Journal of Veterinary Diagnostic Investigation

http://vdi.sagepub.com/ Uterine Neoplasia in 13 Cats

Margaret A. Miller, Jose A. Ramos-Vara, Mary F. Dickerson, Gayle C. Johnson, Lanny W. Pace, John M. Kreeger, Susan E. Turnquist and James R. Turk J VET Diagn Invest 2003 15: 515 DOI: 10.1177/104063870301500602 The online version of this article can be found at: http://vdi.sagepub.com/content/15/6/515

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J Vet Diagn Invest 15:575522 (2003)

Uterine neoplasia in 13 cats

Margaret A. Miller1, Jose A. Ramos-Vara, Mary F. Dickerson, Gayle C. Johnson, Lanny W. Pace, John M. Kreeger, Susan E. Turnquist, James R. Turk
Abstract. Thirteen uterine tumors were diagnosed in 13 cats and accounted for 0.29% of all feline neoplasms received during a 9.6-year period. Age at diagnosis ranged from 3 to 16 years; median 9 years. Six were Domestic Shorthair cats, and 7 were purebred cats of 5 different breeds. Eight adenocarcinomas and 1 mixed Mullerian tumor (adenosarcoma) comprised the endometrial tumors. Myometrial tumors included 3 leio myomas and 1 leiomyosarcoma. One of the adenocarcinomas developed in the uterine stump of an ovariohysterectomized cat; the other cats were sexually intact. Concurrent mammary adenocarcinoma was diagnosed in 1 cat with uterine adenocarcinoma and in another with uterine leiomyoma. Tumors were discovered during elective ovariohysterectomy in 2 cats, but at least 3 others had experienced reproductive problems (infertility or pyometra). Five cats presented for abdominal or pelvic masses. Endometrial adenocarcinomas were positive immunohistochemically for cytokeratins and negative for smooth muscle actin (SMA); 1 of 6 cats was positive for vimentin and 4 of 8 were positive for estrogen receptor (ER ). Adenosarcoma stromal cells were positive for vimentin and ER but negative for cytokeratins and SMA. Smooth muscle tumors were positive for vimentin and SMA and negative for cytokeratins. Leiomyomas, but not the leiomyosarcomas, were positive for ER . Adenocarcinomas in 4 cats had metastasized by the time of ovariohysterectomy. Two other cats were euthanized 5 months after ovariohysterectomy; at least one of these cats had developed an abdominal mass that was not examined histologically. Only 2 cats with endometrial adenocarcinoma had disease-free intervals longer than 5 months after surgery. Metastasis was not detected in any mesenchymal tumor; however, th ese cats were either euthanized on discovery of the tumor or the tumor was rst detected at necropsy.

Endometrial adenocarcinoma, the most common uterine epithelial tumor, is rare in domestic animals other than rabbits and cattle. 26 The most common mesenchymal tumor of the uterus is leiomyoma. 28 Uterine neoplasia is seemingly rare in cats. 44 No uterine neoplasms were recorded in separate reviews of 395 7 and 621 feline tumors, 17 and only 14 cases of uterine neoplasia (leiomyoma, 12,38,46 adenocarcinoma, 14,43,46 adenoma,43 leiomyosarcoma,46 or lymphosarcoma 13) were found in retrospective surveys of 165 571 cats with tumors. Uterine leiomyoma has been the most common tumor in retrospective studies limited to feline genital tract neoplasia. Four leiomyomas, 2 leiomyosarcomas, and 1 endometrial adenocarcinoma comprised the uterine tumors in 1 review. 24 In another report,8 there were 8 leiomyomas, 4 adenocarcinomas, and 3 leiomyosarcomas. In a 20-year survey, 7 leiomyomas, 1 leiomyosarcoma, and no adenocarcinomas were recorded.11 There have been additional case reports of endometrial adenocarcinoma, 5,6,19,27,30,31,3537,39,40 squamous cell carcinoma, 31 mixed Mullerian tumor 34 (also reported as mixed mesodermal tumor 15,20 or parFrom the Veterinary Medical Diagnostic Laboratory and Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, PO Box 6023, Columbia, MO 65205. Current address: Animal Disease Diagnostic Laboratory, 406 S. University St, West Lafayette, IN 47907 (Miller & Ramos-Vara). 1 Corresponding author.

amesonephric carcinosarcoma 37), leiomyosarcoma, 40 endothelioma4 or hemangioma,22 broadenoma,48 cystadenoma,10 and submucosal broma. 37 This study was performed to determine the number of submissions, signalment, histologic classication, immunohisto chemical characteristics, and outcome of feline uterine tumors submitted to the Veterinary Medical Diagnostic Laboratory. Materials and methods Case materials from all cats with uterine neoplasms diagnosed at the Veterinary Medical Diagnostic Laboratory from January 1, 1993, through July 31, 2002, were retrieved. Tissues had been xed in 10% neutral buffered formalin and embedded in parafn. Total fe line accessions, feline neoplasms, feline genital tract neoplasms, and feline uterine neoplasms were counted for the study period. Veterinarians who submitted specimens for necropsy or biopsy were interviewed by telephone to review signalment, pertinent history, and postsurgical outcome. One pathologist reviewed all hematoxylin and eosinstained sections of the tumors to standardize the diagnosis.1,26 Adenocarcinomas were evaluated histologically, without knowledge of tumor presentation or behavior, for features noted to have prognostic value in human endometrial carcinomas 3 (histologic pattern, nuclear atypicality, mitotic gures per 10 high -power
515

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516 Table 1.
Case No.

