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Surgical Oncology William S. Dernell DVM, MS, Diplomate ACVS Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences Colorado State University Principles of Surgical Oncology
Biopsy Principles Knowledge of tumor tissue type is essential for appropriate treatment planning. Obtaining identification prior to treatment is needed if the type of treatment may be altered by or if the owners willingness to treat might be altered by this knowledge. Treatment without prior knowledge of tissue type is only appropriate when treatment or willingness to treat would not be affected. Identification of tissue type can be obtained with cytology or tissue biopsy. Cytology is a simple, fast, and inexpensive method of screening masses. Only a few tumor types can be definitively diagnosed with cytology alone (round cell tumors, lipoma), but cytology can usually differentiate tumor versus non-tumor and tell us if biopsy is needed. Cytology is appropriate for any palpable, external mass, and can be applied to body cavity masses using image guidance. A sample for cytology can be obtained using a fine gauge needle (20 to 25 ga) inserted into the mass and redirected multiple times by partially withdrawing (not exiting skin) and reinserting. True aspiration through the needle is seldom needed (except for very hard masses) as a large number of cells will be obtained merely by needle insertion. It is often best to make several slides of each aspirate and stain some for your own review but keep some unstained in case it is elected to submit samples for review by a pathologist. Cytology labs often prefer to use there own staining techniques.{1,2} Tissue biopsy is usually required for definitive tumor diagnosis. Even though the risk of tumor spread with biopsy exists (in theory), the benefits of obtaining a definitive diagnosis far outweigh such risks. Histology offers cytologic (cell) evaluation as well as tissue architecture evaluation and in the majority of cases is diagnostic. Biopsy can also give an indication of the malignant potential of a tumor by the degree of tumor cell differentiation and invasion or destruction of surrounding stromal tissues. Grading schemes have been adopted for a variety of tumor types which assign a numerical value to pathologic changes. Tumor grade is often highly prognostic and can help guide treatment planning. Biopsy techniques include needle core biopsy, incisional and excisional biopsy.{3,4,5} Needle core biopsy utilizes a coring instrument (usually 12 to 16 gauge) which cuts a core of tissue from the mass, holding it within the needle (e.g. Tru-cutR). Such core instruments can be used to biopsy most palpable external masses and with image guidance can be used to safely and effectively biopsy body cavity masses. Local anesthesia with or without sedation is all that is usually needed. The individual cores are small, but architecture is maintained and multiple samples can be obtained from a single entry site (similar to needle aspiration). Needle core biopsy is less applicable to highly inflamed, cystic or deep, non-palpable masses. If needle core biopsy is not applicable, or a diagnosis can not made from a core sample, incisional biopsy is usually indicated. For skin masses, it is best to biopsy at the junction of normal tissue and mass, to aid in evaluation of tumor behavior. For deeper masses this may not apply. Imaging assistance such as radiographs, ultrasound or computed tomography may help select appropriate biopsy sites for deeper masses. Since anesthesia is usually required for incisional biopsy, the surgeon should strive to obtain adequate amount of tissue to assure a diagnosis. Masses which are highly necrotic, cystic or hemorrhagic will require larger samples to be sure tumor tissue is not missed. Incisional biopsies should always be placed in a location that will not compromise definitive removal in that the entire biopsy site must be removed since it is potentially contaminated with tumor cells. Incisional biopsies on the extremities should be performed parallel to the long axis, rather than perpendicular as this orientation will make definitive resection more feasible in areas with minimal skin for closure. Excisional biopsy is the removal of a mass in its entirety and then submission for histologic diagnosis. This should only be performed if the degree removal would be the same regardless of the diagnosis (i.e. lung mass, splenic mass), or if a smaller resection would not compromise a larger, more definitive resection if the mass ends up cancerous and incompletely resected. The latter is usually only possible for small skin masses on the trunk where a lot of loose skin is available. The advantage to excisional biopsy is that diagnosis and treatment is possible with a single procedure. Excisional biopsies should, however, be applied with caution. Bone biopsy, like soft tissue biopsy, can be performed using needle core, incisional or excisional techniques. Needle core instruments (e.g. Jamshidi) can often result in samples of diagnostic quantity and quality but this may in part depend on the pathologists level of comfort in reading small core samples. The technique is similar to soft tissue needle core biopsy with the exception that sampling should occur from the center of the radiographic lesion rather than at the junction of normal and abnormal tissue. Junctional tissue is often merely reactive bone. Another exception is that even needle core biopsy of bone often requires general anesthesia and appropriate analgesia due to pain response. Multiple cores can be obtained from a single soft tissue site. If a diagnosis can not be obtained by needle core, or for very large, proliferative lesions, an open incisional biopsy may be best. The advantage of this technique is that it affords more tissue, the disadvantages being longer anesthesia and more potential tumor seeding of a larger site which could compromise subsequent definitive treatment. Fracture after biopsy is a risk, especially with highly lytic lesions but the benefits of biopsy still outweigh such a risk. High risk patients should be appropriately supported. Excisional biopsy may be indicated for those cases where knowledge of tumor type would not alter the type or degree of treatment (e.g. rib resection, scapulectomy).{6} Nasal biopsy techniques, like bone biopsy are somewhat unique in comparison to standard soft tissue biopsy. Nasal tumors tend to be very soft, indistinct and have a lot of associated necrosis and inflammatory tissue. These factors don't lend themselves to needle core type biopsy techniques. One successful technique involves a 'straw core' where a large bore plastic catheter sleeve is connected to a syringe and inserted to the level of the medial canthus of the eye and negative pressure applied. This will usually result in a diagnostic sample. A bone curret can also be used to remove tissue. This works better in small dogs and cats compared to the straw core technique. It is often helpful to sift the samples through a gauze square to remove blood clots and isolate out suspected tumor tissue.{7} Endoscopic biopsies can be used to obtain samples from bowel, bladder and prostate. These biopsies are generally mucosal only (versus full thickness) and deeper lesions can be missed. With the increased use of thoracoscopy and laparoscopy, samples can be obtained similarly from body cavity masses using scope visualization, avoiding a more invasive surgical procedure.