Tumors of Muscle

11
Tumors of Muscle


Barry J. Cooper1 and Beth A. Valentine2


1 Cornell University, USA


2 Oregon State University, USA


Muscle tissue occurs within many systems of the body and includes both striated (skeletal and cardiac) and smooth muscle. Skeletal muscle forms the postural, locomotory, abdominal, and respiratory muscles (diaphragm, intercostal, and laryngeal) as well as part of the digestive system (tongue, pharynx, and part of the esophagus in the dog and cat). Cardiac muscle occurs only within the heart. Smooth muscle is widely dispersed throughout the body and is found in the tunics of the gastrointestinal and genitourinary tracts, in the tracheobronchial tree, in the vascular system, in the skin associated with hair follicles (arrector pili muscles), and even within the uveal tract of the eye. As a result, there is a wide range of possible expression of myogenic tumors within the body.


The use of cell culture techniques and specific cell markers has indicated that pluripotential cells of such diverse lineage as germ cell, neural crest, and mesenchyme can undergo myogenic differentiation. Although light microscopic features are still useful for identification of myogenic tumors, in many instances a definitive diagnosis may rely on application of electron microscopic and/or immunohistochemical (IHC) techniques. Separate sections describe both the electron microscopic features and the most useful IHC procedures for diagnosis and differentiation of tumors of smooth muscle and of striated muscle.


The information provided in this chapter is based on a review of the literature, the authors’ own experience, and a search conducted of the pathology files of the College of Veterinary Medicine at Cornell University for a period of 20 years, during which time approximately 83,000 tumor diagnoses were made. All tumors with a diagnosis of rhabdomyoma or rhabdomyosarcoma were reviewed and subjected to IHC studies, but only a representative sample of the smooth muscle tumors were reviewed and immunostained.


TUMORS OF SMOOTH MUSCLE


General considerations


Classification and general histological features


Tumors composed primarily of smooth muscle have been traditionally divided into benign tumors (leiomyomas) or malignant tumors (leiomyosarcomas). The differentiation of leiomyoma from leiomyosarcoma can generally be made with reasonable certainty based on gross and light microscopic features. Mitotic count and determination of nucleolar organizer regions have both been shown to be useful in distinguishing benign from malignant smooth muscle tumors.1 Mitotic count is clearly more easily determined as a routine procedure. Increased nuclear density, variability of nuclear and cellular sizes, lack of sharp demarcation, and infiltration at the periphery of the tumor are still practical means to favor malignant behavior in routine histologic sections.


The recognition of nonlymphoid, non‐angiogenic intestinal mesenchymal tumors of the gastrointestinal tract (NIMT) has produced some confusion about nomenclature while accurately identifying cells of origin for the different mesenchymal tumors in the intestines. Possible cells of origin are smooth muscle cells, fibroblasts, neural cells, and interstitial cells of Cajal. Tumors of the latter cells are classified as gastrointestinal stromal tumors (GISTs).2,3 These tumors are common in dogs and many prior diagnoses and reports of intestinal leyiomyomas and leiomyosarcomas erroneously included GISTs. Future studies need to determine the clinical characteristics of the different NIMTs and whether the name of the tumor is less important than proliferative and nuclear features to predict behavior, analagous to subcutaneous soft tissue saromas.


Presently GISTs are characterized by positive immunolabeling with c‐kit (CD117) and negative staining for KIT is used to rule out GIST. Smooth muscle tumors express smooth muscle actin and should be KIT negative. However, since a proportion of GISTs also express smooth muscle actin, smooth muscle actin cannot be used alone as the criterion for smooth muscle origin. There are no reliable histologic features to distinguish GIST from smooth muscle tumors in sections stained with H&E and therefore KIT and smooth muscle actin should be used in tandem. An intestinal mesenchymal tumor that looks like a smooth muscle tumor but that is smooth muscle actin negative and KIT positive is classified as GIST; a tumor that is smooth muscle actin positive and KIT negative is leiomyoma or leiomyosarcoma; a tumor that is positive for both smooth muscle actin and KIT is also a GIST. Exceptions must exist or will be identified but this general approach is the starting point.


The greatest difficulty in distinguishing a gastrointestinal smooth muscle tumor from a GIST may occur with tumors that have features of sarcoma, and it is likely that over half of gastrointestinal tumors previously designated as leiomyosarcoma in veterinary medicine are actually GISTs.3 This information should be kept in mind when reviewing older literature (including that cited in this chapter) as well as when interpreting the findings from the search of the Cornell University College of Veterinary Medicine files described in this chapter. It is somewhat awkward, but we have inserted “tumors diagnosed as” when the data presented predates use of c‐kit IHC. More information on GISTs is provided in Chapter 13 (Tumors of the Alimentary Tract).


Leiomyomas are discrete, non‐encapsulated, non‐invasive tumors. Characteristic features are a relatively homogeneous population of densely packed spindle cells with indistinguishable cytoplasmic borders and elongate, blunt‐ended (cigar‐shaped) nuclei, arranged in broad interlacing fascicles that mimic normal smooth muscle tissue (Figure 11.1A–C). Fascicles are often described as intersecting at 90 degree angles, forming a herringbone pattern, but in our experience this feature is neither consistent nor pathognomonic. There may be alternating “bands” of nuclei that are elongated and fusiform adjacent to bands of round nuclei created by cutting cells longitudinally or transversely (Figure 11.1C). The cytoplasm is often strongly eosinophilic. Vacuolization, similar to that seen in hypertrophic smooth muscle, may also be seen. Variation from this “typical” histological pattern occurs, however, particularly in cutaneous leiomyomas, in which cells may be more heterogeneous, with scattered binucleate or multinucleate cells and moderate anisokaryosis (Figure 11.1D). These features in a cutaneous smooth muscle tumor most often do not indicate an aggressive growth pattern. Mitoses are uncommon; in one study the average mitotic count of canine leiomyomas was only 0.05 (5 mitoses/100 high power fields (HPF) (400×)).1 Although large tumors may have surface ulceration, these tumors do not typically undergo necrosis. Well‐differentiated leiomyomas may be difficult to distinguish from normal smooth muscle, but the presence of a nodular mass, often with some degree of disorientation of cells, characterizes the mass as a tumor.

Micrograph of gastric leiomyoma in dog illustrating a demarcation between the tumor at the bottom of the figure and the normal gastric smooth muscle at the top.
Micrograph of cutaneous leiomyoma in ferret illustrating the formation of compressive encapsulated dermal nodule.
Micrograph of gastric leiomyoma in dog demonstrating the tumor cells forming broad interlacing fascicles that mimic normal smooth muscle.
Micrograph of nuclear and cellular pleomorphism in a cutaneous leiomyoma of a ferret.

Figure 11.1 Leiomyoma. (A) Gastric leiomyoma, dog. Note clear demarcation between the tumor at the bottom of the figure and the normal gastric smooth muscle at the top. (B) Cutaneous leiomyoma, ferret, forming a compressive encapsulated dermal nodule. (C) Gastric leiomyoma, dog. The tumor cells form broad interlacing fascicles that mimic normal smooth muscle. This example has the characteristic pattern of bands of elongated nuceli, cut longitudnally lying adjacent to bands of round nuclei cut on cross‐section. (D) Nuclear and cellular pleomorphism in a cutaneous leiomyoma, ferret. Despite the pleomorphism this tumor was cured by excision.


Leiomyosarcomas, in contrast, are non‐encapsulated and frequently invasive tumors. Histological features are quite variable. These tumors may be formed by densely packed, relatively homogeneous spindle cells that retain many features of normal smooth muscle cells and tissue, or by more pleomorphic spindle to ovoid or round cells with variable histological patterns. Mitoses are present and may be numerous. An average mitotic count of 1.65 (1–2 mitoses/400× field) has been reported in canine tumors diagnosed as leiomyosarcomas.1 Well‐differentiated leiomyosarcomas may be composed of spindle cells with elongate nuclei with granular chromatin and abundant eosinophilic cytoplasm, forming broad interlacing fascicles (Figure 11.2A); only evidence of invasion, mitotic count, and/or areas of tumor necrosis distinguish them from leiomyoma. Less well‐differentiated leiomyosarcomas appear much more cellular due to diminished cytoplasm and closely packed nuclei that may be round to elongate, with chromatin that may be granular or markedly dispersed (Figures 11.2B and 11.3A,B). The cells may retain the typical broad interlacing fascicular pattern; however fascicles may be short and narrow, forming more of a basketweave pattern, or interlacing fascicles may be inapparent in many areas of the tumor. Binucleate, multinucleate, and bizarre cells are common in more poorly differentiated leiomyosarcomas (Figure 11.4). Areas of tumor necrosis are common, and areas of necrosis and inflammation can result in marked edema and distortion of histological features. A dispersed or plexiform pattern of growth or a microcystic change within the tumor can also obscure the typical leiomyosarcoma pattern of broad interlacing fascicles, leaving pleomorphic and often attenuated cells interspersed in a collagenous or edematous stroma (Figure 11.5). Areas of hemorrhage may also occur. In some instances it may be difficult to distinguish between a leiomyoma and a well‐differentiated leiomyosarcoma. The most useful features suggesting malignancy are (1) a mitotic count of 1/10 400× HPF or more, (2) evidence of invasion, and (3) areas of tumor necrosis.