Miller et al. Signalment and history of 13 cats with uterine tumors.

Diagnosis

Breed

Age (yr)

History or concurrent disease

1 2 3 4 5 6 7 8 9 10 11 12 13 * DSH

Adenocarcinoma Adenocarcinoma Leiomyoma Adenocarcinoma Leiomyoma Leiomyoma Adenocarcinoma Leiomyosarcoma Adenocarcinoma Adenocarcinoma Adenosarcoma Adenocarcinoma Adenocarcinoma Domestic Shorthaired.

DSH* Siamese Himalayan Persian DSH DSH DSH Japanese Bobtail DSH Himalayan DSH Bengal Siamese

11 16 9 5 3 14 13 10 5 9 10 4 8

Weight loss, palpable abdominal mass Mammary adenocarcinoma discovered on routine examination Massive abdominal swelling, uterine enlargement Weight loss; uterus palpably turgid Fibroid noted on elective ovariohysterectomy Mammary adenocarcinoma, hepatic and renal disease, solitary uterine nodule Abdominal mass, pleural effusion, urolithiasis, hematuria Pyometra; nodules throughout uterus Elective ovariohysterectomy Hemorrhagic, malodorous vaginal discharge; infertility; weight loss; abdominal masses; uterine serosal and rete ovarian cysts Lethargy, anorexia; cavitated abdominal masses on ultrasound Infertility Stranguria, constipation, intrapelvic mass

elds, depth [absent, supercial, or deep] of myome trial invasion, and presence of vascular invasion). Histologic pattern was dened as the degree of solid ver sus glandular proliferation and categorized as 5%, 5 50%, or 50% solid. Nuclear atypia was characterized as mild ( ), moderate ( ), or marked ( ). Parafn sections were immunohistochemically stain ed41 using mouse monoclonal antisera against broad-spectrum cytokeratins (clones MNF116 and AE1/AE3), a vimentin-1,a and smooth muscle actin (SMA). a Immunohistochemistry with mouse monoclonal antisera against estrogen receptor (ER )b was performed according to a technique for feline mammary gland, 29 except that sections were steamed for 40 min, rather than being boiled for 25 min, in citric acid buffer, pH 6.0, for antigen retrieval. Epithelial tumors were also immunohistochemically stained using mouse monoclonal antisera against cytokeratin 7, a cytokeratin 8/18, b cytokeratin 20, b high molecular weight cytokeratins, a and low molecular weight cytokeratins. c Diaminobenzidine was used as the chromagen. Reactivity was semiquantitatively evaluated as weak, moderate, or strong with estimates of percentage of reactive cells (125%, 2650%, 5175%, or 76 100%). The age of cats with endometrial tumors was compared with that of cats with smooth muscle tumors by Students t-test. Differences in postsurgical survival of cats with endometrial adenocarcinoma were categorized and compared by histologic pattern (Students ttest), nuclear atypia (one-way analysis of variance), and expression of estrogen receptors (Students t-test). Signicance level was set at 0.05. Results During the 9.6-year period, 4,402 neoplasms were diagnosed from 10,976 feline accessions. Uterine tu-

mors were documented in 13 cats and included 8 adenocarcinomas, 1 adenosarcoma, 3 leiomyomas, and 1 leiomyosarcoma. Uterine tumors comprised 0.29% of all feline neoplasms and 0.12% of feline accessions during the study. The only other tumors of the female genital system during the study period were 4 granulosa-theca cell tumors and 1 adenoma of the oviduct. Signalment and history of the 13 cases of uterine neoplasia are summarized in Table 1. Six cats with uterine tumors were Domestic Shorthairs; 2 were Himalayan; 2 were Siamese; 1 each was Bengal, Persian, and Japanese Bobtail. Age at diagnosis ranged from 3 4.0 years; median, 9 years. to 16 years; mean, 9.0 The age of cats with endometrial tumors (adenocarcinoma or adenosarcoma) did not differ signicantly from that of cats with smooth muscle tumors (leiomyoma or leiomyosarcoma). Cats with adenocarcinoma had diverse histories. One tumor (cat No. 9) was discovered during elective ovariohysterectomy. The tumor in cat No. 2 was found during ovariohysterectomy and mastectomy for a mammary adenocarcinoma that had been discovered on routine physical examination. Two affected cats (Nos. 10 and 12) had historical infertility. Three cats (Nos. 1, 4, and 10) had historical weight loss. Four cats (Nos. 1, 7, 10, and 13) had abdominal or pelvic masses. Cat No. 7 was also dyspneic; clumps of neoplastic epithelial cells were observed on cytologic examination of the pleural effusion. Cat No. 10 had concomitant rete ovarian cysts and uterine serosal cysts. This cat presented with malodorous hemorrhagic to brinonecrotic vaginal discharge. Cat No. 13 had been spayed at the age of 6 months. It was treated with megestrol acetate from 3 to 6 years of age, whereupon the cat was diagnosed with vaginitis and therapy was discontinued. The cat developed stranguria and con-

