Comparative Medicine Copyright 2015 by the American Association for Laboratory Animal Science
Vol 65, No 6 December 2015 Pages 537–539
Case Report
Vaginal Stone in a Cynomolgus Macaque (Macaca fascicularis) Angela M Colagross-Schouten* and Don R Canfield A 20-y-old female cynomolgus macaque (Macaca fascicularis) housed in an indoor primate facility presented for poor appetite and acute weakness after several years of no adverse health events. Physical examination revealed a firm, ovoid mass in the caudal abdomen. Further evaluation revealed the mass to be a vaginal calculus composed of calcium carbonate, apatite, and struvite. To our knowledge, this case is the first reported description of a vaginal stone in an NHP.
Concretions found within the vaginal vault are referred to as vaginal calculi or vaginal stones and are found rarely in humans.12,14 Primary causes of vaginal calculi include urogenital abnormalities such as vesiculovaginal fistulae, which result in urinary leakage and pooling in the vagina. Secondary causes include the presence of a foreign body that serves as a nidus for the crystallization of urinary constituents.10 These stones typically are composed of struvite1,2,5,6,13,14 and are associated with urine stasis, urinary tract infections, and the resulting change in vaginal pH. Reports of vaginal calculi in animals are sparse but have described cases in harbor porpoises (Phocoena phocoena)11 and dolphins.9,18,19 Vaginal stones in pinnipeds are thought to be the result of secondary causes, including the presence of vaginal plugs, fetal bone remnants, and bacterial infections. However, most of the reported calculi in pinnipeds were composed mainly of struvite, suggesting that they, like those in humans, were related to urine pooling within the vaginal vault. Here we report the finding of a large stone in the vaginal vault of an aged cynomolgus macaque.
Case Report
Clinical findings. A 20-y-old, 4.6-kg female cynomolgus macaque with a previously unremarkable history was noted to have poor appetite, with no stool production and a quiet demeanor. The macaque had been acquired as an adult and was a member of the indoor colony at the California National Primate Research Center, an AAALAC-accredited facility, for 15 y in accordance with the federal, state, and local regulations and industry guidelines. Protocols for the maintenance, use, and care of cynomolgus macaques were approved by the University of California–Davis IACUC. The macaque was negative for Macacacine herpesvirus, simian retrovirus, and SIV. The animal was nulliparous despite repeated breeding attempts and had not undergone any experimental procedures or manipulations prior to her presentation other than vaccine trials conducted 10 y previously. In addition, Received: 09 Mar 2015. Revision requested: 27 Mar 2015. Accepted: 17 May 2015. California National Primate Research Center, University of California–Davis, Davis, California *Corresponding author. Email: [email protected]
there was no pertinent previous medical history, and the macaque was surgically naive. A physical examination was performed under sedation with ketamine (12 mg/kg IM, Butler Animal Health Supply, Dublin, OH). Blood (approximately 3 mL) was collected for whole-blood analysis (NOVA-CCX Stat analyzer, Nova Biomedical, Waltham, MA), including hematology and a serum biochemistry profile. Abdominal radiography and ultrasonography were performed. Clinical examination revealed hypothermia (93 °F) and a large firm mass in the caudal abdomen that appeared to be associated with the reproductive tract. Blood work revealed mild lymphopenia (5.0 × 103/µL; reference, 8.1 to 13.1 × 103/µL) with an otherwise unremarkable CBC. Blood chemistry reflected moderate hyperglycemia (149 mg/dL; reference, 43 to 69 mg/dL), mild hypoproteinemia (6.6 g/dL; reference, 7.3 to 8.3 g/dL), and mildly elevated AST (146 U/L; reference, 28 to 58 U/L) and ALT (163 U/L; reference, 39 to 95 U/L).16 All other values were within normal limits. Abdominal radiographs demonstrated a slightly enlarged liver, with the caudoventral liver margins extending beyond the costal arch and displacement of the gastric axis. A large, radiopaque, roughly ovoid object was observed in the area of the lower reproductive tract (Figure 1). Abdominal ultrasonography revealed a normal uterus and empty bladder. On palpation, the ovoid mass appeared to be within the vaginal canal and, due to its large size, could not be dislodged with manual manipulation. Because of the animal’s advanced age and limited future project potential, euthanasia was elected and performed by using pentobarbital (250 mg/kg IV, Vortech Pharmaceuticals, Dearborn, MI) after ketamine sedation. The macaque was submitted for complete necropsy. Pathology. The macaque was presented in good condition with gross evidence of colitis (thickened colonic mucosa, liquid stool). The lesion of interest was a markedly distended vagina, which was significantly larger than either the uterus or urinary bladder and very firm on palpation. Opening the vagina revealed a relatively smooth-surfaced, irregularly polyhedral, pale-tan concretion measuring 33.5 × 32.5 × 25.5 mm and weighing 32.34 g (Figure 2). Histologic examination of the vaginal mucosa re-
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Vol 65, No 6 Comparative Medicine December 2015
Figure 1. Plain radiograph of a 20-y-old female cynomolgus macaque (ventrodorsal positioning) demonstrating the presence of a large radiopaque object in the vaginal canal.