Micrograph of a well-differentiated intra-abdominal leiomyosarcoma of ferret.
Micrograph of vaginal leiomyosarcoma in dog demonstrating haphazardly arranged spindle cells and scattered mitoses.

Figure 11.2 Leiomyosarcoma. (A) Well‐differentiated intra‐abdominal leiomyosarcoma, ferret. (B) Vaginal leiomyosarcoma, dog. Note haphazardly arranged spindle cells and scattered mitoses.

Micrograph of splenic leiomyosarcoma with metastasis to the liver of dog illustrating the interlacing fascicles of densely packed spindle cells in the splenic tumor and the nuclei being crowded together.
Micrograph of infiltrative growth of tumor cells metastatic to the liver of dog illustrating heterogeneous nuclear shapes and sizes, varying from round to fusiform.

Figure 11.3 Splenic leiomyosarcoma with metastasis to the liver, dog. (A) Interlacing fascicles of densely packed spindle cells in the splenic tumor. Nuclei are crowded together and cell borders are not discernible. (B) Infiltrative growth of tumor cells metastatic to the liver. Nuclear shapes and sizes are heterogeneous, varying from round to fusiform; cells with eosinophilic cytoplasm are hepatocytes.

Micrograph of pleomorphic leiomyosarcoma in the spleen of dog illustrating round to spindle cells exhibiting marked cellular and nuclear pleomorphism.
Micrograph of pleomorphic leiomyosarcoma in the spleen of dog illustrating scattered cells demonstrating dense intracytoplasmic desmin expression.
Micrograph of pleomorphic leiomyosarcoma in the spleen of dog illustrating scattered cells with dense intracytoplasmic expression of smooth muscle actin.

Figure 11.4 Pleomorphic leiomyosarcoma, spleen, dog. (A) Round to spindle cells exhibiting marked cellular and nuclear pleomorphism. Tumors this poorly differentiated require IHC for definitive diagnosis. (B) Same tumor with scattered cells demonstrating dense intracytoplasmic desmin expression. (C) Same tumor with scattered cells demonstrating dense intracytoplasmic expression of smooth muscle actin.

Micrograph of the plexiform pattern of leiomyosarcoma illustrating admixed dense collagen in a vaginal leiomyosarcoma of dog.
Micrograph illustrating the patterns of leiomyosarcoma with microcystic change within a colonic leiomyosarcoma of dog.
Two micrographs illustrating the patterns of leiomyosarcoma being positive for muscle-specific actin with positively stained blood vessels providing an internal control.
Two micrographs illustrating the patterns of leiomyosarcoma being positive for muscle-specific actin with positively stained blood vessels providing an internal control.

Figure 11.5 Patterns of leiomyosarcoma. (A) Plexiform pattern of leiomyosarcoma with admixed dense collagen in a vaginal leiomyosarcoma, dog. (B) Microcystic change within a colonic leiomyosarcoma, dog. (C,D) Both tumors were positive for muscle‐specific actin; positively stained blood vessels provide an internal control.


Given that many gastrointestinal tumors previously described as leiomyosarcoma are likely to be GISTs it is difficult to make statements regarding the potential for metastatic spread of leiomyosarcoma with any certainty. A 50% incidence of metastasis (6 of 12) of canine tumors diagnosed as leiomyosarcoma was reported in one study.1 As described in the following text, certain sites of origin appear to have a higher incidence of metastasis (e.g., duodenum, spleen, and liver in the dog). If these tumors arise within abdominal organs or viscera, they may achieve a large size before becoming clinically apparent. Metastasis may be obvious at the time of diagnosis or may become evident months to years later. Metastatic leiomyosarcoma may occur as an expansile tumor nodule within the affected organ. Metastatic foci within the lung and liver, however, often have a locally infiltrative growth pattern, dissecting between hepatic cords and growing along alveolar walls, similar to what may be seen in metastatic hemangiosarcoma in these sites (Figure 11.3B). It must be pointed out, however, that although these tumors demonstrate the interlacing bundles of spindle cells considered characteristic of leiomyosarcoma, in our experience IHC procedures often fail to demonstrate convincing smooth muscle differentiation, and it is quite possible that some of these tumors are actually undifferentiated sarcomas or malignant GISTs.


When these tumors occur within well‐recognized anatomic sites of smooth muscle, such as the intestinal and genitourinary system, a diagnosis of a putative smooth muscle tumor or GIST is readily made. In some cases it may be difficult to distinguish these tumors from other mesenchymal spindle cell tumors, especially when collagenous tissue is a large component of the tumor or when tumors arise from sites such as the arrector pili muscles of the skin, smooth muscle within the hepatobiliary system, or smooth muscle within organ capsules and trabeculae. Special stains, such as Masson’s trichrome, Gomori’s trichrome, and Van Gieson stains, which differentially stain muscle and collagenous elements, may be of some value in the diagnosis of relatively well‐differentiated leiomyomas, but they should not be considered reliable indicators of muscle origin and are not useful in the diagnosis of leiomyosarcoma. Stains such as phosphotungstic acid hematoxylin (PTAH), used to distinguish myofibrils, have not proven to be useful for identification of smooth muscle tumors in our hands. Suspect cases may require electron microscopy or, better yet, IHC procedures for a definitive diagnosis. IHC procedures are rapidly replacing electron microscopy in the determination of tumor cell origin or differentiation, due to their ease of implementation and their sensitivity and specificity. In addition to c‐kit‐positive GISTs, many spindle cell tumors and tumor‐like lesions may have histological features reminiscent of smooth muscle differentiation, including fibroma, fibrosarcoma, collagenous nevus (dermatofibroma), schwannoma, malignant nerve sheath tumor, vaccine‐associated sarcoma in the cat, hemangiosarcoma, hemangiopericytoma, sarcoid, rhabdomyosarcoma, and undifferentiated sarcoma. Although the prognosis may not be different in some cases in which a spindle cell tumor of non‐smooth muscle origin is misdiagnosed as a leiomyoma or leiomyosarcoma (or vice versa), there are cases in which this distinction is important. For example, GISTs may respond to treatment with tyrosine kinase inhibitor drugs, and regression of equine sarcoid may be achieved following various local therapies.


Again, the tumor site is an important consideration. A spindle cell tumor of the stomach is much more likely to be leiomyoma than leiomyosarcoma or a GIST.4,5 In contrast, a spindle cell tumor of the large intestine is more likely to be a GIST.4 Leiomyosarcoma of the oral cavity and subcutis is likely to be overdiagnosed in veterinary pathology; although it is possible that a smooth muscle tumor could arise within the oral cavity, we have been unable to confirm this diagnosis with IHC staining; smooth muscle tumors of the skin and subcutis are extremely uncommon, and most of those identified appear to be benign.


The presence of fibrous connective tissue within a smooth muscle tumor, does not, in the authors’ opinion, warrant designation as a separate entity; hence those female genital tract tumors previously designated as fibroleiomyomas are discussed under the heading of leiomyoma and multicentric leiomyomas/leiomyosarcomas. In many of these female genital tract tumors, differentiation of a neoplastic from a reactive process has not been firmly established. Similarly, dispersed cutaneous leiomyoma is likely to be hamartomatous rather than neoplastic in nature (Figure 11.6). Lastly, there are entities in which a mixture of cell and tissue types, including smooth muscle and vascular elements, has given rise to terms such as angioleiomyoma.

Micrograph of arrector pili hamartoma of a dog illustrating the dispersed pattern of tumor cells mimicking arrector pili muscles in the dermis.
Micrograph of arrector pili hamartoma of a dog, displaying the diffuse expression of desmin within tumor cells.

Figure 11.6 Arrector pili hamartoma, dog. (A) Dispersed pattern of tumor cells mimicking arrector pili muscles in the dermis. (B) Diffuse expression of desmin within tumor cells. The neoplastic cells were also positive for muscle‐specific actin.