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Feline uterine neoplasia Table 2. Immunohistochemistry results in 12 feline uterine tumors.*

Cytokeratins Diagnosis MNF 116 AE1/AE3 7 20 8/18 LMW HMW Vim SMA ER

517

Adenocarcinoma Adenosarcoma Epithelial cells Stromal cells Leiomyoma Leiomyosarcoma

6/6 1/1 0/1 0/2 0/1

6/6 1/1 0/1 0/2 0/1

3/6 ND ND ND ND

4/6 ND ND ND ND

3/6 ND ND ND ND

4/6 ND ND ND ND vimentin; SMA

4/6 ND ND ND ND

1/6 0/1 1/1 2/2 1/1

0/6 0/1 0/1 2/2 1/1

4/8 1/1 1/1 2/2 0/1 estrogen

* Number of positive tumors per number of tumors evaluated. LMW low molecular weight; HMW high molecular weight; Vim not determined. receptor- ; ND Broad-spectrum anticytokeratin.

smooth muscle actin; ER

stipation at the age of 8 years; intrapelvic extension of adenocarcinoma from the uterine stump was found on laparotomy. Although affected uteruses appeared abnormal (enlarged, thickened, or turgid) at surgery or necropsy, a discrete uterine mass was obvious grossly only in cat Nos. 1 and 2. Immunohistochemistry results are summarized in Table 2. All adenocarcinomas tested were positive for broad-spectrum cytokeratins, clones MNF 116 and AE1/AE3. Reactivity was uniform and strong in nonneoplastic endometrial glands. In neoplastic tissue, reactivity was usually moderate to strong and observed in 75% to 100% of tumor cells with clone AE1/AE3. Staining with clone MNF 116 was weaker than with AE1/AE3 in some cats and was observed in only about 25% of the tumor cells in cat No. 1; anti-MNF 116 antibodies seldom bound to cells in less-differentiated solid areas or to those with nuclear atypia. Reactivity with more specic anticytokeratins varied and was not observed in all adenocarcinomas or in all cells in a given tumor. With immunohistochemistry for ER , the
Table 3.
Case No. Nuclear atypia Mitotic index

nuclei of epithelial cells in nonneoplastic endometrial glands were uniformly and strongly positive. Neoplastic epithelial cells in 4 of 8 adenocarcinomas were negative for ER ; up to 25% of tumor cells had nuclear staining for ER in the remaining 4 tumors. Nonneoplastic glandular epithelium, in which nuclei were strongly positive for ER , was sharply demarcated from neoplastic tissue with positive staining only in scattered cells. With 1 exception (cat No. 1), in which patchy reactivity was observed, adenocarcinomas were negative for vimentin. All were negative for SMA. Histologic features and behavior of endometrial adenocarcinomas are summarized in Table 3. A tubulopapillary pattern (Fig. 1) predominated in all adenocarcinomas; solid proliferation of neoplastic cells (Fig. 2) comprised less than 50% of the tumor area in each case and less than 5% of tumor area in 3 cases. Neither histologic pattern nor mitotic index correlated with invasiveness of the tumor or outcome of the case. On the other hand, all 3 tumors with marked nuclear atypia had deep myometrial and vascular invasions; me-

Histologic features and behavior of 8 feline endometrial adenocarcinomas.

Myometrial invasion Vascular invasion Gross ndings

% Solid*

Outcome

1 2 4 7 9 10 12 13

550 550 550 5 5 5 550 550

10 7 5 1 8 2 36 48

Deep Deep Supercial Supercial None None None Deep

Yes Yes No No No No No Yes

Transmural uterine mass; peritoneal carcinomatosis Multiple masses, left uterine horn Thickened endometrium, serosal adhesions Thickened and turgid uterus, pulmonary metastases No metastasis Peritoneal carcinomatosis Unremarkable; mass not evident Peritoneal carcinomatosis

Euthanized on date of surgery Euthanized 5 mo after surgery Healthy 48 mo after surgery Diagnosed at necropsy Healthy 14 mo after surgery Euthanized on date of surgery Weight loss and vomiting 5 mo after surgery; euthanized Euthanized on date of surgery

* Histologic pattern for all tumors was predominantly tubulopapillary; data indicate percentage of histologic pattern comprising solid tumor formation. Number of mitotic gures per 10 high power elds.

