October 2019



Slide A

Signalment (JPC 2799364): Age and breed unspecified cat




HISTOPATHOLOGIC DESCRIPTION: Subcutis (per contributor): Infiltrating the subcutis and compressing the panniculus carnosus is a 1.0 x 0.8 cm, unencapsulated, multilobulated, densely cellular neoplasm composed of spindle cells arranged in long interlacing streams and bundles separated by moderate fibromyxomatous matrix. Neoplastic cells have indistinct borders, a small amount of eosinophilic fibrillar cytoplasm, and an oval to elongate nucleus with finely stippled chromatin and1-3 prominent magenta nucleoli. There is moderate anisocytosis and anisokaryosis and multifocal single cell necrosis. Mitotic figures average 1 per 400x HPF. Multifocally there are peripheral peri-tumoral and perivascular aggregates of macrophages that often contain intracytoplasmic, blue-gray, clumped, granular to globular material (vaccine material). These macrophages are admixed with often nodular aggregates of lymphocytes and fewer plasma cells and neutrophils. There is rare degeneration and atrophy of subjacent myocytes.


MORPHOLOGIC DIAGNOSIS: Subcutis (per contributor): Injection site-associated fibrosarcoma, breed unspecified, feline.


SYNONYMS: Feline injection site sarcoma; formerly known as feline vaccine-associated sarcoma, feline postvaccinal sarcoma


Slide B

Signalment (JPC 2800486): A domestic longhair cat




HISTOPATHOLOGIC DESCRIPTION: Subcutis (per contributor): Expanding the subcutis is an 8 x 10 mm nodule characterized by a central pseudocyst further surrounded by variably mature granulation tissue, fibrosis, and inflammation. The central pseudocyst is characterized by a 7 x 3 mm irregular area of cellular dropout (lytic necrosis) with replacement by anastomosing trabeculae of eosinophilic, lamellated, amorphous, polymerized fibrin admixed with a small amount of necrotic debris.  The pseudocyst is rimmed by loosely arranged reactive fibroblasts often arranged perpendicularly to small caliber blood vessels lined by reactive endothelium (granulation tissue). The pseudocyst is further surrounded by abundant fibrosis and high numbers of large epithelioid macrophages that often contain intracytoplasmic, amphophilic, granular to globular material (vaccine material) admixed with moderate numbers of eosinophils and nodular perivascular aggregates of lymphocytes.

MORPHOLOGIC DIAGNOSIS: Subcutis: Panniculitis, granulomatous, focally extensive, marked, with central pseudocyst, granulation tissue, fibrosis, and intrahistiocytic vaccine material, domestic longhair, feline.


CONDITION: Post-injection panniculitis; Vaccine-associated granuloma



Injection Site-associated sarcoma:

·         Fibrosarcoma is the most common malignant mesenchymal tumor of cats; 3 forms:

·      1. Non vaccine-associated fibrosarcoma: larger, solitary, biologically aggressive (moreso than viral or vaccine induced), commonly in older cats

·      Recur multiple times within a period of weeks to months when removed

·      2. Virus-induced from feline sarcoma virus (FeSV): Rare, cause of multicentric fibrosarcoma in cats usually less than 5 years of age

·         FeSV is a retrovirus; sarcoma formation requires feline leukemia virus (FeLV) as a helper virus > genetic recombination between viruses > induces multiple simultaneous rapidly growing fibrosarcomas

·         Typically locally invasive and metastasize to lung and other sites

·      3. Injection site-associated sarcoma (formerly vaccine-associated sarcoma)

·      Recent studies implicate several different stimuli other than vaccines, including injection of foreign material, trauma, and microchip implantation

·      Locally aggressive with a high rate of local recurrence

·      Occasionally metastasize, especially to the lungs

·      Poor prognosis

·      The majority are fibrosarcomas, but other reported injection site-associated (vaccine-induced) sarcomas include (not limited to): osteosarcoma, chondrosarcoma, rhabdomyosarcoma, histiocytic sarcoma, myxosarcoma, and most recently cutaneous lymphoma (Roccabianca Vet Pathol. 2016)



Injection Site-associated sarcoma:

·      Overzealous reparative response at postvaccinal site of inflammation or wound healing or both > malignant transformation of mesenchymal cells

·      Antigen load and degree of inflammation present at vaccine site are possible influencing factors

·      Postvaccinal granulomatous / necrotizing panniculitis possible premalignant lesion