Figure 2. Isolated reproductive track of a 20-y-old female cynomolgus macaque with an excision through the vaginal wall, revealing a large, firm, smooth mass within the cavity. The uterus (U) is visible to the right, and the bladder (B) is to the left of the mass.
vealed a mild, diffuse vaginitis comprising a variably sparse mononuclear infiltrate in the lamina propria. In addition, mild hyperkeratosis and compression of the surface keratin layer were accompanied by rafts of sloughed keratin with colonies of bacterial cocci, most likely Staphylococcus aureus. These findings are generally consistent with irritation of the vaginal mucosa by an expansile intravaginal foreign body. Crystallographic analysis of the intravaginal concretion revealed predominantly calcium carbonate, 95% in the outer layers and 80% to 89% in the core, with the remainder composed of apatite in surface layers and apatite plus struvite in the core.
Discussion
Vaginal calculi or stones are reported rarely in the veterinary literature and have not been previously reported in an NHP. In humans, vaginal calculi are defined as either primary, generally
as a result of urine pooling, or secondary, due to the presence of a foreign object (nidus), such as migrated surgical wire or an intrauterine device.6,17 Because the vagina does not normally contain urine, stones associated with urine pooling are most commonly the result of a vesiculovaginal fistula with ectopic vaginal ureter, neurogenic bladder, or, less commonly, partial vaginal outlet obstruction.2,7,8 Stones are composed primarily of struvite,1,5,17with crystallization facilitated by infection with bacteria that hydrolyze urea to ammonium, raising urinary pH to neutral or alkaline values. Stones of other composition, such as carbonate apatite, have also been associated with chronic pooling of urine due to abnormalities in the urogenital anatomy.4 Other reports of human vaginal stone analysis have revealed a composition of magnesium and ammonium phosphate in cases not associated with a urinary abnormality.3,5 In the case presented here, the composition of the vaginal calculus was unique in that the majority of the stone was calcium carbonate. Although no evidence of a urogenital abnormality, such as a vesicovaginal fistula, was noted, in the absence of a central nidus, we hypothesize that the central core of this stone suggests a primary urinary origin, possibly associated with a prior vaginal infection by urease-producing bacteria. We suggest that, subsequently, the primary vaginal calculus (highest concentration of struvite) served as a nidus for further, secondary, development of the stone with altered mineral composition (mainly calcium carbonate). It is interesting to note that vaginal stones are often misdiagnosed on the basis of radiography as bladder stones in human medicine.5,6,8 The use of other imaging techniques, such as computed tomography and sonography, and evaluation by direct palpation often elucidates the true location of the stone. The removal of vaginal stones can be challenging, and various methods are described in the literature, including direct removal with forceps, episiotomy, and lithotripsy.1,2,5,6,15 Surgery may be required if the stones are associated with a fistula that results in pooling of urine into the vagina, such as a vesiculovaginal or urethrovaginal fistula, so that the defect can be repaired. Female urogenital fistulas can result from previous trauma, surgery, difficult or prolonged childbirth, and pelvic inflammation. Although the prevalence of vaginal stones in the laboratory animal setting appears to be rare, including this diagnosis on the list of differentials in female NHP that present with stones in the caudal abdomen would be prudent, especially for older patients with increased risk factors, including previous births, genital trauma, or a history of urinary incontinence.