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Figure 1. Uterus; cat No. 9. Endometrial adenocarcinoma with tubulopapillary pattern, negligible solid proliferation, and mild nuclear atypia. HE. Figure 2. Uterus; cat No. 1. Endometrial adenocarcinoma with tubular formations and solid proliferation of neoplastic cells. Nuclear atypia is high. HE. Figure 3. Uterus; cat No. 11. Endometrial adenosarcoma presents as multiple polypoid masses in the opened uterus. HE. Figure 4. Uterus; cat No. 11. Endometrial adenosarcoma. Endometrial stroma is expanded by neoplastic spindle cells. Scattered cystic spaces are lined by well-differentiated glandular epithelium. Inset: Nuclear atypia in malignant stromal cells. HE. Figure 5. Uterus; cat No. 3. Myometrial leiomyoma. Tumor is formed of bundles of well-differentiated smooth muscle cells without mitotic gures. HE. Figure 6. Uterus; cat No. 8. Myometrial leiomyosarcoma. Tumor cells bear little resemblance to smooth muscle. HE.

tastasis was documented in 2 of these cases. Myometrial invasion was supercial or not observed, and vas cular invasion was absent in tumors with mild or moderate nuclear atypia. However, 2 tumors that showed only moderate nuclear atypia, myometrial invasion

that was supercial or absent, and absence of vascular invasion (in the sections examined) metastasized. Postsurgical survival time did not differ signicantly when categorized by the degree of nuclear atypia in tumor cells. The 4 adenocarcinomas that were negative for

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ER included all 3 tumors with marked nuclear atypia (at least 2 of which metastasized) and 1 tumor with moderate atypia (cat No. 7) that metastasized to the lungs. The 4 cats with ER -negative tumors survived 05 months after surgery; mean, 1.2 2.5 months; and the 4 cats with ER -positive tumors survived 0 48 months after surgery; mean, 16.8 21.6 months. This difference was not statistically signicant, and 1 of the 4 ER -positive tumors also metastasized. In all, adenocarcinomas in 4 cats were documented to have spread beyond the uterus as abdominal or pelvic masses, peritoneal carcinomatosis, or pulmonary nodules. Two other cats were euthanized 5 months after surgery but were not evaluated postmortem for metastasis. Only 2 cats with endometrial adenocarcinoma survived longer than 5 months after surgery. One of these cats (No. 9), in which the ER -positive tumor had less than 5% solid histologic pattern and only mild nuclear atypia, was documented to be healthy when last examined, 14 months after surgery. The other surviving cat (No. 4), with 5 50% solid proliferation and moderate nuclear atypia in an ER -positive tumor, was reportedly healthy 48 months after ovariohysterectomy. The cat with endometrial adenosarcoma (cat No. 11, Table 1) was euthanized after presenting with lethargy, anorexia, and multiple cavitated abdominal masses evident ultrasonically. At necropsy, the uterus was distended by about 300 ml of occulent, red -brown uid without appreciable odor. Multiple polypoid masses in the endometrium of each horn protruded into the uterine lumen (Fig. 3). Cystic spaces, up to 1 cm in diameter, within each mass were lled with brown gran ular uid. Histologically, 1 mass consisted only of cys tic endometrial glands separated by abundant endometrial stroma without apparent neoplastic change. This was interpreted as an endometrial polyp. However, in the other masses (Fig. 4), endometrial stroma between the cystic endometrial glands was expanded by sheets of plump spindloid cells with oval hypochromic nuclei, clumped chromatin, considerable variation in nuclear diameter, distinct nucleoli, 45 mitotic gures per 10 high-power elds, and scanty eosino philic cytoplasm with distinct cell borders. Hyperplastic but well-differentiated glandular epithelium lined the cystic spaces. Neoplastic tissue did not invade the myometrium. Endometrium between the polypoid masses was affected by mild cystic endometrial hyperplasia without evidence of neoplasia. With immunohistochemistry (Table 2), the benign epithelial components of the adenosarcoma were consistently positive for cytokeratins and usually positive for ER . The malignant stromal cells were positive for vimentin and negative for SMA and cytokeratin. About 25% of neoplastic stromal cells were positive for ER . No metastasis was detected macroscopically or histologically.

