Do postvaccinal sarcomas occur in Australian cats ?

G BURTON and KV MASON

Animal Skin and Allergy Clinic, 3331 Pacific Highway, Springwood, Queensland 4127
SUMMARY: A soft tissue sarcoma occurred in the interscapular area of a cat, 1 to 7 months after vaccination at that site. The vaccine contained inactivated feline panleucopaenia virus combined with modified live feline herpesvirus and calicivirus. The tumour showed histological features of both fibrosarcoma and malignant fibrous histiocytoma. The tumour was observed to evolve from the site of a presumed postvaccinal granuloma. Local recurrence 6 weeks post excision necessitated more radical resection. Euthanasia was performed 2 years later when pleural effusion developed. The cause of effusion was not determined. There was no palpable evidence of local tumour regrowth at the time of euthanasia. A causal relationship between vaccination and sarcoma formation is considered based on the temporal association between the two events, the anatomical location of the tumour and histopathology consistent with postvaccinal sarcomas reported overseas. Six other vaccine site fibrosarcomas, potentially vaccine associated using the above criteria, are summarised.
Aust Vet J 1997; 75:102-106

Sarcomas are neoplasms of mesenchymal origin. Fibrosarcomas are malignant mesenchymal tumours arising from fibroblasts. They can occur at any anatomical location and are common in cats, comprising 24 to 33% of tumours of skin and subcutis.1 Malignant fibrous histiocytoma is comparatively uncommon in cats.2

Fibrosarcomas occur in two clinical forms: a solitary tumour of older cats (average age 12 years) which is not associated with FeSV1 and a multicentric form in younger cats, usually less than 5 years of age, which is FeSV associated.3 FeSV are transforming viruses which contain oncogenes formed by the recombination of the FeLV genome with the cat's cellular genes. FeSV associated tumours are more anaplastic and more invasive than the solitary, non-FeSV associated fibrosarcomas. Affected cats test positive for FeLV antigen.4 FeSV has rarely been associated with solitary tumours.5 Reports associating vaccination with sarcoma development at the inoculation site have appeared recently.6-11 The presence of aluminium based adjuvants, the chronicity of the inflammation, antigenicity of vaccines and retroviruses have all been implicated in the aetiology.11 FeLV vaccines were the most common vaccine type associated with postvaccinal sarcomas in two studies.9,10 An association between killed virus vaccines for FPL and FRFC viruses with sarcoma formation has been suggested.12 Sarcomas reported are predominantly fibrosarcomas and malignant fibrous histiocytomas.13 Anaplastic sarcomas, rhabdomyosarcomas, osteosarcomas and chondrosarcomas are also recognised.12,13

The incidence has been estimated to be 1 to 2 sarcomas per 10,000 cats vaccinated8 and 13 / 10,000 vaccinations.13 No other host characteristics (sex, breed, FeLV or FIV status) were found to be important. No one manufacturer was implicated and vaccines with and without adjuvants were involved. The practice of giving multiple vaccines sequentially into the interscapular area increased the risk of developing fibrosarcoma at that site.9

Fibrosarcomas occurring at known vaccination sites tended to occur in younger animals, recur more frequently after resection, be larger at the time of diagnosis and be associated with longer survival times, than fibrosarcomas occurring at sites not typically used for vaccination.10 A good review of the background of this disease has been previously presented.11

This article reports one case of a presumed postvaccinal sarcoma in a cat seen by the first author and includes summaries of six other animals in which this diagnosis was also suspected.

Case one

A 7 year old, desexed female, Siamese cat was presented for routine annual vaccination. This was performed into the interscapular area by combining inactivated FPL and live FRFC virus vaccines. The cat re-presented 28 days later with a 5 mm, firm, mobile nodule at the site of vaccination. An inflammatory postvaccinal granuloma was suspected. No investigation was performed.