{4} Tissues obtained for biopsy should be placed in neutral buffered formalin at a volume ratio of 1 part tissue to 10 parts formalin. This will allow adequate fixation of the tissue. Tissue pieces greater than 1-2 cm3 may require incisions into the tissue to allow penetration of the fixative. This can be done in a 'bread loaf' fashion, incising into the tissue from one surface and leaving one surface intact to aid in orientation. If margin evaluation is part of the submission, these bread loaf incisions must be carefully placed to avoid confusion. Large specimens (i.e. an entire spleen) can be fixed in a large container and then appropriate samples placed in a smaller amount of formalin for transport to the pathologist. It is often wise to save the entire specimen though, in case a diagnosis can not be made, in which case more samples can be submitted. Non-routine evaluations such as frozen sections or tissue obtained for immunoflourescence will require different tissue preparation. It is best in these cases to discuss preparation procedures with the lab prior to the biopsy procedure.{4,8} Communication with the pathologist is essential for appropriate interpretation in every biopsy case. The complete history and physical findings in the case is often invaluable in guiding the pathologist to a diagnosis. When margin evaluation is requested, a drawing of the specimen to aid in orientation is also helpful. Once biopsy results are obtained, they must be interpreted. Simplistically, one can believe them or not believe them. Pathology, like clinical medicine, is not an exact science and if the results do not fit the case, they should be questioned. A dialogue with the pathologist may help to fill in needed information, decide whether more tissue is needed, or if new sections or special stains may be appropriate. Submission of slides or blocks to another pathologist for a 'second opinion' should be welcomed by the pathologist in an effort for everyone to be comfortable with the diagnosis.{8} No Margin for Error! Planning and Evaluating Tissue Margins in Surgical Oncology. Definition: A surgical margin denotes a tissue plane on the outside boundary of a resected (removed) Specimen, the tissue beyond which is left within the patient. Knowledge and identification of tissue margins are essential in surgical oncology. Preoperatively, the depth and width of a resection for tumor removal must be preplanned since it dictates the involvement of surrounding structures, necessitates the closure options and may well decide the feasibility of the resection for the patient. Postoperatively, identification of resected margins allows microscopic assessment of the adequacy of tumor removal and will ultimately decide the need for and perhaps the type of additional therapy required. As surgical oncologists, we can not ASSUME we have completely excised a mass by gross interpretation. You will not look worse in the clients eyes to report inadequate resection than if you ignore margins and the tumor grows right back before their eyes! Preoperative assessment of resection margins is an attempt to answer the question of where the tumor is and what normal structures surround it. For surgical oncology, a surgical margin should always be planned within normal surrounding tissue, never within the tumor itself! Preoperative evaluation may require special imaging modalities, especially for deep masses and those within body cavities. Plain radiographs may be helpful in many instances (i.e. bony masses) but often fail to delineate tissue boundaries, especially if the mass is of similar density as surrounding tissues. Ultrasound can be helpful for discerning tissue interfaces for soft tissue masses and for identifying specific organ involvement of body cavity masses. CT is invaluable for evaluating hard tissue masses, especially in regions of multiple bones (skull), or where the decision of joint involvement must be made. MRI is probably the best tool available for evaluation of soft tissue tumors since the resolution allows precise interpretation of interfaces with surrounding tissues. Preoperative planning of tissue margins is ultimately dictated by the tumors biologic behavior which is a function of the tumor type and for certain tumors, the tumor grade. Preoperative biopsy is essential for planning of margins unless there is overwhelming evidence from your preoperative workup to be certain of the diagnosis. We must be confident that the tissue biopsied was representative of the tumor and that the pathologic diagnosis fits the clinical picture! {4,5,8} As a general rule, any tissue that the tumor contacts must be removed with enough of a margin to confidently remove microscopic infiltration. This distance is solely dictated by the biologic behavior of the tumor. For tumors that are typically graded, tumor grade will help guide the level of margins required. For those that are not routinely graded, histologic description of cell morphology can help decide the local aggressiveness of that mass. Anaplastic, undifferentiated tumors tend to show more local invasiveness than those that are well differentiated. Ideally, a margin that includes an additional tissue plane beyond that which the tumor contacts (especially for deep margins) should be planned. As much tissue surrounding the tumor that can be removed without compromising the patient may be a good guide for removal of aggressive tumors. We must, however, define 'compromise' for each patient differently based on the tumor and the chances for surgical cure. Planning surgical margins must take the closure of the wound into account but we must not allow potential difficult or involved closure to compromise our tumor excision. With the advent of a variety of wound closure techniques described for dogs and cats, a three dimensional thought process prior to resection and knowledge of available closure options can assist our planning. Once a tumor is resected, we must then identify the margins of interest to allow our pathologist to target his or her microscopic evaluation of the resection. It helps to initially lay out the specimen in the position it was in the patient to help orientation. Decide where the resection was closest to the tumor and mark this margin. Additional margins to consider would be deep, lateral and a skin margin if a subcutaneous tumor. Areolar tissue margins are difficult to access since they are easily distorted and tend to shrink rapidly on fixation giving the impression of being right on the tumor despite a wide margin. Certainly, masses within organs are more difficult or even impossible to access margins on since surrounding normal tissue is often 'space'. Careful evaluation of organs of contact or peritoneal or pleural structures is necessary and biopsying suspected areas essential for margin interpretation in these cases. Again the suspected biologic behavior of the tumor will often dictate margin identification. Some tumors will tend to move laterally, rather than deep and others will tend to travel along particular tissue planes. If the resected specimen is large, it can be 'loafed' to allow fixation or even cut into pieces, as long as correct orientation can be communicated to the pathologist. It may help to draw a picture of the specimen and label margins for future reference and to allow the pathologist to better chose sampling regions. If margin evaluation is essential to the case, then the entire specimen should be fixed, even if only sections are initially submitted. If the interpretation is then in question the remainder of the specimen can be utilized. Margins of interest can be identified for the pathologist in a variety of ways. India ink can be purchased from art supply stores and can be painted or swabbed onto the tissue in question or the entire specimen dipped into the ink. The specimen should be allowed to air dry for 2-3 minutes prior to placing it into formalin. This results in a fine black line identifiable on histology at the level of the cut margin. It will not penetrate more than a distance equivalent to 1 or 2 cells and thus will not interfere with margin evaluation. Specialty margin marking inks can be obtained from surgical supply houses and have the advantage of multiple colors. This allows marking different margins in different colors to identify where the resection was incomplete. This knowledge may help with planning of adjuvant radiation therapy and will also assist the surgeon in learning where the shortcomings of the resection were for future reference. Suture tags or hypodermic needles can also be used to flag surgical margins if ink is not available. These methods can distort tissues of interest but their main disadvantage is that they identify only a specific point of the margin and areas of interest may be overlooked by the pathologist processing the tissue.