·      Epidemiologic studies suggest:

·      Increased occurrence at repeated vaccination sites

·      FeLV or rabies vaccines; both adjuvant and non- adjuvant vaccines



Injection Site-associated sarcoma:

·      Average age of cats is 9.6 years, which is younger than cats with nonvaccine-associated fibrosarcoma; no known breed or sex predilection

·      Common vaccination sites: Interscapular, dorsal neck, shoulder, flank, and femoral areas

·      Local recurrence following surgical excision is frequent

·      Prognostics: A recent study (Porcellato Vet Pathol. 2017) found that expression levels of gelatinases (MMP-2 and MMP-9) and their inhibitor (TIMP-2) are not prognostically useful, and neither are the STS grading system, depth of infiltration, surgical margins, or Ki-67 index; potentially prognostically useful markers are the size of the tumor (optimal cutoff 3.75 cm) and the mitotic count (20 mitoses/10 HPF)



Injection Site-associated sarcoma:

·      Most typical presentation is a well-circumscribed, irregularly shaped, firm, multilobular, white mass in the subcutis or skeletal muscle; typically larger (greater than 4 cm in diameter) than non-vaccine associated sarcomas

·      Neoplasm often contains a cystic center containing a thin watery or mucinous fluid



Injection Site-associated sarcoma:

·      Neoplastic myofibroblasts, neoplastic multinucleated giant cells, often prominent cellular pleomorphism, often high mitotic rate

·      Unique features of injection site-associated sarcomas (vs. non injection site-associated sarcomas:

·      Macrophages often contain an intracytoplasmic granular to crystalline gray-brown to bluish vaccine material

·      Prominent peripheral lymphoid aggregates with high proportion of T cells

·      Necrosis is often prominent; necrotic core with micro- or macro-cavitations surrounded by neoplastic cells

·      Tumors are often contiguous with granulation tissue

·      Accentuated peripheral vascularity


Vaccine reaction:

·      Classically nodular aggregates of predominately lymphocytes arranged around a central core of caseous necrosis

·      Macrophages with gray-brown (amphophilic) to bluish vaccine material granular vaccine substance material or often embedded in eosinophilic debris or found within phagocytes

·      Strong antigenic stimulus provided by the exogenous antigen sometimes results in the formation of germinal centers; heterogeneity of the cell population and the lack of anaplastic characteristics in the lymphoid cells may differentiate these lesions, sometimes termed pseudolymphoma, from genuine lymphoma



Injection Site-associated sarcoma:

·      Spindle cells, giant cells, histiocytoid cells and cells with myofibroblastic features

·      Similar to fibroblasts; subplasmalemmal dense attachment of plaques and thin cytoplasmic actin myofilaments



Injection Site-associated sarcoma:

·      Immunohistochemistry:

·      Tend to be immunoreactive for PDGF, PDGFR, EGF, EGFR, and TGF-β while non-injection site associated fibrosarcomas are not or less so

·      Immunoreactive for: vimentin, smooth muscle actin

·      Not immunoreactive for: COX-2

·      Histochemistry: Masson’s trichrome highlights collagen of fibrosarcomas

·      Cytology: Abundant large, plump spindle cells individually arranged and in aggregates associated with pink, collagenous material with occasional multinucleated giant cells



Injection Site-associated sarcoma:

·      Gross differentials:

·      Primary or metastatic neoplasms

·      Inflammatory: Granuloma, abscess, foreign body reaction

·      Immune mediated: Post vaccine reaction

·      Histologic differentials:

·      Non vaccine-associated fibrosarcoma (I-N15B): No peripheral lymphocytes / macrophages

·      Giant cell tumor of tendon sheath: Nuclear pleomorphism, abnormal mitoses

·      Hemangiopericytoma: Concentric whorls of spindle cells around capillaries; occurs almost exclusively in dogs

·      Keloidal vaccine-associated fibrosarcoma: Thick bands of hyalinized collagen

·      Leiomyosarcoma: Often retain cigar shaped nucleus

·      Liposarcoma (I-N18C): Lipocytes, pleomorphic, +/- scant collagen

·      Myxosarcoma: Spindloid to stellate cells separated by mucinous material

·      Myofibroblastic sarcoma

·      Nerve sheath tumors (I-N13)



Trauma/inflammation/vaccine-associated neoplasia:

·      Ferrets: Vaccine-site associated fibrosarcomas have been reported; neoplasms were identified by the presence of macrophages with intracytoplasmic vaccine material and/or presence of prominent lymphoplasmacytic infiltrates (Fox 2014)

·      Feline post-traumatic ocular sarcoma (FPTOS) (S-N07) has similar morphologic features to feline injection site sarcomas fibrosarcomas:

·      Second most common primary feline ocular neoplasm

·      Unique to cats (and a few reports in rabbits)

·      Feline eyes subjected to trauma, especially penetrating injury, are prone to develop pleomorphic spindle cell sarcomas following a period of dormancy (average 5 years)

·      Locally invasive (hallmark feature) malignant neoplasm

·      Light microscopic features:

·      Initially, spindle cells line and efface the uveal tract (the inclination to “line the globe” is a repeatable feature used to distinguish primary ocular sarcoma from rare metastatic sarcomas)

·      Eventually the neoplasm extends to the sclera and optic nerve, ultimately diffusely filling the globe

·      Rabbits: Intraocular tumors are variably pleomorphic, poorly differentiated, invasive, intraocular spindle cell neoplasms associated with lens capsular fragments; closely resemble feline post-traumatic ocular sarcomas

·      Dogs: Microchip associated fibrosarcoma (one case report)

Vaccine- or injection-associated disease:

·      Dogs:

·      Post-rabies vaccine panniculitis (poodle patch, I-M35): Immune-mediated dermatoses with cell-poor, mononuclear vasculitis with ischemic follicular atrophy and lymphocytic panniculitis; can present like lupus panniculitis

·       Sheep: Aluminum-based adjuvant injection induces persistent, sterile, subcutaneous granulomas; aluminum translocates to regional lymph nodes via macrophage trafficking (Asin Vet Pathol. 2019)

·      Horse: Injection-site eosinophilic granulomas are progressive (1-3 days post vaccination) nodules with necrotic cores; considered to be a response to the use of silicone-coated hypodermic needles (form of delayed hypersensitivity)



1.    Asın, J, et al. Granulomas Following Subcutaneous Injection With Aluminum Adjuvant-Containing Products in Sheep. Vet Pathol. 2019, Vol. 56(3) 418-428

2.    Fox JG, Muthupalani S, Kiupel M, Williams B. Neoplastic Diseases In: Fox JG, Marini RP, ed., Biology and Disease of the Ferret. 3rd ed. 2014; 602.

3.    Gross TL, Ihrke PJ, Walder EJ, Affolter VA. Other mesenchymal tumors. In: Gross TL, ed. Skin Diseases of the Dog and Cat, 2nd ed. Ames, Iowa: Blackwell Science; 2005:797-801.

4.    Hargis AM, Myers S. The integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Mosby Elsevier; 2016:1065.

5.    Hendrick, MJ. Mesenchymal Tumors of the Skin. In: Mueten DJ, ed. Tumors in Domestic Animals. 5th ed. Ames, IA: John Wiley & Sons, Inc., 2017: 145-146.

6.    Labelle P. The eye. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Mosby Elsevier; 2016:1306.

7.    Madewell BR, Griffey SM, McEntee MC, Leppert VJ, Munn RJ. Feline vaccine-associated fibrosarcoma: an ultrastructural study of 20 tumors (1996-1999). Vet Pathol. 38: 2001: 196-202.

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9.    McPherson L, et al. Intraocular sarcomas in two rabbits. J Vet Diagn Invest. 2009; 21(4):547-551.

10. Porcellato I, Menchetti L, Brachelente C, Sforna M. Feline Injection-Site Sarcoma: Matrix Remodeling and Prognosis. Vet Pathol. 2017; 54(2): 204-211.

11. Raskin RE. Skin and subcutaneous tissues. In: Raskin RE, Meyer DJ, ed. Canine and Feline Cytology. 3rd ed. St. Louis, MO: Elsevier; 2016:67.

12. Riedl M, Truyen U, Reese S, Hartmann K. Prevalence of antibodies to canine parvovirus and reaction to vaccination in client-owned, healthy dogs. Vet Rec. 2015; 177(23):597.

13. Roccabianca P, et al. Cutaneous lymphoma at Injection sites: pathological, immunophenotypical, and molecular characterization in 17 cats. Vet Pathol. 2016; 53(4): 823-832.

14. Wilcock BP, Njaa BL. Special Senses. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016: 486.

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