IMAGING DIAGNOSIS—DISSEMINATED PERITONEAL LEIOMYOMATOSIS IN A DOG MARKAY L. ISAAC, KATHY A. SPAULDING , ZACHARY J. GOODRICH

A 17-month-old male Labrador retriever presented for evaluation of an abdominal mass felt during abdominal palpation. Multiple variably sized cystic masses were identified on sonographic and radiographic images. Exploratory laparotomy revealed multiple peritoneal masses that exhibited atypical contractions and lacked an identifiable organ of origin. Histology and immunohistochemistry of multiple surgically excised masses was consistent with benign tumors of smooth muscle origin (leiomyomas). The presence of multiple peritoneal leiomyomas in this dog is consistent with disseminated peritoneal leiomyomatosis. Two years after diagnosis and multiple surgical interventions, continual insidious enlargement of leiomyomas was identified on ultrasound C 2014 American College of Veterinary Radiology. and CT.  Key words: dog, disseminated peritoneal leiomyomatosis.

Signalment, History, and Clinical Findings

Imaging Findings, Diagnosis, and Outcome

17 MONTH OLD INTACT male chocolate Labrador retriever was referred for a large, firm, nonpainful mass palpated in the cranial abdomen found incidentally during a routine annual examination. A complete blood count revealed neutrophilia, lymphopenia, and monocytosis consistent with a mild stress leukogram. A coagulation profile revealed a slightly elevated prothrombin time (PT) (7.8 s; reference 6–7.5 s), an elevated prothrombin time derived fibrinogen (PT-Fib) (230 mg/dl; reference 64–202 mg/dl), and elevated D-Dimers (739 ng/ml; reference 116.2–371.5 ng/ml). A serum chemistry panel, blood triglycerides, blood cholesterol, and urinalysis were within normal limits.

Radiographically, there was a large soft tissue mass in the midcranial abdomen located caudal to the stomach causing dorsal displacement of the stomach and small intestines (Fig. 1). Sonographically, there were multiple cavitary peritoneal masses within the abdomen without apparent visceral organ origin. The largest mass was located in the right-cranial abdomen and measured 16.5 cm in diameter (Fig. 2A). The masses displaced the stomach in a leftcranial direction and obscured visualization of the adjacent pancreas (Fig. 2B). Minimal blood flow was seen within the wall of the mass, although blood flow was noted communicating between the wall of the mass and the displaced portal vein near the portal hepatis. The lumen of the cranial mass contained fluid surrounding multiple focal luminal smaller masses and an approximately 8.5 cm rounded, echogenic mass containing a focal hyperechoic shadowing area. No blood flow was detected in the masses and no connection with the wall was confirmed. These intraluminal masses were most consistent with focal areas of necrotic tissue or hematomas with focal mineralization. A second mass measuring 15 cm in diameter was located caudal to the first mass and closely adhered to the wall of the first mass (Fig. 2C) The wall was thick, heterogeneous, and appeared to have a spongy or porous appearance. The lumen of the second mass (Fig. 2B) was partially deflated following needle aspiration of the mildly echogenic fluid. There was marked asynchronous wall movement noted following aspiration of fluid from the lumen of the second mass removed (refer to online video on ACVR website). There were several thin-walled cystic structures located in the right

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From the College of Veterinary Medicine and Biomedical Sciences, College of Veterinary Medicine, Texas A&M University, 422 Raymond Stotzer Pkwy, College Station, TX 77845 (Isaac), Department of Small Animal Clinical Sciences, Surgical Residency: Texas A&M University, College Station, TX 77843 (Goodrich), and Department of Large Animal Clinical Sciences, Texas A&M University 4700 University Drive, College Station, TX 77843 (Spaulding). Funding sources: Texas A&M University, Veterinary Medicine and Biomedical Sciences, Department of Large Animal Clinical Sciences Previous presentations or abstracts: On October 05, 2012 Franklin R. Lopez presented a 15-minute report on the pathology in this case to attendees at the Charles Louis Davis, D.V.M. Foundation, 22nd Annual Program and Slide Seminar of the Southcentral Division in Galveston, TX. Address correspondence and reprint requests to Markay L. Isaac, Texas A&M University College of Veterinary Medicine and Biomedical Sciences, College of Veterinary Medicine, 422 Raymond Stotzer Pkwy, College Station, TX, 77845. E-mail: [email protected] Received November 8, 2013; accepted for publication February 13, 2014. doi: 10.1111/vru.12175

Vet Radiol Ultrasound, Vol. 00, No. 0, 2014, pp 1–6.