{9} Once histologic margins have been reported, it becomes the surgeons task to interpret the results. If there is any question as to the report, it may help to review the specimen with the pathologist (if possible) to discuss how the sections were cut in. This will help the pathologist as to orientation of the surgical margins of interest. A report of clean margins (tumor does not extend to marked margins) must be interpreted with caution. It is not feasible for a veterinary pathologist to cut and mount an entire resected specimen unless it is quite small. Therefore, he or she must take what is felt to be representative samples. This is where accurate descriptions and margin identification can be an invaluable aid. It is still possible, despite our combined best efforts that incomplete margins can be missed. A report describing no tumor was found also falls into the category of 'interpret with caution'. This often occurs when re-resection is performed for incomplete margins. This can also occur if a large incisional or excisional biopsy is performed and the entire tumor removed (accidentally).{10} Occasionally a report will describe tumor cells extending to within a few cell widths of a marked margin. Considering this a complete margin is entirely dependent on the known or suspected biologic behavior of the mass. When in doubt, re-resection or adjuvant therapy should be considered. An incomplete margin, no matter where it might be located in reference to the mass must always be interpreted as an incomplete resection. Again, if in doubt, review the specimen with the pathologist. It must be assumed that if the tumor was cut through at any level during resection that the entire wound is potentially contaminated. This requires treatment of the entire previous wound if re-resection or adjuvant therapy is elected. Only in very rare instances can knowledge of the particular margin that is incomplete dictate less treatment. Knowledge of margins preoperatively and identification of resected margins for pathologic assessment postoperatively are essential to the surgical oncologist. Proper presurgical planning and postoperative interpretation can not only improve success in surgical oncology but is vital in appropriate treatment of our patients with cancer. References
Treatment of Soft Tissue Sarcoma
Summary Soft tissue sarcomas (STS) are mesenchymal tumors arising from connective tissue elements grouped together based on a common biologic behavior. The most common histologic types include hemangiopericytoma (not cats), fibrosarcoma and neurofibrosarcoma. These tumors are relatively slow growing yet locally invasive with a high rate of recurrence following conservative management. Aggressive surgical resection, however, will often result in long term remission or cure. Soft tissue sarcomas (STS) are mesenchymal tumors arising from connective tissue elements. They tend to occur in middle aged to older animals with a trend toward medium to large (dogs). There is no apparent breed or sex predilection. They can occur in any location with a prevalence for subcutaneous or muscle sites on the extremities or trunk. The most common histologic types include hemangiopericytoma (not cats), fibrosarcoma and neurofibrosarcoma. Some pathologists prefer to refer to all histologic types with a similar biologic behavior as STS. They are relatively slow growing yet locally invasive with a low rate of metastasis. Tumor grade, based on histologic features is predictive of local invasiveness and metastatic potential.{1,2} Case evaluation for cases of suspected STS ultimately involves a biopsy to confirm the diagnosis and for histologic grade for prognostication.{3} Even if a specific numerical grade is not assigned by the pathologist, cytologic descriptions (differentiated vs undifferentiated) can give the surgeon a feel for potential behavior.{4} Fine needle aspiration cytology should be performed to support the diagnosis of neoplasia and rule out tumors such as mast cell tumor.{5} Cytology is often unrewarding in diagnosing STS since their connective tissue nature does not result in cell shedding in large numbers. A wedge biopsy is preferred to obtain adequate tissue for histologic assessment but multiple needle core biopsies can be adequate, especially for deep masses. Excisional biopsy should only be considered for very small lesions on the trunk when STS is suspected.{3} Assessment of degree of regional involvement is important for treatment planning in cases of STS. Regional radiographs, especially for extremity lesions will demonstrate bony involvement which is essential to know since removal of the effected bone (amputation, rib resection) is required for disease control in these cases. Additional imaging modalities such as ultrasound, CT or MRI can be helpful to differentiate tissue interfaces or involvement of vital structures. Any and all enlarged lymph nodes in the region should be aspirated or biopsied to evaluate for regional spread. Although thoracic metastasis evaluation is of low yield in cases of STS, due to the low rate of metastasis, it is still a recommended preoperative evaluation tool since presence of metastatic disease may well alter the prognosis and treatment plan significantly.{6} Planning of the surgical resection and closure of the wound is based on the location, size and potentially the grade of the mass. Since all various histologic types that fit in the category of STS have similar biologic behavior, histologic type has little bearing on planning of tumor resection. Available treatment options include surgery alone, surgery followed with external beam radiotherapy and surgery followed by chemotherapy.{6} Surgery is the preferred treatment option and with adequate pre-treatment planning and strict attention to principles during resection can result in better than 80% long term disease control with a high potential of cure.{7,8} Wide surgical margins are necessary for complete macroscopic and microscopic resection. Two to three centimeters around the mass in all planes is a target goal and is somewhat dependent on location and the proximity of vital structures. Soft tissue sarcomas will often appear to be encapsulated and this can tempt the uninitiated surgeon into 'peeling the mass out'. These tumors tend to have a psuedocapsule rather that a true capsule. This psuedocapsule is most often comprised of compressed tumor cells and marginal (peel-out) surgeries will invariably be incomplete. Deep margins are often the most deceiving with STS and it is recommended to remove at least one additional tissue plane beyond those tissues that are in contact with the tumor. Such 'radical resection is often more feasible on the trunk. Wide margins on the extremities may require special closure techniques or may not be feasible without amputation. Limb amputation for the treatment of STS should not necessarily be considered a last resort as better than 90% of all animals will have good function following the surgery and the majority can look toward cure with STS disease treated by amputation.