At 7 months after vaccination the cat was returned with a firm nodule 1.5 cm in diameter in the interscapular region. The owner reported that the previous “granuloma” had never resolved and had recently begun increasing in size. An excisional biopsy was performed and samples submitted for histopathological assessment. Fibrosarcoma was diagnosed ( “a fibroplastic tumour with extensive central necrosis and prominent tumour giant cells”). The second author reviewed the sections and suggested the possibility that this was vaccine associated due to the history, location and histopathologic appearance. The tumour was located within the panniculus and well demarcated with prominent central eosinophilic necrosis. Focal, peripheral and perivascular lymphocytic aggregates were present together with a well formed fibrous capsule (Figure 1). The tumour consisted of pleomorphic spindle cells interspersed with numerous multinucleate giant cells (Figure 2). A third opinion was sought from a dermatopathologist familiar with the North American cases who also examined the sections. Although multinucleated giant cells are reported to be common in postvaccinal sarcomas,13 it was considered that the number of such cells in this instance was not typical of vaccine induced fibrosarcomas and a diagnosis of malignant fibrous histiocytoma was more appropriate (J Yager, personal communication).

Tumour extension close to the excision line was evident histologically. Regrowth at the site occurred within 6 weeks of the first surgery. An en bloc excision of the tumour with 3 cm margins in cranial, caudal and lateral directions was then performed. Dissection was continued deeply to include all subcuticular tissue down to the fascia overlying the dorsal spinous processes of the caudal cervical and proximal thoracic spine. A rectangular deficit was created with the long axis extending in a cephalocaudal direction. A centripetal closure was performed including subcuticular walking sutures to relieve wound tension.14 Histopathology was not performed following the second surgery.

The cat was next presented 2 years later with acute respiratory distress. On visual examination and palpation there had been no evidence of local tumour recurrence. A profuse pleural effusion was diagnosed radiologically and confirmed by thoracocentesis. Another veterinarian suspected metastases based on the previous history of soft tissue sarcoma removal. The cat was euthanased after failing to respond to diuretic therapy. Necropsy was not performed, metastases were not confirmed and the cause of the pleural effusion not determined.

Figure1. Biopsy specimen from case one, showing perivascular lymphocytic infiltrate (arrow) , capsule formation (A) and proliferating spindle cells (B). Haematoxylin and eosin, x 200.

Figure 2. Biopsy specimen from case one. Note spindle cells exhibiting cellular pleomorphism typical of anaplastic fibrosarcoma (A) and numerous multinucleated giant cells (B). Haematoxylin and eosin, x 400.

Cases two to seven

Following case one, we contacted five diagnostic pathology laboratories in Brisbane, Sydney, Melbourne and Adelaide for information on suspect postvaccinal sarcomas. Additional cases supplied were fibrosarcomas suspected of being vaccine associated based on suggestive histopathology, tumour location and history of vaccination at that site. We were unable to determine what percentage of submissions diagnosed as feline soft tissue sarcomas were potentially vaccine associated. These cases are summarised in Table 1.

Table 1. Fibroscarcomas occurring at vaccination sites in seven cats.

Case no

Gender,a age(y), breedb

Vaccine typec

Innoculation to tumour time (months)e

Recurrence, times

Disease free interval (months)f

Survival time (months)

Outcome

1

fs, 7, S

FPL / FRFC

7

Yes, 1

1.5

24

Euthanased

2

mc, 7, DSH

FE3

11

Yes, 1

10

10

Euthanased

3

mc, 13, DSH

FE3

30

Yes, 1

3

3

Euthanased

4

fs, 13, DSH

FE3

66

Yes, 2

10

16

Euthanased

5

mc, 10, DSH

FE3K

6

No

7

7

Died

6

mc, 10, DSH

FE3, Rabiesd FeLVd

6

Yes, 4

3

16

Alive

7

fs, 11, DSH

FPL / FRFC

7

Yes, 1

0.5

6

Alive

Discussion

A diagnosis of a vaccine associated sarcoma in case one was based on the temporal association between vaccination and tumour development, the observation of the tumour forming at the site where the vaccine was given and compatible histopathological findings. Postvaccinal sarcomas are usually described as well demarcated, partially encapsulated, with focal, peripheral and perivascular lymphocytic aggregates. 13 A clue to the diagnosis of postvaccinal fibrosarcomas is the focal, usually peripheral, lymphocytic aggregates.15 Lesions in transition between vaccination induced lymphocytic panniculitis featuring extensive central necrosis and proliferating fibrosarcoma have been reported.10