The leiomyomas (Table 1) were solitary uterine masses. Two cases were discovered either at elective ovariohysterectomy (cat No. 5) or as an incidental nding at necropsy in a cat (No. 6) with concurrent mammary adenocarcinoma as well as hepatic and renal disease. Cat No. 3 presented in distress with swollen abdomen; the uterine leiomyoma was discovered during laparotomy. The leiomyosarcoma (Table 1) was discovered during ovariohysterectomy for pyometra and vaginal discharge in cat No. 8 and appeared as multiple nodules throughout both uterine horns and the uterine body. Histologically, leiomyomas comprised somewhat disorganized and hypercellular bundles of slightly atypical smooth muscle cells with no mitotic gures in 10 high-power elds (Fig. 5). Stromal brous collagen was scanty to abundant. Tumor nodules were generally demarcated from adjacent nonneoplastic smooth muscle of the myometrium. The leiomyosarcoma was less circumscribed, and tumor cells were more atypical with 4 mitotic gures per 10 high -power elds (Fig. 6). Smooth muscle tumors were positive for vimentin and SMA and were uniformly negative for broad-spectrum cytokeratins (Table 2). Nonneoplastic uterine smooth muscle cells were uniformly positive for ER . Tumor cells in leiomyomas, but not in the leiomyosarcoma, were also positive for ER but with less staining intensity than in nonneoplastic myometrium. Postsurgical outcome was not available for any smooth muscle tumor because these cats were either euthanized at the time of tumor discovery or lost to follow-up. However, no metastasis was detected in the cat with leiomyosarcoma at necropsy. Discussion Although the uterus was the most common site of feline reproductive tract tumors, the 13 uterine tumors comprised only 0.29% of all feline neoplasms diagnosed during the study period, conrming that uterine tumors are uncommon in cats. 7,17 Both endometrial and smooth muscle tumors were observed mainly in older cats, although tumors were found in cats as young as 3 or 4 years of age. Breed predilection for uterine tumors was not apparent. A higher proportion of purebred cats than in the general diagnostic laboratory population likely reects the probability that more pure bred cats than Domestic Shorthair cats attain advanced age sexually intact. Cats may be protected from uterine neoplasia by the frequent practice of ovariohysterectomy, but 1 cat in this study was spayed at 6 months of age and still developed adenocarcinoma in the uterine stump. Uterine adenocarcinoma has been reported previously in the uterine stump of a spayed cat.31 Endometrial adenocarcinoma was the most common uterine tumor. Although leiomyoma was the most common feline uterine tumor in previous reports, 8,11,24

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Miller et al.

adenocarcinomas were twice as common as smooth muscle tumors in this study. At least 4 of 8 adenocarcinomas had metastasized by the time of diagnosis. Uterine adenocarcinomas have been reported in most domestic species but are considered rare except in rabbits and cows. 26 The rabbit has a reported 79% prevalence of uterine adenocarcinoma after 5 years of age.18 Because this induced ovulator is often housed individually, the laboratory rabbit and perhaps many pet rabbits are under almost constant estrogen stimulation. Virgin (but not breeding) Han:Wistar rats have a similar high incidence of endometrial adenocarcinomas.16 Cats, as another induced ovulator, may also be subjected to long periods of unopposed estrogen stimulation, but the frequent practice of neutering queens or the tendency to periodically breed or induce ovulation in sexually intact queens 44 may explain the low prevalence of endometrial adenocarcinoma in cats. In women, postmenopausal hormone replacement therapy, estrogen in particular, is considered a risk factor for endometrial adenocarcinoma; both estrogen-dependent and higher-grade estrogen-independent adenocarcinomas are recognized. 3 Half the feline adenocarcinomas in this study had cells positive for estrogen receptors by immunohistochemistry. Tumors with marked nuclear atypia and those that metastasized usually did not express estrogen receptors. This loss of expression of estrogen receptors in these tumors suggests estrogen independence and may indicate a worse prognosis. The endometrial carcinoma of cattle is histologically distinct as a scirrhous carcinoma, 26 and affected cows are less likely to have been exposed to prolonged unopposed estrogen stimulation. Identication of broad -spectrum (AE1/AE3 and MNF 116) cytokeratins by immunohistochemistry in all adenocarcinomas tested was not surprising; yet, in another study, an endometrial carcinoma was the only 1 of 28 feline epithelial tumors that did not react to antibodies against high or low molecular weight cytokeratins.30 Use of a different source of commercial antibodies or variation in the differentiation of tumor cells could explain this apparent discrepancy. In this study, reactivity with AE1/AE3 was generally more intense and more frequent than with MNF 116. Staining for low and high molecular weight cytokeratins was variably positive, often infrequent, and usually only weak to moderate in intensity. The main criterion for grading human endometrial adenocarcinomas is the degree of glandular differentiation, with a scheme in which grade 1 tumors have 5% solid pattern; grade 2, 5 50% solid pattern; and grade 3, 50% solid pattern, although some pathologists consider the degree of nuclear atypia to be of equal or greater importance. 3 In comparison to human tumors, feline tumors had greater glandular differen-