The relatively recent recognition of the capacity of fibroblastic cells to differentiate to form myofibroblasts, expressing actin, within tumors as well as within granulation tissue where myofibroblasts were first identified, adds another layer of complexity to the classification of connective tissue tumors. Such tumors are, however, considered by the authors to be primarily of fibroblastic origin and will not be discussed in this chapter.


Clinicopathologic features


Cytologic evaluation of tumors of smooth muscle origin typically reveals a spindle cell population rendering a diagnosis of mesenchymal tumor, but cytologic features do not allow for a more definitive diagnosis.


A smooth muscle tumor–associated paraneoplastic syndrome has been recognized; 12 dogs with intra‐abdominal smooth muscle tumors have presented with profound hypoglycemia with resultant clinical signs of weakness and/or seizures.6–9 Blood insulin levels have been either low6–8 or normal.6,7 In one more recent study of canine gastrointestinal tumors diagnosed as leiomyosarcoma approximately half were hypoglycemic, although peritonitis due to gastrointestinal perforation was considered to be a likely contributing factor in most of these cases.10 Both leiomyoma and tumors diagnosed as leiomyosarcoma have been associated with hypoglycemia, and resection of the tumor resulted in normalization of blood glucose levels. Tumors reported have been in the stomach (6 cases), jejunum (3 cases), duodenum (1 case), spleen (1 case), and liver (1 case). It is interesting to note that this syndrome has not been reported associated with smooth muscle tumors of the genitourinary system. It will be important to see if this paraneoplastic syndrome is reported for GIST or if it remains a unique marker for smooth muscle tumors in the intestines.


IHC staining of four tumors for insulin and glucagon indicated that all tumors were negative for insulin production, but three out of four stained positively for glucagon.7 The mechanism by which these tumors produce hypoglycemia is not clear, as glucagon production would not be expected to do so. Possible mechanisms include increased utilization of carbohydrates by tumor cells and, for tumors within the liver, hepatic dysfunction. Neither of these explanations is considered likely, and the most likely explanation is believed to be production of an insulin‐like molecule, such as insulin‐like growth factor 2 (IGF‐2), resulting in altered glucose homeostasis.6,7 Increased IGF‐2 levels in serum and tumor tissue of a dog with gastric leiomyoma have been reported.9 Anemia is another common, although nonspecific, clinicopathologic finding.10


References



  1. 1. Johnson, G.C., Miller, M.A., and Ramos‐Vara, J.A. (1995) Comparison of argyrophilic nucleolar organizer regions (AgNORs) and mitotic index in distinguishing benign from malignant canine smooth muscle tumors and in separating inflammatory hyperplasia from neoplastic lesions of the urinary bladder mucosa. J Vet Diag Invest 7:127–136.
  2. 2. LaRock, R.G. and Ginn, P.E. (1997) Immunohistochemical staining characteristics of canine gastrointestinal stromal tumors. Vet Pathol 34:303–311.
  3. 3. Russell, K.N., Mehler, S.J., Skorupski, K.A., et al. (2007) Clinical and immunohistochemical differentiation of gastrointestinal stromal tumors from leiomyosarcoma in dogs: 42 cases (1990–2003). J Am Vet Med Assoc 230:1329–1333.
  4. 4. Gillespie, V., Baer, K., Farrelly, J., et al. (2011) Canine gastrointestinal stromal tumors: immunohistochemical expression of CD34 and examination of prognostic indicators including proliferation markers Ki67 and AgNor. Vet Pathol 48:283–291.
  5. 5. Bettini, G., Morini, M., and Marcato, P.S. (2003) Gastrointestinal spindle cell tumours of the dog: histological and immunohisochemical study. J Comp Pathol 129:283–293.
  6. 6. Bagley, R.S., Levy, J.K., and Malarkey, D.E. (1996) Hypoglycemia associated with intra‐abdominal leiomyoma and leiomyosarcoma in six dogs. J Am Vet Med Assoc 208:69–71.
  7. 7. Beaudry, D., Knapp, D.Q., Montgomery, T., et al. (1995) Hypoglycemia in four dogs with smooth muscle tumors. J Vet Intern Med 9:415–418.
  8. 8. Bellah, J.R. and Ginn, P.E. (1996) Gastric leiomyosarcoma associated with hypoglycemia in a dog. J Am Anim Hosp Assoc 32:283–286.
  9. 9. Boari, A., Barreca, A., Bestetti, G.E., et al. (1995) Hypoglycemia in a dog with a leiomyoma of the gastric wall producing an insulin‐like growth factor II‐like peptide. Eur J Endocrinol 132:678–679.
  10. 10. Cohen, M., Post, G.S., and Wright, J.C. (2003) Gastrointestinal leiomyosarcoma in 14 dogs. J Vet Intern Med 17:107–110.

Electron microscopic features


Cytoplasmic filaments with plasma membrane–associated dense bodies are the most characteristic ultrastructural feature of smooth muscle differentiation in tumors (Figure 11.7).1 Other features that may be seen are intercellular attachment plaques and pinocytotic vesicles.1–4 A basal lamina may be present and may be either complete1 or incomplete.2,4

Micrograph of the ultrastructural features of smooth muscle differentiation in gastrointestinal stromal tumor of horse with cells exhibiting bundles of cytoplasmic filaments associated with dense bodies.

Figure 11.7 Ultrastructural features of smooth muscle differentiation in gastrointestinal stromal tumor, horse. Cells exhibit bundles of cytoplasmic filaments with associated dense bodies, partial basal lamina, and surface attachment plaques.


(Image courtesy of John Cummings and Fabio Del Piero, Louisiana State University.)


Immunohistochemical features


The information in this section pertains to IHC studies utilizing formalin‐fixed, paraffin‐embedded tissues and is derived from results of IHC characterization of selected smooth muscle tumors in the Cornell files and from a review of the literature. As a general rule, all IHC procedures should include positive control tissue as well as negative control sections in which the primary antibody has been either deleted or replaced by an irrelevant antibody. Internal control tissue is ideal, and the ubiquitous presence of vascular smooth muscle accomplishes this and allows for ease of interpretation of results of smooth muscle–reactive antibody preparations. If no vascular smooth muscle staining is visible, either there was a procedural error, or the tissue tested is unsuitable for IHC staining for the antibody and technique employed. Special techniques such as trypsinization or microwave exposure of the section may “unmask” hidden antigens. On the other hand, nonspecific background staining that may occur with these procedures can also render accurate interpretation impossible.


Although reports of IHC studies of tumors often imply that interpretation of such preparations is clear‐cut, our experience suggests that in some cases, a definitive interpretation of results may not be possible. Obviously, more differentiated tumors express many markers more effectively, and the results of IHC can be straightforward. Less‐differentiated tumors, however, may have a relatively small percentage of cells that react positively. In these cases, using multiple antibodies, changing antibody concentrations, changing incubation times, or employing additional techniques such as transmission electron microscopy may all be necessary to definitively rule in or rule out muscle origin.


Care must also be taken not to interpret staining of vascular smooth muscle in highly vascular tumors or, especially, entrapped smooth or skeletal myofibers as evidence for muscle origin of the tumor in question. Tumors of myofibroblasts or tumors with myofibroblasts present as a reactive process will also express muscle‐specific actin and α‐smooth muscle actin; interpretation must therefore always take into account the context in which cells expressing muscle actin are encountered. The use of IHC preparations cannot ever replace the instincts of an experienced pathologist.


Antibodies to desmin and muscle‐specific actin, which recognize both skeletal and smooth muscle actins, detect cytoskeletal proteins specific for muscle differentiation, but they do not distinguish among tumors of smooth muscle, cardiac muscle, and skeletal muscle. In one study of canine smooth muscle tumors, 14 of 22 tumors identified histologically as leiomyoma or leiomyosarcoma stained positively for desmin. Only 2 of 11 tumors diagnosed as leiomyomas failed to stain positively, whereas 4 of 11 leiomyosarcomas were negative for desmin, and two gave equivocal results.4 However, no mention was made of internal control (vascular smooth muscle) staining in this report to validate the negative findings. The two leiomyomas that did not stain with desmin were vaginal and perineal, and it is possible that these tumors were fibromas rather than leiomyomas. The leiomyosarcomas that did not stain with desmin were reported to have occurred within the abdomen or intestine and may, in fact, have been GISTs lacking smooth muscle differentiation. In a study of 19 bovine myogenic tumors, 14 of 15 tumors identified as either leiomyoma or leiomyosarcoma stained positively with muscle‐specific actin.5


It has been our experience that desmin may be a less reliable antibody than muscle‐specific actin for diagnosis of tumors of smooth muscle in routinely processed tissue. Therefore, for differentiation of myogenic and nonmyogenic tumors, we have relied on antibodies to muscle‐specific actin. Poorly differentiated smooth muscle tumors may, however, react with antibodies to either desmin or muscle‐specific actin, but not both; therefore, use of both antibodies may be prudent. Antibodies to both desmin and muscle‐specific actin bind diffusely and uniformly to cells of leiomyomas (Figure 11.6B), and either diffuse or patchy staining of varied intensity is often seen in leiomyosarcoma (Figure 11.4A).