Whether this tumour is labelled a fibrosarcoma or a malignant fibrous histiocytoma may not be important clinically. With respect to postvaccinal sarcomas, it has been said that the lesions may be diagnosed as different sarcomas by different pathologists.13 Histopathological features of three individual tumour types ( fibrosarcoma, rhabdomyosarcoma and osteosarcoma ) have been reported at the same injection site of a single patient.16 The literature does not ascribe a difference in prognosis to the varying morphological forms of postvaccinal sarcomas. Cases two to seven were diagnosed histologically as fibrosarcomas and all featured prominent lymphocytic inflammation. Lymphocytic/plasmacytic inflammation of tumour margins has also been reported in some spontaneously occurring fibrosarcomas.2 Histopathology is considered supportive of a diagnosis of postvaccinal sarcoma rather than being pathognomonic. The possibility of these neoplasms being spontaneously occurring must be considered.

The time from last confirmed vaccination to the diagnosis of a sarcoma at that site varied from 7 to 66 months. Five of the seven cases presented within 12 months. It has been reported that 61% of postvaccinal sarcoma cases present within 12 months and 93% within 3 years of the last vaccination at that site.11 Case four had a 66 month period between vaccination and sarcoma development. Similar latent periods have been reported elsewhere.11

The behaviour of the sarcomas presented was consistent with that previously reported.10 Recurrence after surgery appears to be common. Five cats were euthanased due to local recurrence. Metastases were not confirmed in any of the cases, however, detailed necropsies were not performed. Widespread metastases have been reported in one case of vaccine site fibrosarcoma.17 Solitary fibrosarcomas are considered a surgical disease.18 Early detection ( high index of suspicion, fine needle aspirate or cutting needle biopsy to differentiate sarcoma from benign granuloma prior to surgery) and early aggressive surgery would appear to provide the best chance of cure. Adequate margins ( 2 to 4 cm ) around and beneath are recommended.14 Where the size of the tumour makes adequate margins difficult to achieve, referral to a skilled surgeon would be indicated.

The mechanisms involved in formation of postvaccinal sarcomas are incompletely understood. Cellular proto-oncogenes encode for protein products which regulate cell proliferation.19 All neoplasms by definition show dysregulated cell growth. Chromosomal mutation, translation, and incorporation into retroviruses can result in altered or inappropriately activated proto-oncogenes which are referred to as oncogenes.19,20 Oncogene encoded proteins can intervene in growth regulatory pathways at any point (growth factor receptor, receptor ligand, secondary messengers and nuclear proteins ) to influence cell proliferation.21 Depending on the oncogene expressed, this may make cells more sensitive to or independent of, the normally produced tissue growth factors.21

Recent interest has focussed on the role of inflammation postvaccination as a possible trigger to neoplastic transformation.22 Cell proliferation after inflammation can increase the probability that genetically altered cells will arise.23 Modified live vaccines rely on viral replication at the site to stimulate an adequate immune response. Adjuvanted vaccines rely on antigen load and the adjuvant to enhance and prolong the immune response, possibly by activating macrophages to increase antigen presentation and cytokine production.24 Cytokines are protein hormones produced by cells that play a critical role in the cellular responses involved with inflammatory and immunological reactions.25 Cytokine production is upregulated at vaccination sites and influenced by host and vaccine factors. 24,25 The possibility that vaccine type ( specifically the adjuvant method used or lack thereof ) may affect the amount of inflammation at the site of vaccination and thus the risk of subsequent sarcoma formation has been suggested.22

Sarcomas have developed after the use of modified live vaccines incorporating herpes-, calici-, and parvo-viruses.10 A statistical link has only been made previously to FeLV, and possibly rabies, vaccines.9,10 A recently Canadian study demonstrated an association between non-FeLV vaccines and sarcoma formation at vaccination sites. Adjuvanted, killed vaccines for FPL and FRFC were involved. The prevalence in the Canadian study was much higher than previously reported and restricted to a single practice. The reasons for the discrepancy between this practice and other practices using the same vaccines was unknown.12

The vaccines used in cases one, five, six and seven were adjuvanted. Aluminium hydroxide gel was present in the inactivated FPL vaccine used in cases one and seven (M Lindsey, personal communication). Information regarding the type of adjuvants used in cases five and six was not available. Cases two, three and four involved modified live vaccines. The equal prominence of modified live vaccines and inactivated vaccines and the lack of prominence of FeLV vaccines in this report differs from other publications on this subject.