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nodes were enlarged, measuring 11.2 and 11.7 mm wide. The small solid and cystic structures were considered to represent either smaller masses, or lymph nodes reacting to the concurrent mass-associated abdominal disease present.

FIG. 1. Right lateral abdomen (digital radiography): An approximately 24 × 20 cm soft tissue opaque mass was identified radiographically in the midcranial abdomen (black arrows).

caudal abdomen measuring 3–5 cm in diameter. These smaller cystic peritoneal masses were unassociated with each other or other organs. There were several solid, ovoid, encapsulated, and homogenously echogenic structures measuring 4.2 and 16 mm wide. Themedial iliac lymph

Considerations for the a typical cystic thick walled masses included a developmental anomaly of biliary, pancreatic, or lymphatic origin, an atypical blastic developmental tumor, hydatid cysts, or abscesses from other infectious diseases. Atypical metastatic neoplasia or fungal disease was considered but the organ of origin was not identified and this presentation was unusual. An exploratory laparotomy revealed that the multiple mid-abdominal cystic masses were adhered to omentum, and one mass was tightly adhered to the pancreas. There was no obvious direct organ involvement and the stomach, liver, kidneys, spleen, and intestines appeared grossly normal. The largest mass, which corresponded in size and location to the 16.5 cm diameter mass identified on ultrasound, revealed dark yellow-green colored fluid when incised, along with fibrous brown blood clots corresponding to the echogenic amorphous material on ultrasound (Fig. 3A). The second largest mass contained a serosanguinous fluid. This mass and some of the smaller cystic masses exhibited dramatic peristaltictype contractions both during the surgery and after the mass was removed (refer to online video on ACVR website).

FIG. 2. B-mode ultrasonographic images prior to initial laparotomy: (A) Sagittal image of cranial mass measuring 16.5 cm in diameter depicting the rounded to oblong shaped unattached masses and a small amount of echogenic amorphous material within the anechoic fluid filled lumen. (B) Transverse image depicting the masses displacing the stomach in a left-cranial direction and obscuring visualization of the adjacent pancreas. (C) Sagittal panoramic image with the left of the image corresponding to the cranial aspect of the abdomen. The most cranial mass had an anechoic fluid-filled lumen. Caudal to the first mass was a second mass diffusely filled with a mildly echogenic fluid with a thicker, more heterogeneous and porous looking wall. (Siemens brand, Antares model ultrasound, Medical Solutions, Malvern PA).

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FIG. 3. (A) The cranial mass excised at the initial laparotomy: Incision of the mass revealed many fibrous brown colored blood clots identified as echogenic structures and material on ultrasound. (B) Gross appearance of masses at the second laparotomy: Right lateral aspect showing the multiple midabdominal cystic masses adhered to omentum. The duodenum and pancreas are visible coursing along the surface of the cranial mass which was tightly adhered to the pancreas.

A third mass measuring 10 cm in diameter contained chylous type fluid. Due to tight adherence and/or shared blood supply between the masses and the adjacent pancreas and duodenum the second and third largest masses and some of the smaller cystic masses were not completely removed surgically; they were incised, drained, and omentalized. Five months after the initial surgery, the patient represented due to increasing lethargy, hyporexia, and discomfort exhibited for 3 weeks duration. Abdominal ultrasound revealed an increase in the number and size of masses consistent with progression of leiomyomatosis. The ultrasonographic appearance of the masses was similar to prior studies, with one containing fluid and several additional smaller echogenic luminal masses. The second mass had a thick wall and contained echogenic luminal fluid. There were multiple additional smaller cavitary masses present. A second exploratory laparotomy was performed. Two large masses and enlarged, discolored paracecal mesenteric masses/lymph nodes were excised. Approximately 40% of the right limb of the pancreas was removed due to concerns of vascular viability following dissection from the largest mass. The second smaller mass was adhered to the larger mass and the portal vein (Fig. 3B). During blunt dissection, the portal vein was perforated and repaired. Abnormal tissues were incompletely resected due to intimate connection to the portal vein and concern with the safety of resecting these masses. The patient was readmitted 15 months later to reassess the regrowth, accessibility, and the location of the masses by a CT angiogram and ultrasound exam to determine an appropriate course of action and the feasibility of surgical removal. An MRI examination was aborted due to safety concerns because of the multiple surgical metallic hemoclips located in the cranial to mid abdomen from the initial surgery. The multiple varying sized cavitary masses in the dorsal mid abdomen were consistent with the historic clusters of the leiomyomatosis masses (Fig. 4A and B). The masses had close apposition to the portal vein, pancreas,