Alpha‐smooth muscle actin is a specific marker for smooth muscle differentiation and can distinguish smooth muscle tumors from tumors of skeletal or cardiac muscle. It has been used successfully to study routinely processed animal tumors and appears to have in large part supplanted use of the broad‐spectrum muscle actin in diagnostic pathology. In our experience, antibodies to α‐smooth muscle actin react in a similar pattern to, but more intensely than, antibodies to muscle‐specific actin (Figure 11.4C). For routine diagnostic purposes, however, histopathologic features of most cases accurately distinguish smooth muscle tumors from tumors of skeletal muscle. Therefore, use of this antibody can be reserved for those tumors in which rhabdomyoma or rhabdomyosarcoma are on the list of differential diagnoses, as tumors of skeletal muscle origin almost always express desmin and/or muscle‐specific actin but rarely express α‐smooth muscle actin. Furthermore, identification by electron microscopic examination of primitive myofibrils resembling sarcomeric structures will differentiate these tumors (see Special diagnostic procedures in section on Tumors of skeletal muscle). More recently, IHC identifications of caldesmon, estrogen receptors, and progesterone receptors have been employed in diagnosis of genital smooth muscle tumor in women6 and in animals.7,8


Vimentin is an intermediate filament expressed by many tumor cells of mesenchymal origin and may even be expressed by cells of poorly differentiated epithelial tumors. When applied to tumors of suspected smooth muscle origin, vimentin is considered a nonspecific marker more commonly expressed in less well‐differentiated tumors,5 but this expression may be quite variable. For example, we have found strong vimentin expression in cutaneous leiomyomas but not in leiomyomas in other sites. Other authors report vimentin positivity in 60% of canine gastrointestinal leiomyomas.9 The major utility of vimentin may be in differentiating fibroblastic and undifferentiated mesenchymal tumors from smooth muscle tumors (i.e., tumors that are positive for vimentin but that do not express desmin, muscle‐specific actin, or α‐smooth muscle actin are most likely to be fibrosarcomas, undifferentiated sarcomas, or GISTs), but even here the value of vimentin expression is questionable due to its nonspecificity. Vimentin may also be useful as a control for the “stainability” of the tissue, although the vascular elements provide an internal positive control for muscle actin and smooth muscle actin.


References



  1. 1. Anjiki, T., Takeya, G., Hashimoto, N., and Kadota, K. (1991) An ultrastructural study of vulval myofibroblastoma in a cow. J Vet Med A 38:770–775.
  2. 2. Seely, J.C., Cosenza, S.F., and Montgomery, C.A. (1978) Leiomyosarcoma of the canine urinary bladder, with metastases. J Am Vet Med Assoc 172:1427–1429.
  3. 3. Hanzaike, T., Ito, I., Ishikawa, T., Ishikawa, Y., and Kadota, K. (1995) Leiomyosarcoma of soft tissue in a cow. J Comp Pathol 112:237–242.
  4. 4. Andreason, C.B. and Mahaffey, E.A. (1987) Immunohistochemical demonstration of desmin in canine smooth muscle tumors. Vet Pathol 24:211–215.
  5. 5. Une, Y., Shirota, K., and Nomura, Y. (1993) Immunostaining of bovine myogenic tumors. Vet Pathol 30:455.
  6. 6. McCluggage, W.G. (2002) Recent advances in immunohistochemistry in gynaecological pathology. Histopathology 40:309–326.
  7. 7. Ilha, M.R.S., Newman, S.J., van Amstel. S., et al. (2010) Uterine lesions in 32 female miniature pet pigs. Vet Pathol 47:1071–1075.
  8. 8. Cooper, T.K., Ronnett, B.M., Ruben, D.S. and Zink, M.C. (2006) Uterine myxoid leiomyosarcoma with widespread metastases in a cat. Vet Pathol 43:552–556.
  9. 9. Bettini, G., Morini, M., and Marcato, P.S. (2003) Gastrointestinal spindle cell tumours of the dog: histological and immunohistochemical study. J Comp Pathol 129:283–293.

Smooth muscle tumors of the gastrointestinal system


Leiomyoma


Incidence, age, breed, and sex


Although uncommonly reported, benign nonlymphoid mesenchymal gastrointestinal tumors with features of leiomyoma are commonly encountered at necropsy, especially in the dog. These tumors occur in mature to aged dogs. In one report, 2 of 20 canine gastric neoplasms were diagnosed as leiomyomas.1 In a study of laboratory beagles, esophageal/gastric leiomyoma occurred with equal incidence in males and females and was age‐related, with tumors found in 82% of dogs 17–18 years of age.2 Increased incidence of gastric leiomyomas in aged animals was also reported in a study in which 15 of 17 gastric leiomyomas were diagnosed in dogs 11 years of age or older, with an average age of 16 years3 and in another study in which 5 of 6 gastric leiomyomas were in dogs over 11 years of age.4 A strong male predominance was found in two studies,3,5 but not in another study.2 A search of the Cornell pathology files (Table 11.1) found 309 canine leiomyomas in which the system of origin was recorded, and over half (162 cases) occurred within the gastrointestinal tract. However, as mentioned in the introduction of this chapter, many of these tumors located in the intestinal tract could have been GIST.


Table 11.1 Three hundred sixty‐six tumors diagnosed as leiomyoma of the dog, cat, cow, and horse in which the specific site of origin was identified in the Cornell files from 1977 to 1997


































































































































Site Dog Dog, % by site Cata Cow Horse
Esophagus 18 6 0 0 0
Stomach 77 25 6 0 2
Small intestine 21 7 4 0 12
Ileocecal 0 0 1 0 0
Large intestine (including rectum and anus) 43 14 0 0 1
Cecum 3 1 0 0 1
Gall bladder 10 3 1 0 NA
Urinary bladder 29 9 5 0 1
Vulva 16 5 0 0 1
Vagina/cervix 58 19 1 3 3
Uterus 25 8 5 2 2
Ovary 2 0.5 1 0 0
Testis 0 0 0 0 4
Skin 5 2 0 0 0
Spleen 2 0.5 0 0 0
Iris 0 0 1 0 0
Total 309 100.0 25 5 27

NA, not applicable.


aIncludes two exotic cats.


Although leiomyoma occurred in many breeds, the poodle and chihuahua appeared to be overrepresented. More evidence for an apparent breed predilection is found in one study3 in which poodles were the breed most commonly affected by gastric leiomyoma (5 of 17), followed by chihuahuas (3 of 17). No breed disposition for gastrointestinal leiomyoma was found in a study of 10 dogs.4 In the Cornell files, leiomyomas were also common in German shepherds, Labrador retrievers, golden retrievers, and beagles, although this may reflect the popularity of these breeds. Gastrointestinal leiomyoma was also common in German shepherds in a study of files from the Armed Forces Institute of Pathology.5 Interestingly, gastrointestinal leiomyoma appears to be uncommon in the boxer dog, with only one reported case found.5


Leiomyoma of the gastrointestinal tract is much less common in other species. In the Cornell files, gastrointestinal leiomyomas occurred in 11 cats, with no apparent breed or sex predisposition. Intestinal leiomyomas have been reported in 4 horses and 1 mule,6–10 in which ages ranged from 2 years to 15 years. Sixteen leiomyomas of the equine gastrointestinal tract were found in the Cornell files. These occurred in several breeds including mixed breeds; although many were quarter horse–related breeds and thoroughbreds, this may represent the popularity of these breeds. These tumors are uncommonly reported in the cow, perhaps due to the relatively young age at which most cattle are necropsied. A leiomyoma of the spiral colon has been reported in a 10‐year‐old cow.11 We have also seen a leiomyoma of the omasum in a goat.


