation of the stem cell factor receptor leading to activation without binding of the stem cell factor (ligand-independent) can occur. More than 30 such mutations are now known, the most common of which is a duplication (tandem mutation) of exon 11, which encodes the portion of the stem cell factor receptor located directly on the inside of the cell membrane (juxtamembrane domain).Y. Takeuchi et al.: Aberrant autophosphorylation of c-Kit receptor in canine mast cell tumor cell lines. In: Veterinary immunology and immunopathology. Band 137, Nummer 3–4, Oktober 2010, pp. 208–216, . doi:10.1016/j.vetimm.2010.05.009. PMID 20591500. However, mastocytomas without c-KIT mutations also occur in dogs;K. Ohmori et al.: Identification of c-kit mutations-independent neoplastic cell proliferation of canine mast cells. In: Veterinary immunology and immunopathology. Band 126, Nummer 1–2, November 2008, pp. 43–53, . doi:10.1016/j.vetimm.2008.06.014. PMID 18687474. in contrast to US studies, almost no relevant c-KIT mutations were even detected in mastocytomas of German dogs. Whether this was coincidental or methodological or reflects genetic differences in breeding lines needs to be clarified by further investigations.Heike Aupperle et al.: Neue diagnostische Aspekte bei kaninen Mastzelltumoren – Ein Überblick zur aktuellen Studienlage. In: kleintier konkret. S1 (2011), S. 44–48. (Complete text, memento from August 13, 2012) The causes for the clustered occurrence of mastocytoma in dogs are so far unexplained, presumably there are several causes (multifactorial events).M. M. Welle et al.: Canine mast cell tumours: a review of the pathogenesis, clinical features, pathology and treatment. In: Veterinary dermatology. Band 19, Nummer 6, Dezember 2008, pp. 321–339, . doi:10.1111/j.1365-3164.2008.00694.x. PMID 18980632. (Review).
Clinical image
Mastocytomas of the skin present as nodules (papules), raised patches (plaques), or nodules (nodus), which may be superficially ulcerated. Their consistency ranges from soft to coarse-nodular. Locally, redness and itching may occur (Darier's sign). Occasionally, satellite nodules occur, i.e., metastasis of the tumor via lymphatic vessels into neighboring skin areas;James Warland und Jane Dobson: Hauttumore bei Hunden und Katzen. In: Veterinary Focus. Band 21, 2011, pp. 34–41. in about 10% of cases, multiple mastocytomas are formed from the outset (primary multiplicity).Martin Kessler: Der Mastzelltumor des Hundes: ein Tumor mit vielen Gesichtern.
Mastocytomas can form daughter tumors (metastases) to the (regional) lymph nodes responsible for the area as well as to other organs such as the liver, spleen, and bone marrow; other locations are very rare. The metastasis rate for benign mastocytomas is less than 10%; for malignant tumors, it is more than 50%.
Even without the formation of daughter tumors, a mastocytoma can trigger severe general disorders (paraneoplastic syndrome). These are triggered by the release of inflammatory mediators and cytokines. The production of heparin by the mast cells can lead to an increased tendency to bleed, and as a result of the production of fibroblast-inhibiting cytokines (especially FGF-2), to the disruption of wound healing processes. In about one fifth of the dogs with a mastocytoma, feeding instability, vomiting, tarry stools and anemia occur as a result of gastric or duodenal ulcers, in autopsies such ulcers are even detected in more than 80% of patients. About 80% of the dogs with such ulcers are euthanized due to poor general condition.C. Guillermo Couto: Mast cell tumors in dogs and cats. In: Richard W. Nelson und C. Guillermo Couto (Hrsg.): Small animal internal medicine. 3. Auflage, Mosby, St. Louis 2003, , pp. 1146–1149. In particularly severe cases, these ulcers can lead to a life-threatening gastric or intestinal rupture. In addition, a clinical picture reminiscent of a malignant disease of the hematopoietic system can occur. This systemic mastocytosis is observed mainly in animals in which a mastocytoma has previously been removed. It is accompanied by lassitude, aversion to feeding, vomiting, weight loss, pallor, and enlargement of the liver and spleen.
According to the clinical picture, mastocytomas are classified into four stages according to the criteria of the World Health Organization:Martin Kessler: Kleintieronkologie: Diagnose und Therapie von Tumorerkrankungen bei Hunden und Katzen. 2. Auflage, Parey Verlag, Stuttgart 2005, , pp. 210–215. +Stage 1a tumor confined to the skin without lymph node involvement