Acknowledgment
We thank the staff of the GV Ling Urinary Stone Analysis Laboratory for their expertise and analysis. The authors also thank Ms. Tracy Lima and Ms. Sarah Mills for their assistance with the images. This work was supported by the CNPRC base grant (P51 RR000169) from the NIH.
References
1. Avsar AF, Keskin HL, Catma T, Kaya B, Sivaslioglu AA. 2013. A large primary vaginal calculus in a woman with paraplegia. J Low Genit Tract Dis 17:61–65. 2. Chen S, Ge R, Zhu L, Yang S, Wu W, Yang Y, Tan J. 2011. Giant primary vaginal calculus secondary to vesicovaginal fistula with partial vaginal outlet obstruction in a 12-year-old girl. Urology 78:908–910. 3. Giasson J, Chen Y. 2013. Mysterious stones. Clin Chem 60:274–275.
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Vaginal stone in a cynomolgus macaque
4. Ho TC, Lin IL. 2008. Primary vaginal stone in a young active woman. Taiwan J Obstet Gynecol 47:457–459. 5. Ikeda Y, Oda K, Matsuzawa N, Shimizu K. 2012. Primary vaginal calculus in a middle-aged woman with mental and physical disabilities. Int Urogynecol J 24:1229–1231. 6. Karsmakers R, Weis-Potters AE, Buijs G, Joustra EB. 2010. Chronic kidney disease after vesicovaginal stone formation around a migrated intrauterine device. BMJ Case Rep 2010:pii: bcr1220092547. 7. Liu B, Huang X, Lu J, Zhang Z, Wang P, Huang Z. 2008. Vaginal calculi secondary to urethrovaginal fistula with vaginal stenosis in a 14-year-old girl. Urol Res 36:73–75. 8. Malhotra N, Kumar S, Roy KK, Agarwal R, Verma V. 2004. Vaginal calculus secondary to vaginal outlet obstruction. J Clin Ultrasound 32:204–206. 9. McFee WE, Carl AO. 2004. Struvite calculus in the vagina of a bottlenose dolphin (Tursiops truncatus). J Wildl Dis 40:125–128. 10. Miah S, Madan S, Khan M, Urwin G, Stower M. 2008. A giant bladder calculus with a synchronous giant secondary vaginal stone: a case report. Curr Urol 2:206–207. 11. Norman SA, Garner MM, Berta S, Dubpernell S, Klope M. 2011. Vaginal calculi in a juvenile harbor porpoise (Phocoena phocoena). J Zoo Wildl Med 42:335–337.
12. Oguzkurt P, Ince E, Ezer SS, Temiz A, Demir S, Hicsonmez A. 2009. Primary vaginal calculus secondary to urethrovaginal fistula with imperforate hymen in a 6-year-old girl. J Pediatr Surg 44:e11–e13. 13. Plaire JC, Snodgrass WT, Grady RW, Mitchell ME. 2000. Vaginal calculi secondary to partial vaginal outlet obstruction in pediatric patients. J Urol 164:132–133. 14. Raghavaiah NV, Devi AI. 1980. Primary vaginal stones. J Urol 123:771–772. 15. Ranawaka RS, Goyal A, Shabani A, Hennayake S, Dickson AP, Cervellione RM. 2015. Novel approach to vaginal calculus in a girl with urogenital sinus anomaly. J Pediatr Surg. [In press] 16. Summers L. Veterinary pharmaceutical formulary and clinical reference handbook. Davis (CA): Regents of the University of California. 17. Tavakkoli M, Ghoreifi A. 2014. Large vaginal and bladder calculi in a woman with previous operation of bladder exstrophy: a case report. Nephrourol Mon 6:e13637. 18. Van Bressem MF, Van Waerebeek K, Siebert U, Wunschmann A, Chavez-Lisambart L, Reyes JC. 2000. Genital diseases in the Peruvian dusky dolphin (Lagenorhynchus obscurus). J Comp Pathol 122:266–277. 19. Woodhouse CD, Rennie CJ 3rd. 1991. Observations of vaginal calculi in dolphins. J Wildl Dis 27:421–427.