Clinical characteristics and sites


These tumors are most often encountered in the dog as incidental findings at necropsy. Large masses may cause clinical signs of obstruction, particularly if they occur at outflow sites such as the esophageal/gastric area or pylorus or at sites such as the colorectal or anorectal region, where signs of obstruction and/or obvious tumor occur. They may be multiple, especially in the stomach wall. In one report, canine leiomyomas were most common at the esophageal/gastric junction.2 In another report, 5 of 14 canine gastrointestinal leiomyomas occurred in the stomach.3 A study from the Armed Forces Institute of Pathology found that 22 of 29 (76%) of canine leiomyomas occurred in the stomach, 4 occurred in the esophagus, and 1 each was found in small intestine, large intestine, and rectum.5 The stomach was also the most common site of canine gastrointestinal spindle cell tumors diagnosed as leiomyoma in the Cornell pathology files (77/309 cases; 25%). The large intestine was the second most frequent site of canine spindle cell tumors diagnosed as leiomyomas (46 cases; Table 11.1). Large intestinal spindle cell tumors diagnosed as leiomyomas were most common in the colorectal or anorectal region, although 3 were found in the cecum. The diagnosis of leiomyoma of the esophagus and of the small intestine occurred at about equal frequency in the dog (18 and 21 cases, respectively). Interestingly, no intestinal leiomyomas were diagnosed in one study of 64 dogs with intestinal tumors.3


In the Cornell files, feline gastric and small intestinal spindle cell tumors diagnosed as leiomyomas occurred with about equal frequency (6 and 4 cases, respectively). One feline leiomyoma occurred at the ileocecal junction, but none was diagnosed in more distal large intestine. In the horse, intestinal spindle cell tumors diagnosed as leiomyoma may occur in either the small or large intestine and may cause obstruction and colic6 or intussusception,7,8 or they can be an incidental finding.9 A small intestinal obstruction caused by an equine jejunal spindle cell tumor diagnosed as leiomyoma resulted in gastric rupture.10 Spindle cell tumors diagnosed as leiomyoma of the stomach were found as an incidental finding at necropsy in two horses at Cornell, and equine tumors diagnosed as leiomyoma were more common in the small intestine (12 cases) than in the large intestine (2 cases). The spiral colon leiomyoma in the cow resulted in ruminal stasis and melena,11 and the omasal tumor in the goat was an incidental finding at necropsy.


Gross morphology


These tumors within the gastrointestinal tract can be seen to arise from within the smooth muscle tunics and are generally broad‐based, sessile tumors that frequently bulge into the lumen or from the external wall of the affected organ. These tumors are not encapsulated but are discrete. Neither mucosal ulceration nor tumor necrosis are characteristic, although the large size of many leiomyomas may result in mechanical ulceration. On section, these masses are semifirm to firm, solid, and pale pink to tan. The edges of the tumor may be distinct or may blend with the adjacent smooth muscle.


Histological features, growth, and metastasis


Histological features of gastrointestinal leiomyomas are as described above under Classification and general histological features. The degree of fibrous connective tissue admixed with smooth muscle varies considerably, and defining a leiomyoma as a well‐differentiated spindle cell tumor with minimal fibrous stroma is inappropriate, as leiomyomas may have a substantial collagen component. A proliferating population of fibroblasts, however, is not typical of leiomyoma, and if present, the tumor is more appropriately classified as a GIST and IHC stains for c‐KIT and smooth muscle actin should be applied. Gastrointestinal leiomyomas are non‐invasive and do not metastasize; therefore surgical excision of the tumor and any associated devitalized bowel is generally curative. If hypoglycemia was present preoperatively it will be corrected by removal of the tumor.


Leiomyosarcoma


Incidence, age, breed, and sex


Gastrointestinal spindle cell tumors diagnosed as leiomyosarcoma are most common in the dog, and are second only to epithelial malignancy within the canine gastrointestinal tract.3,12 A review of records for a 5‐year period at the Animal Medical Center found that 23 of 44 spindle cell tumors diagnosed as leiomyosarcomas in dogs occurred within the gastrointestinal tract (16 of 44 were in the spleen).12 Results of review of the Cornell cases of spindle cell tumors diagnosed as leiomyosarcoma are presented in Table 11.2. Of the 158 total canine tumors diagnosed as leiomyosarcomas in the Cornell files, 100 (61%) were reported as occurring in the gastrointestinal tract, and approximately 50% of these were in the small intestine. As previously described, however, a proportion of these tumors, particularly those in the small and large intestine, would likely prove to be GISTs if c‐KIT and other IHC procedures were employed. An earlier study reported that spindle cell tumors diagnosed as leiomyosarcoma of the intestine occurred in female dogs approximately twice as frequently as in males,3 but a similar female predisposition was not found in a subsequent study,12 a male predisposition was found in another study,13 and no sex predisposition was apparent following review of the Cornell files.


Table 11.2 One hundred eighty‐two tumors diagnosed as leiomyosarcoma of the dog, cat, and horse in which the specific site of origin was identified in the Cornell files from 1977 to 1997






























































































Site Dog Dog, % by site Cat Horse
Esophagus 1 0.5 0 0
Stomach 11 7 2 0
Small intestine 46 29 6 1
Ileocecal 3 2 3 1
Large intestine (including rectum and anus) 15 10 3 0
Cecum 24 15 0 0
Spleen 21 13 2 0
Liver 1 0.5 0 0
Urinary bladder 15 10 4 0
Ureter 1 0.5 0 0
Vulva/vagina 13 8 0 0
Uterus 1 0.5 1 0
Perineal/pelvic canal 6 4 1 0
Total 158 100.0 22 2

Although an intestinal leiomyosarcoma was diagnosed in a 17‐month‐old dog,14 the majority of cases occurred in dogs 10 years of age or older. The average age of dogs with gastric spindle cell tumors diagnosed as leiomyosarcoma was reported to be 7 years, and it was 11 years for dogs with intestinal spindle cell tumors diagnosed as leiomyosarcoma.3 Intestinal leiomyosarcoma has been reported in all breeds and may be more common in mixed breeds,3 but no breed predisposition for spindle cell tumors diagnosed as leiomyosarcoma was reported in a study of 44 cases.12 One study suggested that German shepherds may be predisposed to leiomyosarcoma,3 and German shepherds and poodles were the most common breeds diagnosed with this tumor in the Cornell files.


Gastrointestinal leiomyosarcoma is much less common in other species. Of the 22 feline spindle cell tumors diagnosed as leiomyosarcomas in the Cornell files, 14 occurred within the gastrointestinal tract; this is slightly higher than the number of feline gastrointestinal leiomyomas (11). Feline cases occurred in domestic cats as young as 2 years of age, but they were most common in middle‐aged to aged cats. No apparent sex or breed predisposition was found. Gastrointestinal spindle cell tumors diagnosed as leiomyosarcomas in two horses were found in the Cornell files, and there are four reported cases in the literature.15–17 One case occurred in a 4‐year‐old horse,17 but all others occurred in horses 10 years of age or older. No sex predisposition is apparent, and breeds include thoroughbred (3), cob (2), and quarter horse (1). Gastrointestinal leiomyosarcoma is apparently very rare in ruminants and pigs, as no cases were found in the literature or in the Cornell files.


Clinical characteristics and sites


Gastrointestinal leiomyosarcomas most often cause clinical signs of gastrointestinal dysfunction (i.e., vomiting and/or diarrhea, which may contain blood), and intestinal tumors have been associated with intussusception of the involved segment. Tumors may result in intestinal perforation and fever, lethargy, and anorexia due to septic peritonitis.18 In contrast to leiomyoma, canine gastrointestinal spindle cell tumors diagnosed as leiomyosarcoma more commonly occur in the intestine than in the stomach. In the Cornell files, 88% of canine tumors diagnosed as leiomyosarcomas occurred within the intestine (46% in the small intestine, 39% within the large intestine, and 3% at the ileocecal junction), and only 11% occurred in the stomach. In a study of 20 gastric tumors in the dog, only 1 leiomyosarcoma was reported.1 Of tumors in which the involved segment of intestine was identified, the jejunum accounted for just over half of the canine small intestinal spindle cell tumors diagnosed as leiomysarcomas at Cornell (17 cases), followed by the duodenum (11 cases), with only rare involvement of the ileum (3 cases). The cecum was the second most frequent site (24 cases), followed by, in decreasing order, colon or rectum (15 cases), and ileocecal junction (3 cases), which is similar to an earlier report.3 Leiomyosarcoma of the esophagus is rare, and only one was found in the Cornell files.