caudate liver lobe, and caudal vena cava. The largest mass measured 5 cm in diameter and was located dorsal to the portal vein and between the portal vein and the caudal vena cava. The mass was abutting the ventral border of the caudal vena cava, the right kidney, and the pancreas. There were suspected adhesions to the surrounding organs as defined borders were not discernible. The portal vein was focally dilated caudal to the porta hepatis (Fig. 4C). The appearance corresponded to turbulent venous flow seen in a large aneurysmal dilation of the portal vein identified on a concurrent ultrasound study. The aneurysmal dilated portal vein measured up to 4.3 cm in diameter and was larger than the combined diameter of the aorta and caudal vena cava (Fig. 4D). The cause for the aneurysm was attributed to the previous surgical removal or debulking of the masses and repair of a focal rupture in the portal vein. There was a focal cluster of 7–9 smaller masses located to the left of the larger mass and directly ventral to the caudal vena cava and the aorta (Fig. 4E). They had a homogeneous central core and a mildly enhancing smooth thin wall around the rim of each mass. No metastasis to the lungs or other visceral organs was identified. Multiple, surgically excised, peritoneal, cystic, and fluid filled masses that sometimes contained a large to moderate amount of intraluminal necrotic debris and few paramesenteric lymph nodes were fixed in 10% buffered formalin and submitted for histopathologic evaluation. Multiple sections of the abdominal masses were routinely processed and stained with hematoxylin and eosin. The masses were composed of a poorly demarcated, encapsulated, densely cellular mesenchymal neoplasm formed by a population of well differentiated spindle to ovoid cells arranged in interweaving streams and intersecting bundles. The cells have variably distinct cell borders, a variable amount of fibrillar eosinophilic cytoplasm, and oval to cigar-shaped nuclei with finely stippled chromatin and inconspicuous nucleoli. Anisocytosis and anisokaryosis is mild and mitoses are

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FIG. 4. Post-Contrast CT images (103 ml iohexol (240 mgI/ml) IV): (A), (B) Dorsal plane: multiple varying sized cavitary masses (labeled M and N) in the dorsal mid abdomen consistent with the historic clusters of the leiomyomatosis masses. (C) Sagittal plane: focal dilation of the portal vein (labeled PV) caudal to the porta hepatis measuring up to 4.3 cm in diameter. (D) Axial plane showing portal vein aneurysm (labeled P). (E) Axial plane: focal cluster of 7–9 smaller masses (labeled N) located to the left of the larger mass (labeled M) and directly ventral to the caudal vena cava (labeled CVC) and the aorta (labeled AO). (Siemens brand, Somatom Definition AS 40 model CT, Muenchen, Germany; Helical acquisition (1.0 pitch, 0.0 tilt), 3 mm slice thickness, soft tissue window, 300 mA, 120 kVp).

uncommon. Scattered throughout the neoplasm are few areas of coagulative necrosis and hemorrhage. Multifocally the neoplasm was also infiltrated by a moderate number of macrophages, neutrophils, lymphocytes, plasma cells, and numerous mast cells. The neoplasm was strongly positive for smooth muscle actin (SMA), desmin, and vimentin; weakly positive to sarcomeric actin and negative for myoglobin and CD117. Thet cytologic and immunohistochemical characteristics of this neoplasm were consistent with a tumornlrg of smooth muscle origin, leiomyoma. A similar neoplastic population was infiltrating and effacing the normal lymphoid architecture of multiple paramesenteric lymph nodes removed during the second exploratory laparotomy.