{7-12} Once a tumor is resected, it is important not to assume the resection is complete, even with radical margins. Margins of interest should be identified for pathologic evaluation. Decide where the resection was closest to the tumor and mark this margin. Additional margins to consider would be deep, lateral and a skin margin if a subcutaneous tumor. Areolar tissue margins are difficult to access since they are easily distorted and tend to shrink rapidly on fixation giving the marked margins the appearance of being right on the tumor despite a wide margin. If the resected specimen is large, it can be partially 'loafed' to allow fixation. It may help to draw a picture of the specimen and label margins for future reference and to allow the pathologist to better chose sampling regions. If margin evaluation is essential to the case, then the entire specimen should be fixed, even if only sections are initially submitted. If the interpretation is then in question the remainder of the specimen can be utilized.{4,13} Once histologic margins have been reported, it becomes the surgeons task to interpret the results. If there is any question as to the report, it may help to review the specimen with the pathologist to discuss how the sections were cut in. This will help the pathologist as to orientation of the surgical margins of interest.{14} A report of clean margins (tumor does not extend to marked margins) must be interpreted with caution. It is not feasible for a veterinary pathologist to cut and mount an entire resected specimen unless it is quite small. Therefore, he or she must take what is felt to be representative samples. This is where accurate descriptions and margin identification can be an invaluable aid. It is still possible, despite our combined best efforts that incomplete margins can be missed. A report describing "no tumor was found" also falls into the category of 'interpret with caution'. This often occurs when re-resection is performed for incomplete margins. This can also occur if a large incisional or excisional biopsy is performed and the entire tumor removed. Occasionally a report will describe tumor cells extending to within a few cell widths of a marked margin. Considering this a complete margin is highly dependent on the tumor grade. Such a margin may be adequate with low grade but must be suspect for high grade STS An incomplete margin, no matter where it might be located in reference to the mass must always be interpreted as an incomplete resection. A histologically incomplete margin for a STS will invariably result in local recurrence.{7} Again, if in doubt, review the specimen with the pathologist. It must be assumed that if the tumor was cut through at any level during resection that the entire wound is potentially contaminated. This requires treatment of the entire previous wound if re-resection or adjuvant therapy is elected. If resection margins are incomplete, re-resection of the lesion should be considered first, if the original resection was in a location allowing new wide margins. Margin goals are still the same and since the entire previous wound must be considered contaminated, the new margins must be around the entire previous wound. Re-examination of the new resected margins should likewise be performed. If resection margins are incomplete and it is suspected that only microscopic disease remains in the patient (no bulky disease), external beam radiation therapy can be considered adjuvantly.{15-17} Megavoltage radiation of a STS wound bed containing microscopic disease has been shown to result in a 70-80% control rate at one year in veterinary patients. Side effects to the radiation in the majority of these patients is relatively superficial (confined to the skin) and transient. Certainly each case must be approached on an individual basis. For STS that are not amenable to wide local resection or if radical surgery is not favored by the owner, marginal resection of the mass and adjuvant radiation therapy could be planned from the treatment outset. Radiation therapy for bulky disease has resulted in marginal success.{18} Chemotherapy for bulky disease has not been shown to be highly effective in cases of STS.{19} Therefore, chemotherapy can not be considered a good option for initial therapy planning. Chemotherapy for microscopic disease (after marginal or incomplete resections) has not been completely evaluated for veterinary patients. Cisplatin has shown efficacy against a variety of sarcomas and could be considered for adjuvant therapy for STS. Other drugs that could be considered might include doxorubicin, mitoxantrone and taxol.{20} None of these drugs is well proven for treatment of STS in animals but could be considered on a case by case basis. We have treated 30 STS patients using intracavitary cisplatin released from a biodegradable polymer with preliminary local disease control similar to that of marginal resection and radiation therapy.{21} A porous biodegradable solid polymer termed Open cell PolyLactic Acid which is (OPLAa) impregnated with cisPlatin (OPLA-Pt) is placed within the wound following a marginal resection and prior to wound closure. This 'intracavitary therapy' results in cisplatin concentrations within the wound cavity which far exceed those obtainable with intravenous administration without high systemic concentrations which would result in toxicity. It is felt that such intracavitary therapy is effective treatment for microscopic disease left behind following incomplete resection. Fifty percent of our study population developed local tissue reaction to the platinum/polymer combination with 15 % requiring removal of the implant. We are presently investigating a third generation injectable polymer for similar use in the hope that we can decrease this local toxicity. Other drugs may be potentially used for intracavitary therapy of STS as well. This method may prove effective, allowing limb salvage options on extremity masses without having to rely solely on adjuvant radiation. Longer follow-up and additional case accrual is needed before definitive conclusions can be made. Re-evaluation of STS patients after treatment focuses on local recurrence of disease.{6} Physical examinations with careful palpation of the tumor site is paramount, with biopsy of suspected areas. Recurrent tumors tend to have more aggressive biologic behavior than the original mass, showing more rapid growth and possible increased tissue invasion and metastatic potential. Options for treatment of recurrence are similar to those for the primary lesion. If, however, aggressive therapy was performed on the primary mass and local recurrence resulted, even more aggressive secondary therapy must be considered. Grade of the recurrent mass may help guide therapy.{4} Metastasis evaluation might be recommended on a 6 month basis, dependent somewhat on tumor grade. Proper treatment planning for STS based on knowledge of typical biologic behavior as well as expected behavior (grade) is essential with familiarity with all potential treatment options. Proper postoperative assessment and follow-up is vital for monitoring disease control and prompt treatment of uncontrolled disease. Soft tissue sarcomas can be a frustrating disease to treat, but adherence to solid surgical oncology principles can greatly increase the odds of good disease control. References