In the cat, the small intestine was the most common site of gastrointestinal spindle cell tumors diagnosed as leiomyosarcoma (6 of 14) in the Cornell files; 4 of 6 cases occurred in the jejunum, 1 was in the duodenum, and the specific site of origin was not specified in 1 case. Feline tumors diagnosed as leiomyosarcoma occurred with equal frequency (3 cases each) in the large intestine/rectum and the ileocecal junction. Only 2 gastric leiomyosarcomas were recorded in cats. No reported cases of feline gastrointestinal leiomyosarcoma were found in a literature search. Equine gastrointestinal spindle cell tumors diagnosed as leiomyosarcoma have been reported to involve the duodenum (2 cases),15 stomach (1 case),16 and rectum (1 case).17 The 2 equine cases in the Cornell files were in the jejunum and at the ileocecal junction. Colic was the presenting sign for equine intestinal leiomyosarcomas,15 and the gastric leiomyosarcoma caused anorexia and weight loss.16 The rectal tumor intermittently protruded through the anus.17


Gross morphology


Tumors can be seen to arise within the muscular tunic of the involved organ and can become quite large, resulting in considerable narrowing of the lumen of the affected segment (Figure 11.8). Smaller tumors can be seen growing from the muscular tunic and are still covered by an intact mucosa. Mural thickening may be annular or nodular. Tumors may be relatively well circumscribed or may extend into the adjacent omentum. Necrosis and hemorrhage of either the mucosal or serosal surface, with associated inflammation, is common. Leiomyosarcomas of the rectum are locally invasive and may fill the pelvic canal. The rectal leiomyosarcoma in the horse was polypoid and pedunculated,17 suggesting that this case may in fact represent a rectal leiomyoma, as no light microscopic features were reported. On section, leiomyosarcomas are firm, generally solid, cream colored, and may have obvious interstitial fibrosis and/or hemorrhage. Multiple areas of necrosis may give leiomyosarcomas a cystic or multicystic appearance.

Photo displaying irregular thickening of the intestinal wall by a spindle cell tumor diagnosed as leiomyosarcoma in dog.

Figure 11.8 Irregular thickening of the intestinal wall by a spindle cell tumor diagnosed as leiomyosarcoma, dog. Spindle cell tumors of the gastrointestinal tract should be stained with antibodies for KIT and smooth muscle actin to differentiate GIST and smooth muscle tumors.


Histological features, growth, and metastasis


Histological features are as described above in the section on Classification and general histological features. The diagnosis of a confirmed, non‐GIST, gastric leiomyosarcoma in a dog, consisting of a mixture of spindle cells and round cells, warranted designation as a pleomorphic variant of leiomyosarcoma.19 Gastrointestinal spindle cell tumors diagnosed as leiomyosarcoma are frequently described as locally invasive but slow to metastasize; however, metastasis may be more common than previously recognized, and its occurrence is probably underestimated due to lack of follow‐up information. In the Cornell files, 16% of all canine spindle cell tumors diagnosed as leiomyosarcomas (27 cases) had evidence of metastasis, and of those for which a primary site was recorded, metastasis was recorded for 14% of all canine gastrointestinal spindle cell tumors diagnosed as leiomyosarcomas. In some cases metastasis was evident at the time of surgery, and in others metastasis was detected at varying times, from 1 to 2 months to 2 years following initial diagnosis. Metastasis of small intestinal tumors diagnosed as leiomyosarcoma was most common (8 cases). Although small intestinal spindle cell tumors diagnosed as leiomyosarcoma occurred most commonly in the jejunum (17 cases), duodenal tumors diagnosed as leiomyosarcoma were more likely to metastasize; 4 of 11 (36%) canine duodenal leiomyosarcomas metastasized.


In the literature, metastasis of duodenal spindle cell tumor diagnosed as leiomyosarcoma was present at the time of diagnosis in one dog20 and occurred within 1 month after surgery in another,21 providing further evidence that a cautious prognosis must be given for duodenal spindle cell tumors with features of malignancy in the dog. Two of 17 canine jejunal tumors in the Cornell files metastasized (12%), and only 1 of 11 canine gastric spindle cell tumors diagnosed as leiomyosarcoma underwent metastasis (9%). Of tumors of the lower intestinal tract in dogs in the Cornell files, metastasis of cecal tumors diagnosed as leiomyosarcoma was most common and was recorded in 4 of 24 tumors (17%). One of three ileocecal spindle cell tumors diagnosed as leiomyosarcoma underwent metastasis (33%), and metastasis of 1 of 15 colonic/rectal tumors (7%) was recorded. In a study of 44 canine spindle cell tumor diagnosed as leiomyosarcoma, 31% of gastric and small intestinal tumors metastasized, and 20% of cecal tumors metastasized, although 1 dog was alive and well 3 years following surgery, despite evidence of peritoneal metastasis at the time of surgery.12 Tumors diagnosed as gastric leiomyosarcoma in 2 dogs in another study had evidence of metastasis at the time of surgery; sites were liver (both cases) and duodenum (1 case).22 Another study of canine gastrointestinal tumors diagnosed as leiomyosarcoma found evidence of metastasis in approximately half of cases. Peritoneal metastasis was most common, with 1 case having both splenic and hepatic metastases.13 Survival of dogs with metastatic tumors that did not succumb during the immediate postoperative period was also relatively long in this study, with a mean survival of approximately 2 years.13


Future studies need to utilize c‐KIT and smooth muscle actin to differentiate GIST versus smooth muscle origin, especially for prognostic purposes. However, from these prior studies it can be concluded that spindle cell tumors in the intestines of dogs diagnosed as leiomyosarcoma can be aggressive and are reported to spread to regional lymph nodes, liver, or spleen in approximately 25% of cases, with a reported range of 7–50%.


Evidence of metastasis of feline gastrointestinal spindle cell tumors diagnosed as leiomyosarcoma was not found in the Cornell files, although no follow‐up studies of biopsy diagnoses were attempted. One feline colonic tumor diagnosed as leiomyosarcoma was apparently multicentric, which in retrospect suggests the possibility of multicentric GIST. Evidence of metastasis was not found in the reported equine gastrointestinal leiomyosarcomas, but metastasis of an ileocecal tumor diagnosed as leiomyosarcoma was found at necropsy in one horse in the Cornell files. Metastasis to liver and to mesenteric lymph nodes was most common in all cases of metastatic gastrointestinal tumors diagnosed as leiomyosarcoma, although pulmonary, splenic, omental/mesenteric, and renal metastases were also seen.


References



  1. 1. Sautter, J.H. and Hanlon, G.F. (1975) Gastric neoplasms in the dog: A report of 20 cases. J Am Vet Med Assoc 166:691–696.
  2. 2. Culbertson, R., Branam, J.E., and Rosenblatt, L.S. (1983) Esophageal/gastric leiomyoma in the laboratory Beagle. J Am Vet Med Assoc 183:1168–1171.
  3. 3. Patnaik, A.K., Hurvitz, A.I., and Johnson, G.F. (1977) Canine gastrointestinal neoplasms. Vet Pathol 14:547–555.
  4. 4. Bettini, G., Morini, M., and Marcato, P.S. (2003) Gastrointestinal spindle cell tumours of the dog: histological and immunohistochemical study. J Comp Pathol 129:283–293.
  5. 5. Frost, D., Lasota, J., and Miettinen, M. (2003) Gastrointestinal stromal tumors and leiomyomas in the dog: a histopathologic, immunohistochemical, and molecular genetic study of 50 cases. Vet Pathol 40:42–54.
  6. 6. Kasper, C. and Doran, R. (1993) Duodenal leiomyoma associated with colic in a two‐year‐old horse. J Am Vet Med Assoc 202:769–770.
  7. 7. Collier, M.A. and Trent, A.M. (1983) Jejunal intussusception associated with leiomyoma in an aged horse. J Am Vet Med Assoc 182:819–821.
  8. 8. Wilson, T., Modransky, P., and Savage, C.J. (1994) Small intestinal intussusception in a mule. Equine Prac 16:36–38.
  9. 9. Haven, M.L., Rottman, J.B., and Bowman, K.F. (1991) Leiomyoma of the small colon in a horse. Vet Surg 20:320–322.
  10. 10. Hanes, G.E. and Robertson, J.T. (1983) Leiomyoma of the small intestine in a horse. J Am Vet Med Assoc 182:1398.
  11. 11. Saidu, S.N.A. and Chineme, C.N. (1979) Intestinal leiomyoma in a cow. Vet Rec 104:388–389.
  12. 12. Kapatkin, A.S., Mullen, H.S., Matthiesen, D.T., and Patnaik, A.K. (1992) Leiomyosarcoma in dogs: 44 cases (1983–1988). J Am Vet Med Assoc 201:1077–1079.
  13. 13. Cohen, M., Post, G.S., and Wright, J.C. (2003) Gastrointestinal leiomyosarcoma in 14 dogs. J Vet Intern Med 17:107–110.
  14. 14. Laratta, L.J., Center, S.A., Flanders, J.A., et al. (1983) Leiomyosarcoma in the duodenum of a dog. J Am Vet Med Assoc 183:1096–1097.
  15. 15. Mair, T.S., Taylor, F.G.R., and Brown, P.J. (1990) Leiomyosarcoma of the duodenum in two horses. J Comp Pathol 102:119–123.
  16. 16. Boy, M.G., Palmer, J.E., Heyer, G., and Hamir, A.N. (1992) Gastric leiomyosarcoma in a horse. J Am Vet Med Assoc 200:1363–1364.
  17. 17. Clem, M.F., DeBowes, R.M., and Leiopold, H.W. (1987) Rectal leiomyosarcoma in a horse. J Am Vet Med Assoc 191:229–230.
  18. 18. Eckerlin, R.H. (1974) Perforated duodenum associated with nonobstructive leiomyosarcoma in a dog. J Am Vet Med Assoc 165:449–450.
  19. 19. Park, C‐H., Ishizuka. Y., Tsuchida, Y., and Oyamada, T. (2007) Gastric pleomorphic leiomyosarcoma in a Shetland sheepdog. J Vet Med Sci 69:873–876.
  20. 20. Weller, R.E. and O’Brien, E. (1979) Intestinal leiomyosarcoma in a dog. Mod Vet Prac 60:621–623.
  21. 21. Kolaja, G.J. and Fairchild, D.G. (1973) Leiomyosarcoma of the duodenum in a dog. J Am Vet Med Assoc 163:275–276.
  22. 22. Swann, H.M. and Holt, D.E. (2002) Canine gastric adenocarcinoma and leiomyosarcoma: a retrospective study of 21 cases (1986–1999) and literature review. J Am Anim Hosp Assoc 38:157–164.