Discussion The multicentric, cavitated, and variable sized abdominal masses composed of smooth cells in this intact male dog resemble a rare and benign condition referred to as disseminated peritoneal leiomyomatosis (DPL) in human literature. Disseminated peritoneal leiomyomatosis represents one type of rare extrauterine leiomyoma growth pattern where numerous variably sized nodules are adhered to omental or peritoneal surfaces within the abdomen.1 Veterinary literature references one case report of diffuse peritoneal leiomyomatosis in a 6-year-old Quarter Horse mare. The mare presented due to abdominal enlargement, occasional periods of mild colic, inappetance, pyrexia, and decreased weight. The ultrasonographic appearance of the

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mare’s abdomen was described similarly to this case in a dog. There was an abdominal mass made up of numerous variable sized cystic lesions detected next to the body wall in multiple locations. Dispersed within the cavitated structures were many rounded hyperechoic nodules. Histology of the mass provided the diagnosis of DPL. The mare experienced no complications or recurrences after undergoing a celiotomy and 34 kg mass removal.2 The etiology of DPL is controversial. In humans, leiomyomas occur most frequently as uterine neoplasms. Both uterine and atypical extrauterine growth patterns occur most commonly in women of reproductive age. Concurrent or previously resected primary uterine leiomyomas are frequently associated with subsequent development of histologically identical extrauterine leiomyomas.3,4 A review of the literature suggests a strong correlation between leiomyoma growth and estrogen and progesterone hormonal stimulation in humans; DPL is postulated to arise from subperitoneal mesenchymal stem cells under the influence of hormonal stimulation leading to tissue metaplasia. Therapies aimed at hormone manipulation including ovarioectomy and use of GnRH analogs have led to tumor regression in some cases.5–10 There are reports of DPL in males and post-menopausal women without evidence of excessive hormone production. In some of these cases, a hormonal influence has been theorized due to evidence of elevated tumor estrogen and progesterone receptors and sensitivity to normal hormone levels.8 Various pathological mechanisms that have been linked to extrauterine leiomyomas include hematogenous implantation, metastases, and laparoscopic iatrogenic dissemination from a primary uterine tumor.9–11 There are also rare but well-documented cases of leiomyomatosis associated with X-linked Alport syndrome, a hereditary nephropathy resulting from deletion mutations within COL4A5 and COL4A6 genes.12 Mutations in the fumarase hydratase (FH) gene are also known to cause leiomyomas.13 The possibility of an underlying genetic syndrome has also been suggested with reports of familial clustering of DPL.14 The young age, male sex, and lack of clinical signs of hyperestrogenism/feminization to substantiate a pathogenic hormonal influence provide no evidence to support castration or other therapeutic hormonal manipulation to influence tumor growth in this patient. It is the author’s opinion that the dog in this case may have at least one heritable genetic alteration leading to neoplastic growth. Ultrasonography, CT, and MRI are utilized in human medicine to help distinguish rare types of extrauterine leiomyomas from malignant abdominal tumors. Variable presentations range from numerous small masses to fewer large masses. Solid tumors are described as the classic leiomyoma appearance in human literature. Extrauterine