Mast cell tumors (MCT) are the most common cutaneous tumor in the dog and the 2nd most common in the cat. Older names for MCT include mast cell sarcoma and histiocytic mastocytoma. Mast cell tumor must be differentiated from mastocytosis, which is a systemic mast cell condition. Mastocytosis can be seen in animals with MCT but is not common. In people, mastocytosis is seen, whereas mast cell tumors are not. Mast cells are normal inflammatory cells containing a variety of bioactive compounds, which are partially responsible for clinical syndromes seen with MCT. Histamine and heparin are the major constituents and cause the typical metachromatic staining on Wright stains. Some anaplastic lesions will not stain well and in these cases, immunohistochemistry may be helpful. Heparin, as well as proteolytic enzymes, present in mast cells can be responsible for hemorrhage from the surgery site as well as delay in wound healing. Histamine can cause local or systemic allergic-type reactions as well as gastric ulceration. Mast cell tumors have a wide range of biologic behaviors, which can be partially predicted by histologic grade. The standard grading scheme for MCT is divided into well differentiated (grade I), moderately differentiated (grade II) and undifferentiated (grade III). Grade I lesions are minimally invasive and do not metastasize. Grade II lesions are locally aggressive and invasive with a 10-20% rate of metastasis. Grade II lesions are locally invasive with a high (70-90%) rate of metastasis. Metastasis is typically to regional lymph nodes, liver, spleen or bone marrow. Most MCT present as solitary masses. Low-grade tumors may be firm and have a lengthy duration. Higher-grade tumors may present with erythema, edema and/or ulceration. Manipulation of mast cell tumors can cause erythema and wheal formation (dariers sign) following mast cell degranulation. Metastasis can present locally or regionally (lymph node) or can be disseminated, involving organomegally and mastocythemia. A fine needle aspirate is usually diagnostic for MCT, unless the mass is anaplasic (undifferentiated). Tumor grade cannot be determined from cytology, but requires histology. Agrophilic nucleolar organizer regions (AgNORs) are an indirect measurement of nuclear activity and correlate with tumor grade. Although not a test performed by all laboratories, AgNORs have the advantage of being able to be performed on cytology, as well as histology specimens. Full staging of the patient presenting for MCT is indicated, unless it is known that the lesion is grade I. Aspiration of any enlarged lymph nodes, abdominal ultrasound with spleen and liver aspiration and a bone marrow aspirate are indicated. The discovery of systemic disease has a major impact on prognosis and can greatly alter treatment planning. Evaluation of the buffy coat for mast cells is a simple screening step to look for mastocythemia, however, false negatives exist and a bone marrow aspirate is preferred. Indicators of mastocythemia can also be noted on complete blood count if basophilia or eosinophilia is seen. Biopsy, prior to tumor resection is indicated for larger lesions, extremity lesions or those in difficult locations. Tumor grade may well alter the treatment planning or the owner's willingness to treat in these cases. For small, trunk located lesions; an excisional biopsy may be reasonable if the need for re-resection (following incomplete initial resection) would not compromise the patient. In these cases, staging could be delayed until tumor grade is determined. Surgical removal is the treatment of choice for local MCT disease. Grade II and III lesions warrant aggressive local resection, obtaining 3 cm lateral margins and one additional tissue margin deep to what the tumor touches. In certain areas, this type of resection will require some type of reconstructive procedure, or possibly a regional resection to be complete. Normal tissue margins should always be identified after removal so that the pathologist can assess the completeness of resection. In cases of incomplete resection, re-resection should be considered first if feasible. For re-resections, new margins are obtained as described above surrounding the old scar. Regional resection may also be re-considered. Complete surgical resection for dogs with no evidence of metastasis will result in upwards of 90% 1-year remission. For incomplete resection that is not amendable to surgery, radiation therapy to the site can be successful. Fractionated doses of approximately 50 Gy have resulted in 80-90% 1-year remissions. For dogs with grade II tumors or evidence of metastatic disease, adjuvant chemotherapy should be considered. Although to date, no chemotherapy protocol has been proven efficacious, a combination protocol combining vinblastine, cytoxin and prednisone has shown some clinical responses. Previously evaluated drugs include cytoxin and vincrisine, which were not shown to be efficacious alone. Responses have also been seen following the use of doxorubricin, mitoxantrone and L-asparginase but are typically of short duration. Prednisone will consistently result in tumor response but the duration is short (30 days) and when used alone, it may induce drug resistance. Further evaluation of aggressive drug protocols may prove successful, however, to date, the overall survival for metastatic or grade III MCT is less that 6 months. Ancillary therapy for MCT may also be indicated, especially for disseminated disease. Histamine (H1 and/or H2) blockers are indicated for the prevention of allergic reactions and gastric ulceration. Gastrointestinal protectant agents may also be helpful in cases of suspected or confirmed ulceration. Feline MCT generally behave in a less aggressive manner than in the canine. There are three distinct forms of MCT in the cat; mastocytic, histiocytic and visceral. The majority of cutaneous feline mast cells are mastocytic. Mastocytic MCT are further subtyped histologically into compact and diffuse. The most common subtype is diffuse, which behave very similarly to grade I MCT in the dog. Conservative surgical resection is generally curative. Diffuse mastocytic MCT tend to behave in a more aggressive manner, more similar to grade II or III MCT in the dog. Complete staging and aggressive treatment is indicated for the diffuse mastocytic form. Although the grading scheme for MCT in the dog does not apply to the cat, differentiation between compact and diffuse forms may help predict behavior and guide treatment planning. Histocytic mast cell disease is most common in younger, Siamese cats. These cats usually present with multiple, inflamed, puritic lesions, which may actually spontaneously regress. This may be more of an allergic phenomenon than a true neoplasia. Biopsy is needed to differentiate this form from the mastocytic form. The visceral form of feline MCT can present isolated to the spleen or intestine, or can be diffuse. Splenic MCT will present with vague signs and splenomegaly. Up to 50% will have bone marrow involvement and coagulation abnormalities are not uncommon. Up to 30% can present with abdominal effusions. Intestinal MCT does not usually present with mastocythemia, but will often have evidence of regional metastasis to lymph nodes, liver or peritoneum. For MCT isolated to the spleen or intestine, complete resection can result in a long-term (approximately 1-year) remission. Cases presenting with