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Vol 65, No 6 December 2015 Pages 537–539
Case Report
Vaginal Stone in a Cynomolgus Macaque (Macaca fascicularis) Angela M Colagross-Schouten* and Don R Canfield A 20-y-old female cynomolgus macaque (Macaca fascicularis) housed in an indoor primate facility presented for poor appetite and acute weakness after several years of no adverse health events. Physical examination revealed a firm, ovoid mass in the caudal abdomen. Further evaluation revealed the mass to be a vaginal calculus composed of calcium carbonate, apatite, and struvite. To our knowledge, this case is the first reported description of a vaginal stone in an NHP.
Concretions found within the vaginal vault are referred to as vaginal calculi or vaginal stones and are found rarely in humans.12,14 Primary causes of vaginal calculi include urogenital abnormalities such as vesiculovaginal fistulae, which result in urinary leakage and pooling in the vagina. Secondary causes include the presence of a foreign body that serves as a nidus for the crystallization of urinary constituents.10 These stones typically are composed of struvite1,2,5,6,13,14 and are associated with urine stasis, urinary tract infections, and the resulting change in vaginal pH. Reports of vaginal calculi in animals are sparse but have described cases in harbor porpoises (Phocoena phocoena)11 and dolphins.9,18,19 Vaginal stones in pinnipeds are thought to be the result of secondary causes, including the presence of vaginal plugs, fetal bone remnants, and bacterial infections. However, most of the reported calculi in pinnipeds were composed mainly of struvite, suggesting that they, like those in humans, were related to urine pooling within the vaginal vault. Here we report the finding of a large stone in the vaginal vault of an aged cynomolgus macaque.
Case Report
Clinical findings. A 20-y-old, 4.6-kg female cynomolgus macaque with a previously unremarkable history was noted to have poor appetite, with no stool production and a quiet demeanor. The macaque had been acquired as an adult and was a member of the indoor colony at the California National Primate Research Center, an AAALAC-accredited facility, for 15 y in accordance with the federal, state, and local regulations and industry guidelines. Protocols for the maintenance, use, and care of cynomolgus macaques were approved by the University of California–Davis IACUC. The macaque was negative for Macacacine herpesvirus, simian retrovirus, and SIV. The animal was nulliparous despite repeated breeding attempts and had not undergone any experimental procedures or manipulations prior to her presentation other than vaccine trials conducted 10 y previously. In addition, Received: 09 Mar 2015. Revision requested: 27 Mar 2015. Accepted: 17 May 2015. California National Primate Research Center, University of California–Davis, Davis, California *Corresponding author. Email: [email protected]
there was no pertinent previous medical history, and the macaque was surgically naive. A physical examination was performed under sedation with ketamine (12 mg/kg IM, Butler Animal Health Supply, Dublin, OH). Blood (approximately 3 mL) was collected for whole-blood analysis (NOVA-CCX Stat analyzer, Nova Biomedical, Waltham, MA), including hematology and a serum biochemistry profile. Abdominal radiography and ultrasonography were performed. Clinical examination revealed hypothermia (93 °F) and a large firm mass in the caudal abdomen that appeared to be associated with the reproductive tract. Blood work revealed mild lymphopenia (5.0 × 103/µL; reference, 8.1 to 13.1 × 103/µL) with an otherwise unremarkable CBC. Blood chemistry reflected moderate hyperglycemia (149 mg/dL; reference, 43 to 69 mg/dL), mild hypoproteinemia (6.6 g/dL; reference, 7.3 to 8.3 g/dL), and mildly elevated AST (146 U/L; reference, 28 to 58 U/L) and ALT (163 U/L; reference, 39 to 95 U/L).16 All other values were within normal limits. Abdominal radiographs demonstrated a slightly enlarged liver, with the caudoventral liver margins extending beyond the costal arch and displacement of the gastric axis. A large, radiopaque, roughly ovoid object was observed in the area of the lower reproductive tract (Figure 1). Abdominal ultrasonography revealed a normal uterus and empty bladder. On palpation, the ovoid mass appeared to be within the vaginal canal and, due to its large size, could not be dislodged with manual manipulation. Because of the animal’s advanced age and limited future project potential, euthanasia was elected and performed by using pentobarbital (250 mg/kg IV, Vortech Pharmaceuticals, Dearborn, MI) after ketamine sedation. The macaque was submitted for complete necropsy. Pathology. The macaque was presented in good condition with gross evidence of colitis (thickened colonic mucosa, liquid stool). The lesion of interest was a markedly distended vagina, which was significantly larger than either the uterus or urinary bladder and very firm on palpation. Opening the vagina revealed a relatively smooth-surfaced, irregularly polyhedral, pale-tan concretion measuring 33.5 × 32.5 × 25.5 mm and weighing 32.34 g (Figure 2). Histologic examination of the vaginal mucosa re-
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Vol 65, No 6 Comparative Medicine December 2015
Figure 1. Plain radiograph of a 20-y-old female cynomolgus macaque (ventrodorsal positioning) demonstrating the presence of a large radiopaque object in the vaginal canal.