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leiomyomas have shown variable enhancement patterns and homogenous or heterogeneous attenuation similar to uterine leiomyomas on CT and ultrasound. MRI is particularly useful because leiomyomas exhibit signal intensity similar to smooth muscle on T1-weighted and T2-weighted sequences. Classic leiomyomas demonstrate homogenous enhancement following contrast administration.15 Degenerative leiomyomas with varying degrees of cavitation and areas of fibrosis and mineralization are reported in human literature.3,4,15–20 These masses are described as exhibiting heterogeneous signal intensity on T2-weighted images with necrotic areas lacking contrast enhancement.3,4,15 Extensive central necrosis, invasive growth, and a heterogeneous appearance are imaging findings described as suggestive but not definitively diagnostic of leiomyosarcoma.4,15 On ultrasound and gross examination, the masses present in this case in a dog as well as those described in the equine case, display imaging characteristics resembling degenerative cavitated masses. This is in contrast to the classic solid leiomyoma appearance typical of the majority of human cases referred to in the literature. Findings suggestive of possible malignant potential in this case report include tumor regrowth/recurrence without evidence to support hormonal influences, evidence of tumor cell lymph node invasion and the presence of large, degenerative, cavitated masses identified by ultrasonographic and CT examination. Case reports in human literature where malignant transformation was highly suspect displayed similar tumor characteristics.20 Diagnosis and treatment of DPL requires unique considerations. Despite the extreme rarity of this disease, it is important to include leiomyomatosis in the differential diagnosis of canine peritoneal masses in cases where there is contraction/peristalsis of masses or when similarly described cavitated masses without origination from an organ are seen. Prognosis is variable despite exhibiting predominately benign characteristics because of compression and/or occlusion of essential organs and vascular structures. Masses may be deemed nonresectable due to intimate connections, such as attachments and shared blood supply to the visceral organs, pancreas, portal vein, and the root of the mesentery seen in this case. Aggressive surgical excision has been curative in some cases described in human literature as well as in the equine case reported in veterinary literature. Although surgical excision has failed to fully eradicate the disease in this patient, alternatives such as chemotherapy and radiation therapy have been deemed poor considerations due to the slow rate of tumor growth in this case. It is important to note that discussion of treatment and options for management of this disease are primarily based on human literature since little can be concluded from treatment of a single veterinary patient. Continual monitoring for signs of potential malignant transformation of residual tumors is recommended. Ultrasound and further

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advanced imaging (CT, MRI) may aid in monitoring progression of disease in such cases. In summary, DPL, a rare form of multiple abdominal smooth muscle tumors has been diagnosed in a young, intact male dog. This disease should be considered in veterinary patients with similar clinical findings. The disease manifested as multiple cystic thick walled masses, some of which exhibited dramatic, atypical wall movement seen on the ultrasound study and gross specimen during and following surgical resection. It was attributed to stimulation

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of the muscular components of the mass. In the future, MRI and CT imaging in veterinary cases of DPL may help differentiate leiomyomas from highly aggressive abdominal neoplasms and potentially aid in surgical planning and outcome of similar cases. ACKNOWLEDGMENTS

The authors wish to sincerely thank J. Mansell and B. Porter for contributing to histology, immunohistochemistry and final diagnosis in this case. We also thank C. Wolff for contributing gross surgical images from the second exploratory laparotomy in this case.

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13. Tomlinson IPM, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomatoma and and papillary renal cell cancer. Nature Genetics 2002;30:406– 410. 14. Halama N, Grauling-Halama SA, Daboul I. Familial clustering of Leiomyomatosis peritonealis disseminata: an unknown genetic syndrome? BMC Gastroenterol 2005;5:33. 15. Fasih N, Prasad Shanbhogue AK, Macdonald DB. Leiomyomas beyond the uterus: unusual locations, rare manifestations. Radiographics 2008;28:1931–1948. 16. Billings SD, Folpe AL, Weiss SW. Do leiomyomas of deep soft tissue exist? An analysis of highly differentiated smooth muscle tumors of deep soft tissue supporting two distinct subtypes. Am J Surg Pathol 2001;25:1134– 1142. 17. Sala EJ, Atri M. Magnetic resonance imaging of benign adnexal disease. Top Magn Reson Imaging 2003;14:305–327. 18. Kim JC, Nam SL, Suh KS. Leiomyoma of the ovary mimicking mucinous cystadenoma. Clin Imaging 2000;24:34–37. 19. Wong-You-Cheong JJ, Woodward PJ, Manning MA, Sesterhenn IA. Neoplasms of the urinary bladder: radiologic-pathologic correlation. RadioGraphics 2006;26:553–580. 20. Bekkers RLM, Willemsen WNP, Schijf CPT, Massuger LFAG, Bulten J, Merkus JMWM. Leiomyomatosis peritonealis disseminata: does malignant transformation occur? A literature review. Gynecol Oncol 1999;75:158–163.

Supporting Information Additional supporting information may be found in the online version of this article at the publisher’s web site.