metastatic disease carry a much more guarded prognosis. Chemotherapy protocols similar to the dog are presently being evaluated for diffuse mastocytic disease or visceral MCT with evidence of metastasis. References Piscopo SE. Canine Mast Cell Tumors. Veterinary Forum, June 1999:32-41 Multimodality Treatment of Solid Tumors Cancer disease that is categorized as 'solid tumors' include all non-hematopoetic (blood-origin) tumors. Hematopoetic tumors include lymphoma, the leukemia's and myeloma. This leaves a large number of tumors within the solid tumor group. Treatment decisions for solid tumors are based on a number of factors including the anatomical area and the known or suspected tumor type. The three broad categories of tumor type are based on their tissue of origin. Carcinomas originate from epithelium such as the skin or gastrointestinal tract. Sarcomas are tumors that arise from connective tissues such as muscle or bone. Round cell tumors arise from cells found in a variety of tissues and sites. Such cells would include melanocytes and inflammatory cells such as mast cells and plasma cells. The biologic behavior of each of these tumor types can be variable between different pathologies, anatomic locations and even species. However, there are often common characteristics that allow the clinician to predict behavior in general, allowing appropriate choices for work-up as well as treatment. A pathologic feature that can often predict biologic behavior is the tumor grade. For most sarcomas and some carcinomas and round cell tumors grade is highly predictive of both local aggression and metastasis potential. Grade is merely a description of what the tumor is doing microscopically based on how rapidly the cells are dividing, how much the normal tissue is disrupted and if the cells are invading into local blood and lymph vessels. Most tumors are graded either high/low or numerically 1-3, 3 being the high grade form. Carcinomas tend to have both moderate local aggression (invasiveness) and metastasis potential overall. For example, 50% of mammary carcinomas will metastasize and 50% won't. Metastasis is also split 50/50 between regional lymph nodes and lungs. Therefore, when staging (looking for disease in the whole body) a carcinoma, it is appropriate to palpate lymph nodes, or pursue ultrasound to evaluate nodes in body cavities as well as take thoracic radiographs. This improves our ability to find distant spread which is invaluable in predicting outcome (prognosis). The key to successful treatment of local disease is complete surgical removal of all gross and microscopic disease. Of course, the surgeons ability to remove all tumor cells is dependent on the tumor location, size and sometimes the type and grade, since some are more locally aggressive than others. If this is not obtained, we can predict that the tumor will recur. Likewise, carcinomas are moderately sensitive to radiation therapy, both at a macroscopic and microscopic level. Sarcomas tend to have a high local aggression and a low metastatic potential overall. For example, soft tissue sarcomas have a 20% overall metastatic rate. Obviously there are exceptions such as osteosarcoma (bone) and hemangiosarcoma (spleen and liver), whose metastatic rate approaches 90%. Tumor grade (and of course type of sarcoma) is highly predictive for outcome in sarcomas which supports the need for a biopsy before treatment when a sarcoma is suspected. This not only allows confirmation of a sarcoma diagnosis, but allows the grade to help with prediction of prognosis. Sarcomas rarely metastasize to lymph nodes, rather if they metastasize it is almost always to lung. Therefore, staging for sarcomas definitely includes thoracic radiographs, but ultrasound for cavity nodes is not commonly warranted. As with carcinomas, local tumor control of sarcomas is dependent on ability to obtain a complete resection. Again, this supports the need to have the resected tumor evaluated for completeness of resection (margin evaluation). The overall radiation sensitivity of sarcomas is low for macroscopic disease and moderate for microscopic disease. Therefore an attempt to remove gross disease prior to radiation for sarcomas is important. The behavior of round cell tumors is more variable than either carcinomas or sarcomas. Even within the type of round cell tumor, the behavior can vary widely. An example would be mast cell tumors, whose behavior can vary greatly depending on anatomic location and even species (cat versus dog). Fortunately, tumor grade is highly predictive for mast cell tumors and can be used for prognostic prediction. However, grade has not been shown to be as predictive for other round cell tumors, making them more difficult to predict. Round cell tumors typically spread to regional lymph nodes, but can go to different sites within the same tissue (such as skin) or to the bone marrow. Typical staging for round cell tumors includes lymph node palpation, ultrasound evaluation and bone marrow aspiration. In contrast to sarcomas, round cell tumors rarely spread to lung. Round cell tumors tend to be very radiation sensitive overall, even for large tumors. For this reason, surgical removal of gross disease prior to radiation is not always indicated. As tumor type (and grade) have been shown to be vital information for decision making with solid tumors, even in selection of staging tests, a preoperative diagnosis is often essential. In some diseases, specifically round cell and carcinomas, fine-needle-aspirate cytology can give a definitive diagnosis. Cytology is at least a good screening tool, even if a diagnosis can't be made and should be considered in all cancers. Treatment plans for solid tumors are based on what is discovered in the preoperative workup (biopsy and staging) as well as owner factors such as goals, acceptance of adverse affects and, of course, cost. Alternative therapies are being continuously developed and evaluated, but as of yet, are not well proven. Such therapies would include vaccine, gene, immune therapies, enzyme inhibitors as well as eastern medicine modalities. At this point in time, the only truly proven therapies are still surgery, radiation and chemotherapy. For optimal treatment of the patient, an understanding of how each of these therapies might play a role and potential interact with each other or alternative therapies is essential. Surgery is still the primary treatment modality for solid tumors. It is the sole treatment for many solid tumors, especially those of medium or low grade. This includes carcinomas, sarcomas and round cell tumors. Complete (microscopic) resection of these tumors will often result in long-term remission, if not cure. Since the key to surgical success is obtaining complete margins, margin planning and assessment is crucial to surgical oncology. A separate section of notes on margins is part of this note set and the reader is referred there for more information. If complete surgical resection is not possible, due to size or location, for many tumors, it still plays a primary role in reducing tumor burden to allow adjuvant radiation therapy to be more effective. This is true for both sarcomas and carcinomas. With low or medium grade disease, local tumor control is the primary focus and combinations of surgery and radiation therapy can still result in long term remission or cure. Surgery also plays a primary role in the treatment of high grade malignancies. These tumors have the additional burden of a high metastatic potential. Even with complete resection of local disease, microscopic metastasis is often present and remission or cure is not possible