The first report of neoplasia in new world camelids, published in 1974, described gastric squamous cell carcinoma in a guanaco (1). Since then, there has been increasing interest in neoplasia of llamas and alpacas especially as these animals have had increased popularity for their fiber and as companion and pack animals for integrated sheep protection. The majority of the earlier reports have been individual cases or brief communications with only very rare publications looking at overall prevalence of neoplasia in new world camelids (2, 3). Prevalence studies indicate that while common, neoplasia is not a primary cause of death and that llamas might have a slightly higher incidence of neoplasia than alpacas, although alpacas appear to have predisposition for developing neoplasia at a relatively younger age. Publications of neoplasia in camelids often report disseminated or metastatic disease at the time of diagnosis, making early diagnosis especially important in these animals.

Sample size in most of the reports in new world camelid literature is limited with only 6% of publications (5 of 83 publications) on neoplasia in camelids reporting numbers greater than five animals. Case reports are rather common and often report bizarre or highly aggressive neoplastic behavior discovered at the time of necropsy, leaving a gap in the current knowledge as to the outcome of these tumors. Pathologists, clinicians, and owners are often challenged with prognostication relating to cutaneous or visceral neoplasia that have been underreported or previously unreported. A guide to differentiate benign from malignant tumors is of crucial importance in those cases. A systematic review of neoplasia, to the authors' knowledge, has yet to be published on neoplasia in llamas and alpacas.

The current article presents a systematic review of neoplasia and proliferative diseases in new world camelids including cases from both the published literature and 201 case submissions to the Veterinary Diagnostic Laboratory at Colorado State University (CSU-VDL) from 1995 to 2020. The case series published here is the largest summary data ever reported on this subject and almost doubles the number of the known cases of neoplasia reported in South American camelids. This review will serve to broaden the knowledge base on camelid neoplasia and will highlight the most common neoplastic diseases and likelihood of malignancy and will also identify novel neoplastic/proliferative lesions in new world camelids.

Examination of archived camelid submission to CSU-VDL in the period between April 20, 1995 to December 31, 2020, confirms that neoplasia in camelids is heterogeneous and affects both alpacas and llamas of wide age ranges. The prevalence of neoplasia and proliferative lesions in both species is 8.8% of the total camelid pathology submissions to CSU-VDL, which is higher than the prevalence of camelid neoplasia reported in the literature from other regions (5%) (2, 3). The considerably longer duration of the study period and the higher number of total camelid submissions including more alpacas than llamas might be among the reasons for this variation.

In the South American camelid species, there was a female predisposition for developing neoplasia with 113 female alpacas and llamas (57% of the total cases) developing one or more neoplastic/proliferative lesions compared to 64 male camelids (32%). The relative commonality of mammary and uterine neoplasia and the relative scarcity of testicular tumors, in part, explain why female camelids might be overrepresented in the current review. The predisposition of female alpacas to develop non-genital neoplasia was also observed especially in the case of lymphoma (58% of lymphoma cases were diagnosed in females). Females also had a much higher prevalence of sarcomas (84%) than males in both alpacas and llamas.

Round cell tumors were by far the most commonly diagnosed/reported neoplasia in camelids with lymphoma being the top tumor diagnosed from the CSU-VDL. Interestingly, lymphoma was diagnosed much more commonly in alpacas (75%) than llamas (19%) (p = 0.0192) and the most common tumor diagnosed in animals <5 years of age (Figure 1). Lymphoma was most likely to be disseminated at the time of diagnosis and was the most common tumor to affect the brain. The high prevalence of lymphoma in alpacas and in younger animals suggests a possible genetic link, as is observed in humans and dogs (84). B vs. T cell lymphomas were evenly distributed in cases that had been further immunophenotyped. Also, there is a single case report of bovine leukemia virus-associated lymphoma in an alpaca (55). Evaluation of CSU-VDL cases for bovine leukemia virus was not performed but could be an interesting area for further investigation.

Other round cell tumors included mast cell tumor and histiocytic sarcoma. The CSU-VDL submissions have increased numbers of these tumors when compared to the literature. Histiocytic sarcoma is reported here for the first time in the alpaca species. It occurred in a very young cria, suggesting that the tumor might have developed in utero as it was of considerable size at 2 weeks of age. None of the mast cell tumors found in the CSU-VDL submissions were found to have metastasized.

Malignant epithelial tumors accounted for 69% of camelid epithelial neoplasia. Squamous cell carcinomas were the most common malignant epithelial neoplasia with an overall prevalence of 9.5%, and intestinal, mammary, and uterine adenocarcinomas had an overall prevalence of 27%. Locations of the squamous cell carcinomas included cutaneous, oral, ocular, and visceral. To the authors' knowledge, oral squamous cell carcinomas are a novel category; however, gastric squamous cell carcinoma, ocular-third eyelid squamous cell carcinoma, and squamous cell carcinoma arising from a cutaneous scar have previously been reported in the literature (1, 3, 14, 17, 18). Although the exact etiopathogenesis of the squamous cell carcinomas encountered in camelids is largely unknown, genetic make-up, environmental conditions, and infectious agents are among the possibilities (18). In cases from the CSU-VDL database, only two squamous cell carcinomas were found to have metastasized at the time of the diagnosis, indicating that complete excision of these tumors could be potentially curative in affected animals. Reports from the literature find these tumors to be more aggressive than our database suggests, but this may represent a skewed dataset where only novel and aggressive lesions are published (3, 15, 16, 20).