Figure 2. Isolated reproductive track of a 20-y-old female cynomolgus macaque with an excision through the vaginal wall, revealing a large, firm, smooth mass within the cavity. The uterus (U) is visible to the right, and the bladder (B) is to the left of the mass.
vealed a mild, diffuse vaginitis comprising a variably sparse mononuclear infiltrate in the lamina propria. In addition, mild hyperkeratosis and compression of the surface keratin layer were accompanied by rafts of sloughed keratin with colonies of bacterial cocci, most likely Staphylococcus aureus. These findings are generally consistent with irritation of the vaginal mucosa by an expansile intravaginal foreign body. Crystallographic analysis of the intravaginal concretion revealed predominantly calcium carbonate, 95% in the outer layers and 80% to 89% in the core, with the remainder composed of apatite in surface layers and apatite plus struvite in the core.
Discussion
Vaginal calculi or stones are reported rarely in the veterinary literature and have not been previously reported in an NHP. In humans, vaginal calculi are defined as either primary, generally
as a result of urine pooling, or secondary, due to the presence of a foreign object (nidus), such as migrated surgical wire or an intrauterine device.6,17 Because the vagina does not normally contain urine, stones associated with urine pooling are most commonly the result of a vesiculovaginal fistula with ectopic vaginal ureter, neurogenic bladder, or, less commonly, partial vaginal outlet obstruction.2,7,8 Stones are composed primarily of struvite,1,5,17with crystallization facilitated by infection with bacteria that hydrolyze urea to ammonium, raising urinary pH to neutral or alkaline values. Stones of other composition, such as carbonate apatite, have also been associated with chronic pooling of urine due to abnormalities in the urogenital anatomy.4 Other reports of human vaginal stone analysis have revealed a composition of magnesium and ammonium phosphate in cases not associated with a urinary abnormality.3,5 In the case presented here, the composition of the vaginal calculus was unique in that the majority of the stone was calcium carbonate. Although no evidence of a urogenital abnormality, such as a vesicovaginal fistula, was noted, in the absence of a central nidus, we hypothesize that the central core of this stone suggests a primary urinary origin, possibly associated with a prior vaginal infection by urease-producing bacteria. We suggest that, subsequently, the primary vaginal calculus (highest concentration of struvite) served as a nidus for further, secondary, development of the stone with altered mineral composition (mainly calcium carbonate). It is interesting to note that vaginal stones are often misdiagnosed on the basis of radiography as bladder stones in human medicine.5,6,8 The use of other imaging techniques, such as computed tomography and sonography, and evaluation by direct palpation often elucidates the true location of the stone. The removal of vaginal stones can be challenging, and various methods are described in the literature, including direct removal with forceps, episiotomy, and lithotripsy.1,2,5,6,15 Surgery may be required if the stones are associated with a fistula that results in pooling of urine into the vagina, such as a vesiculovaginal or urethrovaginal fistula, so that the defect can be repaired. Female urogenital fistulas can result from previous trauma, surgery, difficult or prolonged childbirth, and pelvic inflammation. Although the prevalence of vaginal stones in the laboratory animal setting appears to be rare, including this diagnosis on the list of differentials in female NHP that present with stones in the caudal abdomen would be prudent, especially for older patients with increased risk factors, including previous births, genital trauma, or a history of urinary incontinence.