without systemic therapy targeted to these micrometastases. Chemotherapy is the only systemic therapy with proven efficacy against micrometastases for a number of high grade tumors such as osteosarcoma, hemangiosarcoma and high grade mast cell disease. Newer modalities will likely play a role in the future. It is still essential to surgically remove the primary (local tumor disease with these high grade tumors, or at least control this local tumor with surgery and radiation. Without control of the local disease, continuous metastases occurs an chemotherapy loses it's ability to 'keep up' resulting in systemic failure. An example of this would be splenic hemangiosarcoma where splenectomy alone results in an average 60 day survival, yet surgery and chemotherapy results in a 10 month survival. This is not to discount the importance of local treatment for control of symptoms. Radiation therapy is the sole treatment for a few tumor diseases including nasal and brain tumors. Even though this rarely results in cure, remission times can be prolonged. Surgery does not play a role in these diseases based on the high morbidity (brain) or inability to remove enough local disease to be advantageous (nasal). These diseases are not typically metastatic, however, if the potential were high, chemotherapy could be used adjuvantly. Radiation may play a sole therapy role in tumors that occur in anatomic locations that do not allow surgical resection. An example would be spinal or vertebral tumors. In these cases, radiation takes a lead role by default as the other modalities are either not feasible or effective. The vast majority of these cancers have guarded to poor prognoses. Radiation is more commonly used adjuvantly to surgery as mentioned above. Radiation can be applied either following surgery or prior to surgery. The advantages of either sequence is dependent on a number of factors the details of which are discussed in the attached notes on radiation therapy. Radiation can also be used as a sole treatment for palliation of symptoms. Patients with untreatable cancers, or disease that an owner elects not to treat for control can often be helped by radiation in an effort to relieve the symptoms of their tumor. This is especially true for cancers involving bone, either primarily or metastatically. Palliative radiation is generally of shorter duration to avoid side effects. Chemotherapy is the sole therapy for hematopoetic neoplasias such as lymphoma, leukemia's and myeloma. These diseases are systemic in nature and require 'whole body' therapy to control. Surgery and radiation can still play an adjuvant role in these cancers, but are usually applied to down stage (reduce tumor burden) or to control symptoms until the disease can be controlled with the chemotherapy. Chemotherapy is used adjuvantly for high grade disease to control micrometastases after surgical or radiation treatment of the primary tumor (mentioned above). Chemotherapy is also used in combination with radiation to 'sensitize the tumor to the effects of radiation. This involves either a magnification of the radiation damage or some synergistic effect. The most common application for this in veterinary oncology would be the treatment of nasal tumors. The reader is again referred to the detailed notes on chemotherapy. Appropriate treatment of solid tumor cancer disease involves decision making that is based on knowledge of the tumor type, stage and predicted biology. Through appropriate planning and treatment implementation, specifically the selection of the appropriate modality or combination, we can maximize or control of many cancer diseases and minimize their impact on our patients. Vaccine Associated Sarcomas in Cats: An Update An association between soft tissue sarcoma formation and sites of vaccination was first recognized in the early 1990's.(1) Since that time, recognition of this phenomenon has increased exponentially, exploding into a public and political disease issue. The true etiology or at least the relationship between vaccination (or other injection) and the formation of what are now called Vaccine Associated Sarcomas (VAS) remains unknown. Initial suspicions revolved around vaccine adjuvant materials, especially adjuvants containing metals (aluminum). Further investigation revealed VAS formation without adjuvant products and has raised the suspicion of metaplastic and neoplastic change secondary to an inflammatory reaction that appears to be unique to cats. Although vaccine reactions occur in dogs, they are less frequent and VAS formation has not been documented. Until the etiology and/or association can be elucidated, our attention needs to be focused on appropriate treatment control or prevention. The incidence of VAS is estimated to be somewhere between 1/1000 to 1/10,000 cats vaccinated.(2) Although feline leukemia vaccine and rabies have been most widely implicated, all feline vaccines and a number of non-vaccine injectable agents, generally repository type medications, have been associated with sarcoma formation. A suspicion of VAS is raised by the finding of any one or more of several pathologic criteria. These tumors are generally high grade (grade III if evaluated by the canine soft tissue sarcoma schemes) with substantial evidence of an inflammatory component. The inflammation most often consists of mononuclear cells, particularly macrophages. The finding of refractile material within the cytoplasm of inflammatory cells may represent metallic vaccine adjuvant and has been associated with VAS.(3) These tumors behave in a very aggressive manner, yet are generally confined to local tissue growth and invasion, rather than distant metastasis. The distant metastatic rate is estimated at 10-25%, and is often seen as a late event. This rate may actually increase as control of local tumor disease improves, allowing metastasis to occur. Local recurrence rates are high and are only partially related to the status of margins. Although it is suspected that macroscopically or microscopically incomplete margins are associated with an increased rate of recurrence, recurrence rates seem to be higher than expected for cases in which a microscopically complete resection is obtained.(4,5) Local recurrences (in the face of clean margins) are often referred to as 'field recurrence', 'skip lesions' or regional 'metastases'. These terms refer to local re-growth that is not necessarily within the original surgical wound bed. Mechanistic theories for this include; induction of distant tissues through macrophages containing inductive material traveling through lymphatics; metaplastic induction secondary to the 'regional' inflammatory response; and true metastases of tumor cells through lymphatic or vascular channels. The latter theory is not as well supported owing to the fact that the distant metastatic rate is relatively low. Regardless of the mechanism, this biology requires that local therapy be aggressive or more appropriately, be regional in nature. Cats are generally presented for a palpable mass in or near the injection site. The timing of VAS occurrence following vaccination is highly variable. The minimum time appears to be somewhere between 3 and 6 months following vaccination. The maximum time is not known, however there have been reports of VAS occurring several years following vaccination in a particular site. Most masses evaluated prior to 3 months after vaccination are histologically consistent with granuloma. Because it appears that long-standing granulomas may be associated with VAS formation, it is recommended that any mass present for longer than 3 months undergo incisional or excisional biopsy. Care must be taken in planning the biopsy track for ease of subsequent removal at the time of definitive surgery. This is especially true for excisional biopsies since it is unlikely that this procedure will result in complete margins if the mass is diagnosed as a VAS. Although the metastatic potential of VAS is low, (10-25%) staging with 3-view thoracic radiographs is still recommended. The finding of metastases is a negative prognostic indicator, yet it is possible that these lesions may progress slowly and local site treatment may still be warranted. Repeating the thoracic radiographs in 3-4 weeks will help to identify metastases with a slow doubling time which would be indicative of slow growth. Further staging involves evaluation of regional lymph nodes through palpation or imaging (ultrasound) followed by fine needle aspiration cytology of enlarged lymph nodes. Lymph node spread, however, is rare.