Smooth muscle tumors (leiomyoma) of the gall bladder


Incidence, age, breed, sex, and clinical characteristics


Although uncommonly reported, benign smooth muscle tumors of the gall bladder are encountered at necropsy, especially in the dog. Ten leiomyomas of the gall bladder were found in the Cornell files, occurring in mature to older dogs. These tumors are much less common in other species; only one leiomyoma of the gall bladder was found in an adult cat. Not surprisingly, no leiomyomas of the gall bladder have been seen in horses.


Clinical characteristics


These tumors may be encountered as an incidental finding at necropsy, however large masses may cause clinical signs of obstruction. The Cornell files contained 3 dogs in which a leiomyoma of the gall bladder was an incidental finding at necropsy and 7 dogs in which the tumor was diagnosed following exploratory surgery and biopsy. The feline case was associated with cholecystitis, biliary obstruction, and jaundice.


Gross and histological features, growth, and metastasis


Tumors within the biliary tree arise from within the smooth muscle wall, and the gross morphology is similar to leiomyomas within the gastrointestinal tract. Histological features of leiomyomas of the gall bladder are as described in the section on Classification and general histological features, above. We are not aware of any diagnoses of leiomyosarcoma within the biliary tree of domestic animals. These tumors are non‐invasive; therefore, surgical excision of the tumor is generally curative, provided a patent biliary tree can be maintained.


Smooth muscle tumors of the urinary system


Leiomyoma


Incidence, age, breed, and sex


Leiomyoma of the urinary system most commonly occurs in the adult dog and has no apparent sex predisposition. Twenty‐nine leiomyomas of the canine urinary system were recorded in the Cornell files. Mesenchymal tumors are much less common in this system than are epithelial neoplasms; in one study only 2 of 115 canine urinary tract tumors were reported as leiomyomas,1 and in another study of tumors of the canine urinary bladder, only 1 of 21 tumors was reported as leiomyoma.2 Another report found 5 leiomyomas and 3 fibroleiomyomas in 130 canine urinary bladder tumors; the mean age of the dogs was 12.5 years for leiomyoma, but no information was available regarding the age of dogs with fibroleiomyoma.3 Of the 1547 urinary bladder tumors recorded in dogs in Table 15.4, there were 57 (4%) leiomyomas and 18 (1%) leiomyosarcomas.


This tumor is much less common in other species. In the Cornell files only 5 leiomyomas of the urinary system were identified in adult cats; 1 feline urinary bladder leiomyoma in a 12‐year‐old cat was reported in a series of 9 feline urinary bladder tumors.3 The intravenous leiomyoma reported in the urinary bladder wall of a 5‐year‐old cat might best be designated as angioleiomyoma (for more information see the section on Cutaneous smooth muscle tumors).4 We have seen only 1 leiomyoma of the urinary bladder in horses, and that was in an aged pony.


Clinical characteristics and sites


The wall of the urinary bladder is by far the most common site of leiomyoma of the urinary system. All canine and feline urinary tract leiomyomas in the Cornell files were in the urinary bladder, as were 4 reported canine leiomyomas1,5 and 1 feline leiomyoma.3 Leiomyomas within the urinary bladder and urethra may cause hematuria and, if large enough, dysuria. Leiomyoma of the urethra is uncommon, but urethral leiomyoma was reported to cause postrenal failure in a 12‐year‐old dog6 and urinary obstruction in a 13‐year‐old cat.7 Leiomyoma of the kidney was reported as an incidental finding in an adult male dog.8


Gross and histological features, growth, and metastasis


Leiomyomas within the urinary system generally have a similar gross and histological appearance to leiomyomas located in other organs. An exception is the feline intravascular smooth muscle tumor (angioleiomyoma) that demonstrated intraluminal growth in markedly dilated veins and lymphatics and was thought to have arisen within venous smooth muscle.4 Leiomyomas are discrete tumors that, if adequately excised, do not recur.


Leiomyosarcoma


Incidence, age, breed, and sex


Leiomyosarcoma represents only a very small proportion of tumors arising in this system. A study of 115 canine bladder and urethral tumors found only 1 leiomyosarcoma,1 and none were reported in a study of 21 canine urinary bladder neoplasms.2 Another study found 4 leiomyosarcomas in 130 urinary bladder neoplasms, occurring in dogs from 2 to 11 years of age, with a mean age of 7 years.3 No leiomyosarcomas were observed in a report of 9 feline urinary bladder tumors.3 The Cornell files contained 16 leiomyosarcomas of the urinary system in dogs, 4 in cats, 1 in a cow, 1 in a skunk, and 1 in a woodchuck. Leiomyosarcoma of the urinary system is most common in the dog, followed by the cat. This tumor is rare in other species. This tumor occurs in middle‐aged to older animals, with no apparent breed or sex predisposition.


Clinical characteristics and gross morphology


Sites

The urinary bladder is by far the most common site of leiomyosarcoma in the urinary system. In the Cornell files, 15 of the canine urinary tract leiomyosarcomas were in the urinary bladder, and only 1 was in the ureter. The tumor reported in the study of 115 canine urinary tract tumors was a leiomyosarcoma of the urinary bladder1 and 1 leiomyosarcoma was described in a series of 3 dogs with smooth muscle neoplasia of the urinary bladder.5 One report describes a renal leiomyosarcoma in a dog.9 A urinary bladder leiomyosarcoma was reported in a cat,10 and all 4 feline urinary tract leiomyosarcomas in the Cornell files occurred in the bladder. The bovine leiomyosarcoma also occurred in the urinary bladder. The most common clinical signs are hematuria and/or dysuria, although a ureteral leiomyosarcoma in a dog resulted in anorexia, lethargy, and an acutely painful abdomen.11 If large enough to be obstructive, azotemia, uremia,10 or pelvic limb edema11 may be evident.


Gross morphology

Leiomyosarcoma of the urinary bladder often results in irregular and nodular thickening of the affected wall and can compromise the patency of the ureters and/or urethra. The ureteral leiomyosarcoma was a large lobulated mass in the retroperitoneal space intimately associated with a ureter.11 The renal leiomysarcoma in a dog completely replaced the kidney tissue.9


Histological features, growth, and metastasis


Histological features of urinary tract leiomyosarcomas are similar to those at other sites, although in our experience urinary bladder leiomyosarcomas may have a prominent multinucleate giant cell component and can be mistaken for botryoid rhabdomyosarcoma of the bladder. Metastasis is uncommon; none were recorded in the Cornell files, and only one report was found of a canine urinary bladder leiomyosarcoma that underwent widespread metastasis to abdominal and thoracic organs.12 Extensive local infiltration, rendering complete surgical excision difficult, results in frequent recurrence following excision, necessitating euthanasia.