tiation and always less than 50% solid pattern, even in cases with marked nuclear atypia and in cases that metastasized. Nuclear atypia, however, was striking in some of the feline adenocarcinomas. All 3 tumors with marked nuclear atypia were locally invasive; at least 2 of the 3 tumors metastasized and none expressed estrogen receptors. Staging of adenocarcinomas in this study was hampered by the fact that only portions of most tumors were submitted for histologic evaluation. Thus, determination of the degree or presence of myometrial or vascular invasion may have been inaccurate. Mitotic index did not correlate with other grading or staging criteria or with tumor behavior. For all tumors, correlation of histologic appearance with biologic behavior was difcult because many cats we re euthanized at the time of diagnosis and few were subjected to necropsy. In a study33 using transuterine fetal injection with allogeneic mammary carcinoma cell lines, 3 of 13 queens developed metastasizing uterine carcinomas, 6 to 31 months after injection. The authors hypothesized that the immunotolerant status of the pregnant uterus facilitated transplantation of tumor cells that had leaked into the uterus during fetal injection. Those tumors were apparently transplanted mammary carcinomas rather than adenocarcinomas derived from endometrial epithelium. In this study, none of the tumors developed in pregnant cats. One adenocarcinoma was documented in a cat that also had mammary adenocarcinoma and both tumors were considered primary. The adenosarcoma may have arisen in endometrial polyps. The tumor masses resembled endometrial polyps grossly, and at least 1 mass was histologically consistent with feline endometrial polyp. 23 Adenosarcoma is an endometrial stromal tumor that is composed of both mesenchymal and epithelial elements. 1 These mixed Mullerian tumors are categorized as adenobro ma, adenosarcoma, carcinobroma, or carcinosarcor na, depending on whether epithelial and mesenchymal components are benign or malignant; however, many pathologists doubt the existence of mixed Mullerian tumors with benign stromal components (adenobro ma or carcinobroma). 1 Carcinosarcomas are the most common mixed Mullerian tumors in women, 1 and previously reported feline mixed Mullerian tumors15,20,34,37 differed from the cat in this report in that the tumors had both malignant epithelial and stromal elements and thus would be classied as carcinosarcomas. The epithelial component of adenosarcoma, on the other hand, lacks features of malignancy, whereas the stromal cells have low-grade malignant features. 1 Human endometrial adenosarcomas may be polypoid and multiple, as was the tumor in the cat in this study, and seldom invade the myometrium. 1 Leiomyoma was the second most common tumor in

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this study. It is also the most common genital tumor in zoo felids and was observed (usually in the uterus) in 24% of 219 zoo felids surveyed. 9 Genital tract leiomyomas in bitches may affect the uterus but are more common in vaginal smooth muscle. 11 Uterine leiomyoma is the most common tumor of aged female guinea pigs and frequently accompanies cystic rete ovarii. 21 In this study, rete ovarian cysts were observed in 1 cat only, and this cat had endometrial adenocarcinoma. Uterine leiomyoma is the second most common tumor (after pituitary adenoma) in the gray short-tailed opossum, Monodelphis domestica.25 Six of 9 female whales had genital tract bro leiomyomas; 1 was in the uterus; half the tumors had 1030% ER-positive cells.32 Both leiomyomas tested in this study were positive for ER by immunohistochemistry. Leiomyoma (broid) is the most common uterine tumor in women of reproductive age. 2 Eker rats have high incidence of spontaneous uterine leiomyoma and have been developed as an animal model of broids. 45 The rat tumor and tumor-derived cell lines have heightened estrogen responsiveness; estrogen receptor antagonists, such as tamoxifen and raloxifene, suppress proliferation of tumor cell lines or transplanted tumors in nude mice and reduce the incidence of spontaneous tumors in the Eker rat. 45 Progesterone may increase risk for uterine leiomyoma in women 42 and experimentally in rats,47 but no correlation between progestin therapy and presence of genital tract leiomyomas was apparent in zoo felids. 9 Only 1 cat in this study was known to have been treated with the progestin megestrol acetate, and this cat developed endometrial adenocarcinoma. The intact female cat, unless induced to ovulate or treated with synthetic progestins, is more frequently subjected to high levels of estrogen than progesterone, especially if persistent seasonal or nonseasonal estrus develops; therefore, hormonally responsive uterine disease in cats is more likely the result of estrogen stimulation. 44 Although women with uterine leiomyoma are often younger (premenopausal)2 than those with endometrial carcinoma, 3 age differences between cats with smooth muscle cell tumors and those with adenocarcinoma were not noted in this study. Feline uterine leiomyomas may be multiple,8,11,12,35 but were apparently solitary in the 3 cats of this study. The case of leiomyosarcoma did present as multiple masses. Leiomyosarcoma was less common than leiomyoma as in other studies of domestic cats, 8,11,24 zoo cats,9 and women.2 Uterine leiomyosarcoma in women is less well circumscribed than is leiomyoma with higher mitotic index and myometrial invasion. 2 In zoo felids, mitotic index was not useful in distinguishing malignant from benign smooth muscle tumors, but the pres-

ence of local invasion did predict aggressive behavior. 9 The feline leiomyosarcoma in this study had histologic features of malignancy but had not metastasized by the time of necropsy. In a previous study, metastasis was documented in 2 of 3 feline uterine leiomyosarcomas.8 Results of this study conrm the rarity of uterine tumors in cats; yet, the uterus is the most common site for neoplasia in the feline genital tract. Purebred and Domestic Shorthair cats from 3 to 16 years of age were affected. With 1 exception, affected cats were sexually intact. Endometrial adenocarcinomas were more common than smooth muscle tumors. At least half the adenocarcinomas metastasized. Only 2 cats with adenocarcinoma survived longer than 5 months after ovariohysterectomy. Metastasis was not documented for any mesenchymal tumor. Nuclear atypia and loss of estrogen receptor expression may predict metastatic potential, but postsurgical follow-up of more cases of feline uterine tumors is needed to characterize their behavior. Acknowledgements
The authors thank Drs. D. Bojrab, D. Brinker, V. Capron, C. Cupp, D. Farmer, V. Gaeke, T. Holt, C. Johannes, D. Lange, J. Mrkvicka, S. Sczepanski, C. Truss, and A. Watkins for submission of tumor specimens and provision of historical and follow-up information. The authors also thank Don Connor and Howard Wilson for assistance with preparation of illustrations.