An association between nonvaccine injections and sarcoma formation has not been shown.9 Three of the cases presented (including case one) had no history of nonvaccine injections, two cases had a history of antibiotic injections (one of which also received subcutaneous fluids) and in two cases we could not confirm or rule out other injections, at that site, in the 12 months prior to tumour diagnosis.

Retroviral transduced oncogenes are the most potent carcinogens known.19 Inflammation has been demonstrated to be important in the pathogenesis of retroviral induced sarcomas in other species.26,27 The existence of exogenous feline retroviruses (FeLV, FeSV, FIV and feline syncytium forming virus) and endogenous feline retroviruses (found as part of the normal cat genome, such as RD-114, MAC-1, and enFeLV ) makes it tempting to consider that retroviruses play a role in the formation of these sarcomas. Both FeLV and FeSV have proven oncogenic potential.5 Oncogenic tumour viruses do not act in isolation but rather in concert with other factors ( genetic, immunologic, environmental and possibly other carcinogenic agents ) which may all influence the progression toward malignancy.21 The abundance of feline retrovirus genome may help explain why postvaccinal sarcomas appear to be predominantly a feline phenomena.

We are not aware of studies which have identified retrovirus provirus in postvaccinal sarcomas. In vitro studies have shown that some FeSV infected cells can revert to normal morphology but retain FeSV provirus.28 This suggests the potential for latent infections which could allow for provirus to persist locally and result in FeLV virus negative fibrosarcomas.5

These cases are presented to alert clinicians to the possibility of vaccination associated sarcomas in cats in Australian. Vaccine manufacturers estimate that there are 3,000,000 pet cats in Australia and 30 to 40% of these attend veterinary clinics regularly with 20 to 25% (600,000 to 750,000 cats) routinely vaccinated. Not all these cats are vaccinated annually. The average cat receives five vaccinations per life time (M Lindsey, personal communication). From these figures the number of cats vaccinated per year is approximately 250,000 to 307,000. The seven cases presented have occurred from 1991 to 1996. The prevalence of postvaccinal sarcomas based on the more conservative estimate of vaccinations per year, would be at least one per 178,600 vaccinations. This is a low estimate because not all pathology laboratories were contacted, not all tumours are submitted or appropriate details may be lacking. Nevertheless, the rate seems low when compared with the overseas frequency .

Although this paper focusses on a potential negative aspect of vaccination we must remember that the benefits of vaccination to our feline patients far outweighs the very low risk of developing a soft tissue sarcoma at the site. Routine annual vaccination of cats remains an important aspect of prophylactic medicine.

Adjuvants used in overseas vaccines may differ considerably from those in Australian vaccines. This information is largely confidential and not obtainable. Whether differences in adjuvants explains the possible discrepancy in numbers of reports of postvaccinal sarcomas between Australia and North America is unknown and awaits further elucidation of the pathomechanisms of these tumours.

Our recommendations, based on those of Macy and Hendrick,22 are as follows:

  1. Site, vaccine used ( type and manufacturer ) and date given should be carefully recorded for all vaccinations.
  2. Owners should be advised to examine for and report any lumps occurring at vaccination sites.
  3. Postvaccinal granulomas that do not spontaneously resolve or are continuing to enlarge should be biopsied and if sarcoma is confirmed an early, planned, wide excision performed. Details of location of tumour and vaccination history should be supplied to the histopathologist with the biopsy .
  4. Repeated vaccinations sequentially into the interscapular area should be avoided.

Acknowledgments

We are grateful for the assistance from Drs S Fearn, S Lemin, J Nicholls, R Straw and M Lindsey (Arthur Websters Pty Ltd) and the Knox Veterinary Clinic, Central Veterinary Diagnostic Laboratory (Melbourne) and Veterinary Pathology Services (Adelaide and Brisbane).

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(Accepted for publication 13 December 1996).

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