References



  1. 1. Norris, A.M., Laing, E.J., Valli, V.E.O., et al. (1992) Canine bladder and urethral tumors: A retrospective study of 115 cases (1980–1985). J Vet Intern Med 6:145–153.
  2. 2. Strafuss, A.C. and Dean, M.J. (1975) Neoplasms of the canine urinary bladder. J Am Vet Med Assoc 166:1161–1163.
  3. 3. Osborne, C.A., Low, D.G., Perman, V., and Barnes, D.M. (1968) Neoplasms of the canine and feline urinary bladder: Incidence, etiologic factors, occurrence and pathologic features. Am J Vet Res 29:2041–2055.
  4. 4. Patnaik, A.K. and Greene, R.W. (1979) Intravenous leiomyoma of the bladder in a cat. J Am Vet Med Assoc 175:381–383.
  5. 5. Heng, H.G., Lowry, J.E., Boston, S., et al. (2006) Smooth muscle neoplasia of the urinary bladder wall in three dogs. Vet Radiol Ultrasound 47:83–86.
  6. 6. Blackwood, L., Sullivan, M., and Thompson, H. (1992) Urethral leiomyoma causing post renal failure in a bitch. Vet Rec 131:416–617.
  7. 7. Swalec, K.M., Smeak, D.D., and Baker, A.L. (1989) Urethral leiomyoma in a cat. J Am Vet Med Assoc 195:961–962.
  8. 8. Mills, J.H.L., Moore, J.T., and Orr, J.P. (1977) Canine renal leiomyoma – An unusual tumor. Can Vet J 18:76–78.
  9. 9. Sato, T., Aoki, K., Shibuya, H., et al. (2003) Leiomyosarcoma of the kidney in a dog. J Vet Med 50:366–369.
  10. 10. Burk, R.L., Meierhenry, E.F., and Schaubhut, C.W., Jr. (1975) Leiomyosarcoma of the urinary bladder in a cat. J Am Vet Med Assoc 167:749–751.
  11. 11. Berzon, J.L. (1979) Primary leiomyosarcoma of the ureter in a dog. J Am Vet Med Assoc 175:374–376.
  12. 12. Seely, J.C., Cosenza, S.F., and Montgomery, C.A. (1978) Leiomyosarcoma of the canine urinary bladder, with metastases. J Am Vet Med Assoc 172:1427–1429.

Smooth muscle tumors of the genitalia


Leiomyoma


Incidence, age, breed, and sex


Leiomyomas of the genitalia occur far more frequently in females than males, and they are among the most commonly encountered tumors of the female reproductive system in almost all domestic species. They are most common in older intact females. There were 309 canine leiomyomas in the Cornell files in which the specific site of origin was recorded, and almost one‐third of these (101 cases) occurred in the female reproductive tract. In a survey of vulvar and vaginal tumors in 99 dogs, approximately 25% were classified as leiomyoma (26 cases), and tumors occurred most frequently in intact female dogs.1 A survey of tumors of the reproductive tract in 90 intact female dogs found 66 vulvar/vaginal and 10 uterine leiomyomas in dogs averaging 10.8 years of age.2 Boxers were overrepresented. There is some confusion in the literature regarding differentiation of leiomyoma, fibroleiomyoma, myofibroblastoma, and fibroma. Fibroma is easily distinguished by a lack of myogenic differentiation following appropriate IHC staining; in our opinion the presence of myogenic differentiation qualifies the tumor as leiomyoma, although there is some justification for considering that some fibroblastic tumors may have a myofibroblastic component.


Five bovine genital leiomyomas were recorded in the Cornell files. In cattle, large uterine wall leiomyomas are frequently encountered in abbatoir samples, possibly due to interference with reproductive ability in affected cows. A report of 71 connective tissue tumors from a survey of 9.5 million cattle, sheep, and pigs examined at slaughter indicated that all of the smooth muscle tumors (8 cases) occurred within the female reproductive system. Five of eight were considered to be leiomyomas, which represented approximately 6% of all connective tissue tumors identified in cattle, 8% of connective tissue tumors in sheep, and 16% of connective tissue tumors identified in pigs.3 In a survey of tumors of the genitalia of sows,4 leiomyoma was reported in 6 of 1445 sows and accounted for 50% of the total tumors in this system. Uterine leiomyoma that can be multiple is common in aging potbellied pigs5,6 (mean age 9.7 years; range 5–19 years)5 and this species has been proposed to be an animal model of uterine leiomyoma (fibroid) in women.


We have seen similar tumors in the uterus and vagina of the cat and horse, as well as in nonhuman primates, ferrets, rabbits, and elephants. Seven leiomyomas of the feline female reproductive tract were found in the Cornell files and 3 leiomyomas in cats from 3 to 14 years of age were reported in a study of 13 cats with uterine neoplasia.7 Six leiomyomas in the equine female reproductive tract were found in the Cornell files and there is one report of ovarian fibroleiomyoma in a mare.8 No breed predisposition was apparent. Leiomyomas of the male reproductive system occur, but they are far less frequent in all species than those in the female genitalia; only 4 leiomyomas of the male genitalia have been recorded at Cornell, all in horses. One leiomyoma of the male reproductive tract has been reported in a dog,9 and a search of the Veterinary Medical Data Base for 20 years found 3 leiomyomas of the prostate in 1397 canine prostatic tumors.10


Clinical characteristics and sites


Leiomyomas in all species occur most frequently in the uterus, cervix, or vagina and may interfere with reproductive function. It may be difficult to distinguish the exact site of origin of very large tumors within the pelvic canal. If large enough, leiomyoma may also result in urinary or colonic obstruction or abdominal distension. In potbellied pigs tumors can also involve the broad ligament.6 In the Cornell files, leiomyoma of the canine vagina and cervix was approximately twice as common (58 cases) as leiomyoma of the uterus (25 cases) or vulva (16 cases). The most common clinical presentation of vaginal, vulvar, and cervical leiomyomas is vulvar discharge and/or a protruding vulvar mass.1,2 In the Cornell files, 5 feline leiomyomas occurred in the uterus, and 1 was present in the cervix of a lion. The 5 bovine leiomyomas occurred in the uterus (2 cases) and in the vagina (3 cases). In the horse, vaginal, uterine, and vulvar leiomyomas were found with almost equal frequency (2 uterine, 3 vaginal, and 1 vulvar). A leiomyoma within the testis has been reported in an aged ram,11 and leiomyoma of the testicular tunica albuginea has been reported in a 7‐year‐old horse12 and in a dog.9 Prostatic leiomyoma has been reported in 3 dogs.10 Leiomyoma of the ovary is uncommon; 1 ovarian leiomyoma has been reported in a sow.3 The equine ovarian fibroleiomyoma was found in an pregnant mare with a history of intermittent signs of colic.8 Two canine ovarian leiomyomas and one in the ovary of a leopard were found in the Cornell files.


Gross and histological features


Leiomyomas of the genitalia often have a similar appearance to those in the gastrointestinal tract. Leiomyomas arising from the vagina, cervix, or vulva may, however, be polypoid and/or pedunculated.1,2 Caudal vaginal tumors often protrude through the vulva and may become ulcerated and secondarily inflamed. The testicular leiomyoma in the ram was a circumscribed, red‐brown, multilobular, soft tumor arising within the testis,11 and the canine testicular tunic leiomyoma resulted in hydrocele and atrophy of the affected testis.9


Histological features


Histological features of leiomyomas within the genitalia are similar to those of the gastrointestinal tract, although there may be a more prominent fibrous component. In the past, the term fibroid has been applied to leiomyomas of the uterus and vagina in humans and animals, but this is no longer considered an appropriate designation for these smooth muscle tumors. If smooth muscle is present, even with a large fibrous component, the diagnosis is leiomyoma or leiomyosarcoma. In addition to smooth muscle actin immunoreactivity, uterine leiomyomas in cats and in potbellied pigs often express estrogen and progesterone receptors.5,7


Growth and metastasis


There is evidence to suggest that leiomyomas within the female reproductive tract have a hormonal basis. In women it is suggested that some uterine leiomyomas may regress after menopause. A similar hormonal basis for tumor growth is evident in studies of multicentric smooth muscle tumors within the female reproductive tract in animals. Leiomyomas are non‐invasive and do not metastasize.


Leiomyosarcoma


Incidence, age, breed, and sex


Almost all cases of leiomyosarcoma of the genitalia that we are aware of have occurred in females and are most common in intact females. One case of testicular leiomyosarcoma occurred bilaterally in retained testes in an 11‐month‐old thoroughbred,13 and prostatic leiomyosarcoma has been reported in a 10‐year‐old intact male boxer dog.10

Only gold members can continue reading. Log In or Register to continue

Related posts:

  1. An Overview of Molecular Cancer Pathogenesis, Prognosis, and Diagnosis
  2. Tumors of the Eye
  3. Mast Cell Tumors
  4. Tumors of Bone

Stay updated, free articles. Join our Telegram channel
Tags:
Mar 30, 2020 | Posted by in INTERNAL MEDICINE | Comments Off on Tumors of Muscle

Full access? Get Clinical Tree
Get Clinical Tree app for offline access