Sources and manufacturers

a. Broad-spectrum cytokeratin, code M0821, clone MNF116; broad-spectrum cytokeratin, code M3515, clone AE1/AE3; cytokeratin 7, code M7018; highmolecular weight cytokeratins, code M0630; vimentin-1, code M0720; smooth muscle actin, code M0851; Dako, Carpinteria, CA. b. Estrogen receptor- , code NCL-ER-6F11; cytokeratin 8/18, code NCL-5D3; cytokeratin 20, code NCL-CK20; Novocastra Laboratories, Newcastle upon Tyne, UK. c. Low-molecular-weight cytokeratins, code 5T35D3; Thermo Shandon, Pittsburgh, PA.

References
1. Anderson MC, Robboy SJ, Russell P: 2002, Endometrial tumors with a stromal component. In: Pathology of the female reproductive tract, ed. Robboy SJ, Anderson MC, Russell P, pp. 361 387. Churchill Livingstone, London, UK. 2. Anderson MC, Robboy SJ, Russell P: 2002, Uterine smooth muscle tumors. In: Pathology of the female reproductive tract, ed. Robboy SJ, Anderson MC, Russell P, pp. 389 414. Churchill Livingstone, London, UK. 3. Anderson MC, Robboy SJ, Russell P, Morse A: 2002, Endometrial carcinoma. In: Pathology of the female reproductive tract, ed. Robboy SJ, Anderson MC, Russell P, pp. 331359. Churchill Livingstone, London, UK. 4. Ball V: 1932, Le cancer de luterus chez les femelees domes tiques. Rec Vet J Med Vet 84:72. 5. Belter LF, Crawford EM, Bates HR: 1968, Endometrial adenocarcinoma in a cat. Pathol Vet 5:429 431.

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Miller et al. tems. In: Tumors in domestic animals, ed. Meuten DJ, 4th ed., pp. 547573. Iowa State University Press, Ames, IA. Martn de las Mulas J: 2000, Immunohistochemical analysis of estrogen receptors in feline mammary gland benign and malignant lesions: comparison with biochemical assay. Domest Anim Endocrinol 18:111125. Martn de las Mulas J, Espinosa de los Monteros A, Carrasco L, et al.: 1995, Immunohistochemical distribution pattern of intermediate lament proteins in 50 feline neoplasms. Vet Pathol 32:692701. Meier H: 1956, Carcinoma of the uterus in the cat: two cases. Cornell Vet 46:188200. Mikaelian I, Labelle P, Dore M, Martineau D: 2000, Fibroleiomyomas of the tubular genitalia in female beluga whales. J Vet Diagn Invest 12:371374. Minke JM, Hensen EJ, Misdorp W: 1995, Uterine carcinomas in mother cats after intrafetal inoculation of allogeneic tumor cells (K248 C and P). Vet Immunol Immunopathol 46:361 366. Nico`tina PA, Zangh` A, Catone G: 2002, Uterine malignant mixed Mullerian tumor (metaplasic carcinoma) in the cat: clinicopathologic features and proliferation indices. Vet Pathol 39: 158160. Norris HJ, Garner FM, Taylor HB: 1969, Pathology of feline ovarian neoplasms. J Pathol 97:138143. ORourke MD, Geib LW: 1970, Endometrial adenocarcinoma in a cat. Cornell Vet 60:598604. Papparella S, Roperto F: 1984, Spontaneous uterine tumors in three cats. Vet Pathol 21:257258. Patnaik AK, Liu SK, Hurvitz AI, McClelland AJ: 1975, Nonhematopoietic neoplasms in cats. J Natl Cancer Inst 54:855 860. Preiser H: 1964, Endometrial adenocarcinoma in a cat. Vet Pathol 1:485490. Priester WA, McKay FW: 1980, The occurrence of tumors in domestic animals. Natl Cancer Inst Monogr 54:1210. Ramos-Vara JA, Beissenherz ME: 2000, Optimization of immunohistochemical methods using two different antigen retrieval methods on formalin-xed parafn -embedded tissues: experience with 63 markers. J Vet Diagn Invest 12:307 311. Rein MS, Barbieri RL, Friedman AJ: 1995, Progesterone: a critical role in the pathogenesis of uterine myomas. Am J Obstet Gynecol 172:1418. Schmidt RE, Langham RF: 1967, A survey of feline neoplasms. J Am Vet Med Assoc 151:13251328. Stabenfeldt GH, Pedersen NC: 1991, Reproduction and reproductive disorders. In: Feline husbandry: diseases and management in the multiple-cat environment, ed. Pedersen NC, pp. 129162. American Veterinary Publications Inc., Goleta, CA. Walker CL: 2002, Role of hormonal and reproductive factors in the etiology and treatment of uterine leiomyoma. Recent Prog Horm Res 57:277294. Whitehead JE: 1967, Neoplasia in the cat. Vet Med Small Anim Clin 62:357358. Yamate J, Tsujino K, Kumagai D, et al.: 1998, Inuence of progesterone and oestrogen on growth and morphology of a transplantable rat uterine smooth muscle tumour (SMT-Y). J Comp Pathol 119:443457. Zietzschmann H: 1901, Ein Fall von Fibroadenom pericanaliculare im Euter der Katze. Bericht uber das Veterinarwesen im Konigreich Sachsen 46:198200.