Acknowledgment
We thank the staff of the GV Ling Urinary Stone Analysis Laboratory for their expertise and analysis. The authors also thank Ms. Tracy Lima and Ms. Sarah Mills for their assistance with the images. This work was supported by the CNPRC base grant (P51 RR000169) from the NIH.
References
1. Avsar AF, Keskin HL, Catma T, Kaya B, Sivaslioglu AA. 2013. A large primary vaginal calculus in a woman with paraplegia. J Low Genit Tract Dis 17:61–65. 2. Chen S, Ge R, Zhu L, Yang S, Wu W, Yang Y, Tan J. 2011. Giant primary vaginal calculus secondary to vesicovaginal fistula with partial vaginal outlet obstruction in a 12-year-old girl. Urology 78:908–910. 3. Giasson J, Chen Y. 2013. Mysterious stones. Clin Chem 60:274–275.
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Vaginal stone in a cynomolgus macaque
4. Ho TC, Lin IL. 2008. Primary vaginal stone in a young active woman. Taiwan J Obstet Gynecol 47:457–459. 5. Ikeda Y, Oda K, Matsuzawa N, Shimizu K. 2012. Primary vaginal calculus in a middle-aged woman with mental and physical disabilities. Int Urogynecol J 24:1229–1231. 6. Karsmakers R, Weis-Potters AE, Buijs G, Joustra EB. 2010. Chronic kidney disease after vesicovaginal stone formation around a migrated intrauterine device. BMJ Case Rep 2010:pii: bcr1220092547. 7. Liu B, Huang X, Lu J, Zhang Z, Wang P, Huang Z. 2008. Vaginal calculi secondary to urethrovaginal fistula with vaginal stenosis in a 14-year-old girl. Urol Res 36:73–75. 8. Malhotra N, Kumar S, Roy KK, Agarwal R, Verma V. 2004. Vaginal calculus secondary to vaginal outlet obstruction. J Clin Ultrasound 32:204–206. 9. McFee WE, Carl AO. 2004. Struvite calculus in the vagina of a bottlenose dolphin (Tursiops truncatus). J Wildl Dis 40:125–128. 10. Miah S, Madan S, Khan M, Urwin G, Stower M. 2008. A giant bladder calculus with a synchronous giant secondary vaginal stone: a case report. Curr Urol 2:206–207. 11. Norman SA, Garner MM, Berta S, Dubpernell S, Klope M. 2011. Vaginal calculi in a juvenile harbor porpoise (Phocoena phocoena). J Zoo Wildl Med 42:335–337.
12. Oguzkurt P, Ince E, Ezer SS, Temiz A, Demir S, Hicsonmez A. 2009. Primary vaginal calculus secondary to urethrovaginal fistula with imperforate hymen in a 6-year-old girl. J Pediatr Surg 44:e11–e13. 13. Plaire JC, Snodgrass WT, Grady RW, Mitchell ME. 2000. Vaginal calculi secondary to partial vaginal outlet obstruction in pediatric patients. J Urol 164:132–133. 14. Raghavaiah NV, Devi AI. 1980. Primary vaginal stones. J Urol 123:771–772. 15. Ranawaka RS, Goyal A, Shabani A, Hennayake S, Dickson AP, Cervellione RM. 2015. Novel approach to vaginal calculus in a girl with urogenital sinus anomaly. J Pediatr Surg. [In press] 16. Summers L. Veterinary pharmaceutical formulary and clinical reference handbook. Davis (CA): Regents of the University of California. 17. Tavakkoli M, Ghoreifi A. 2014. Large vaginal and bladder calculi in a woman with previous operation of bladder exstrophy: a case report. Nephrourol Mon 6:e13637. 18. Van Bressem MF, Van Waerebeek K, Siebert U, Wunschmann A, Chavez-Lisambart L, Reyes JC. 2000. Genital diseases in the Peruvian dusky dolphin (Lagenorhynchus obscurus). J Comp Pathol 122:266–277. 19. Woodhouse CD, Rennie CJ 3rd. 1991. Observations of vaginal calculi in dolphins. J Wildl Dis 27:421–427.
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