Adenocarcinomas have a much more aggressive clinical course with most cases having had metastasized at the time of diagnosis. Gastrointestinal tumors were the most common category with all having metastasized at the time of diagnosis and one case having developed widespread carcinomatosis identified in CSU-VDL cases and one reported in the literature (21). It is unknown if these tumors metastasize early or if the frequent metastasis is due to the difficulty in detecting these tumors early in the course of the disease. Diagnosis of adenocarcinoma also had an increased female prevalence. This is likely due to the diagnoses of uterine and mammary carcinomas. Uterine and mammary adenocarcinomas were found to have metastasized in 66 and 33% of cases, respectively, indicating increased incidence of metastasis when compared to squamous cell carcinomas but less than gastrointestinal adenocarcinomas. Other organs that were affected by adenocarcinomas/carcinomas include thyroid, liver (biliary carcinomas), and kidney.

Fibropapilloma is the most prevalent benign epithelial neoplasm. The prevalence of fibropapilloma diagnosed at CSU was higher than in the Cornell study but lower than in the Oregon study, as the authors of the latter study combined both fibropapillomas and fibromas into one category (3, 5). Interestingly, there is a single report of papillomavirus isolated from a llama fibropapilloma which was 73% homologous with bovine papillomavirus type 1 (BPV1) (7). Evaluation for BPV1 in the fibropapillomas diagnosed at CSU was not performed but is of interest for future investigation.

Mesenchymal neoplasia occurred in 52 camelids with an overall prevalence of 26.5, 36% of which were identified as malignant. Fibroma was the most common benign mesenchymal neoplasm at 30.8% of mesenchymal neoplasia and overall prevalence of 8%. There was an even distribution between llamas and alpacas diagnosed with sarcomas and a higher number of females than males. Fibrosarcoma or soft tissue sarcoma, especially of the oral or nasal cavity, was the most common diagnosis. Only two of eight were found to have metastasized at the time of diagnosis. In the literature, there are no reports of metastasis of these tumors, suggesting good prognosis following complete surgical excision. Other less common diagnoses included osteosarcoma, liposarcoma, myxosarcoma, and hemangiosarcoma. Only the visceral sarcomas (affecting the liver and spleen) were found to have metastasized similar to the aggressive behavior of these tumors in other species (85).

Several neoplastic and proliferative lesions, never reported, were identified from the CSU-VDL submissions. These include osteosarcoma, liposarcoma, myxosarcoma, cutaneous hemangiosarcoma, gastric leiomyoma, thymoma, pilomatricoma, sarcoid, malignant giant nevus, pituitary hyperplasia, adrenal cortical hyperplasia, and malignant pheochromocytoma. There were additionally many non-neoplastic and proliferative lesions identified. While these lesions are unlikely to be of clinical relevance, they are important differentials as they could mimic more aggressive neoplastic lesions using imaging modalities including ultrasound or radiographs, or even upon gross exam or necropsy.

The previously unreported congenital giant nevus with malignant transformation in a newborn alpaca is an interesting case. In this mass, there was abnormal cutaneous proliferation of melanoblasts present at birth in the periauricular skin and choristomas discoloring the lungs, liver, and meninges. A similar condition has been described in humans, in which giant congenital melanocytic nevi underwent malignant transformation (86, 87).

Here we summarize and review neoplastic/proliferative lesions in llamas and alpacas. Overall, the behavior of these tumors is similar to the behavior reported in other species, indicating that complete surgical excision may be curative in many incidences of proliferative and neoplastic lesions. There is a substantial risk of aggressive disease outcome and metastasis with certain types of neoplasia and with tumors in particular locations, indicating that staging of some patients is prudent. The current article will likely help to provide relevant prognostication to guide owners and clinicians of the possible outcome and best treatment plan. Risk factors appear to be female sex and increased age except in the case of lymphoma, which tends to occur in younger camelids. Lymphoma, melanomas, and adenocarcinomas (especially of gastrointestinal tract) carry an increased risk of dissemination in a single-organ system or widespread metastases. Sarcomas and squamous cell carcinomas in contrast are less likely to metastasize, and resection of these tumors may be curative in many cases. An important and interesting follow-up would be evaluation of disease-free interval and survival following medical intervention in camelids affected by the most common malignant tumors. In conclusion, camelid neoplasia constitutes a reasonable proportion of pathology submissions to veterinary teaching hospitals and veterinary diagnostic laboratories and, therefore, merits further studies to establish standards for their classification and prognostication.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

AV: writing of manuscript, literature review, figures, and manuscript editing. MW: review and summary table Colorado State University cases. AH and JF: writing of manuscript and manuscript editing. TA: writing of manuscript, figures, and manuscript editing. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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