6. Breton C, Fontaine JJ: 1990, Cas dadenocarcinoma uterin chez une chatte. Point Vet 22:767773. 7. Brodey RS: 1970, Canine and feline neoplasia. Adv Vet Sci Comp Med 14:309354. 8. Carpenter JL, Andrews LK, Holzworth J: 1987, Tumors and tumor-like lesions. In: Diseases of the cat: medicine and surgery, ed. Holzworth J, pp. 406 596. WB Saunders, Philadelphia, PA. 9. Chassy LM, Gardner IA, Plotka ED, Munson L: 2002, Genital tract smooth muscle tumors are common in zoo felids but are not associated with melengestrol acetate contraceptive treatment. Vet Pathol 39:379385. 10. Collet P: 1933, Tumeur primitive de 1uterus chez une chatte. Bull Soc Sci Vet Lyon 36:199202. 11. Cooper BJ, Valentine BA: 2002, Tumors of muscle. In: Tumors in domestic animals, ed. Meuten DJ, 4th ed., pp. 319 363. Iowa State University Press, Ames, IA. 12. Cotchin E: 1956, Further examples of spontaneous neoplasms in the domestic cat. Br Vet J 112:263272. 13. Cotchin E: 1957, Neoplasia in the cat. Vet Rec 69:425 434. 14. Cotchin E: 1959, Some tumours of dogs and cats of comparative veterinary and human interest. Vet Rec 71:1040 1050. 15. Cotchin E: 1977, Spontaneous tumors of the uterus and ovaries in animals. In: Animal tumors of the female reproductive tract: spontaneous and experimental, ed. Cotchin E, Marchant J, pp. 2665. Springer-Verlag, New York, NY. 16. Deerberg F, Rehm S, Pitterman W: 1981, Uncommon frequency of adenocarcinomas of the uterus in virgin Han:Wistar rats. Vet Pathol 18:707. 17. Dorn CR, Taylor DO, Schneider R, et al.: 1968, Survey of animal neoplasms in Alameda and Contra Costa Counties, California. II. Cancer morbidity in dogs and cats from Alameda County. J Natl Cancer Inst 40:307318. 18. Elsinghorst TA, Timmermans HJ, Hendriks HG: 1984, Comparative pathology of endometrial carcinoma. Vet Q 6:200 208. 19. Engle GC, Brodey RS: 1969, A retrospective study of 395 feline neoplasms. J Am Anim Hosp Assoc 5:21 31. 20. Evans JG, Grant DI: 1977, A mixed mesodermal tumour in the uterus of a cat. J Comp Pathol 87:635 638. 21. Field KJ, Grifth JW, Lang CM: 1989, Spontaneous reproduc tive tract leiomyomas in aged guinea-pigs. J Comp Pathol 101: 287294. 22. Fukui K, Matsuda H: 1983, Uterine haemangioma in a cat. Vet Rec 113:375. 23. Gelberg HB, McEntee K: 1984, Hyperplastic endometrial polyps in the dog and cat. Vet Pathol 21:570 573. 24. Gilmore CE: 1965, Tumors of the female reproductive tract. Calif Vet 19:1215. 25. Hubbard GB, Mahaney MC, Gleiser CA, et al.: 1997, Spontaneous pathology of the gray short-tailed opossum (Monodelphis domestica). Lab Anim Sci 47:1926. 26. Kennedy PC, Cullen JM, Edwards JF, et al.: 1998, Tumors of the uterus. In: Histological classication of tum ors of the genital system of domestic animals, ed. by Cullen JM & Edwards JF, 2nd ed., pp. 3233. Armed Forces Institute of Pathology, Washington, DC. 27. Kermen WR: 1935, Ovarian cyst in a cat [and adenocarcinoma of the uterus]. J Am Vet Med Assoc 86:96 97. 28. MacLachlan NJ, Kennedy PC: 2002, Tumors of the genital sys-

29.

30.

31. 32.

33.

34.

35. 36. 37. 38.

39. 40. 41.

42.

43. 44.

45.

46. 47.

48.

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