(6) The assessment of local disease extent and thus the surgical dose required for resection of larger, longer-standing lesions can be greatly aided by advanced imaging. The use of contrast-enhanced computed tomography (CT) has been shown to improve assessment of tissue plane invasion beyond what can be discerned by palpation, ultrasound or non-contrast CT. Due to the large inflammatory component to these tumors, CT may over estimate tissue involvement due to inflammatory changes within surrounding tissues. The use of CT images for radiation therapy computerized planning is very helpful in cases of VAS, especially larger, deeper masses as involvement with multiple tissue planes within the radiation field are likely.(7) Fields will often include dose-limiting tissues such as spinal cord. If radiation therapy is planned to follow surgery, computerized planning of radiation from CT images obtained after surgery is recommended, rather than from pre-operative images, in order to better assess the position of tissue planes involved. Magnetic resonance (MR) imaging may be a very useful too, in assessment of the degree of local disease, but it has yet to be evaluated for VAS. Early local failure following treatment of VAS resulted in the institution of more aggressive surgical resections. The accepted standard for soft tissue sarcomas of 2-3 cm lateral margins and one additional tissue plane deep to what the tumor touches (Figure 1) will generally result in microscopically clean margins, yet an unacceptably high recurrence rate. The present recommendations are 3-5 cm laterally and 2 additional tissue planes deep to discernable mass. Obtaining these resection margins may require partial scapulectomy, thoracic or abdominal wall resection or extremity amputation. In these cases the decision to attempt surgical cure needs to be balanced against the potential for patient compromise. The overall (national) recurrence rate is estimated to be 50% at 1 year following surgery alone.(4,5) This includes a wide array of margin distances. In one study, the institution of 5 cm lateral and 2 tissue plane deep margins has resulted in an improved local recurrence rate of less than 5% after 6 month median follow-up.(8) Although this study is somewhat immature, it does hold promise of surgical cures with aggressive resection. Due to lack of local tumor control early in the treatment of VAS, radiation has been implemented either as a primary treatment or in the adjuvant setting. Until the true efficacy of surgery alone (including radical resection) can be elucidated, the use of adjuvant radiation for the treatment of VAS is recommended. The advantage of radiation is that it allows regional therapy without compromise. Early reports of local disease control following radiation ranged from 50% with radiation alone to 75% with a combination of radiation and surgery.(9) Earlier radiation protocols ranged from as low as 45 Gy to as high as 64 Gy in daily or every-other-day schemes. With experience, it has been shown that cats appear very tolerant to higher doses of radiation, especially in truncal areas where skin is the acutely responding tissue. Dogs show severe moist desquamation and often go through a period of intense pruritus. Cats, on the other hand, tend to show a dry desquamation that is associated with few clinical signs. This has allowed for protocols with increased total radiation dose, improving tumor control. Presently recommended protocols administer total doses in the low 60Gy range. The use of electron therapy (as opposed to photon therapy) can be beneficial in that electrons are more superficially penetrating and will often spare deeper tissues from appreciable radiation doses. This is especially true for masses over the thorax, so that lung and heart can be spared, and over the spine to allow increased dose yet spare the spinal cord. Electron therapy requires a linear accelerator for administration. Increasing fractionation schemes (hyperfractionation) may also allow increased dose delivery with better sparing of normal tissues than course fractionation schemes. Many institutions and practices advocate radiation therapy prior to surgery for VAS. The advantages to preoperative radiation are based on two main premises. The first is that surgery disturbs tissue planes through dissection as well as postoperative edema, and hemorrhage, potentially increasing the field size, depth and margins needed for effective treatment. Part of this concern stems from the radiation therapist being unaware of the boundaries of the surgical resection. Close association and communication between the surgeon and radiation therapist can decrease this concern. In addition, the placement of metallic clips (hemoclips) at the boundaries (lateral as well as deep) of the dissection can aid in the treatment planning. The second concern is the induction of hypoxic regions within the surgical site. Hypoxic tissues and cells are resistant to radiation. This is a normal change following tissue disturbances, but can be decreased by gentle tissue handling, appropriate hemostasis and tension-free closure. If surgery is performed prior to radiation, preplanning the surgical excision is important, keeping these concerns in mind. In addition, less aggressive surgery may be indicated, to avoid detrimental changes, if radiation is planned postoperatively. The primary disadvantage of performing surgery following radiation therapy is related to the tissue changes encountered. Irradiated tissues are compromised, especially in vascular supply. These tissues are slow to heal and less resistant to infection and tension. With this in mind the surgeon also needs to have gentle tissue handling, appropriate hemostasis and strive for a tension-free closure. If it is possible to excise all the irradiated tissue and repair the defect with a vascularized graft, this may be preferred. The use of vascularized omental grafts may also greatly aid healing. Another concern regarding post-radiation surgery is the lack of discernable margins. If the tumor has decreased in size from the radiation, margin measurement becomes difficult. The recommendation at this point is to plan the margins based on the original tumor size and tissue involvement. This will require some method of documentation of the original tumor, either with skin markings, photographs or CT/MR images. Although the rate of distant metastasis is low for VAS, combination treatment protocols including chemotherapy have been suggested and trials are being conducted using adjuvant chemotherapy. The reasons for chemotherapy are based on the theoretical increase in metastasis secondary to improved local disease control as well as the potential benefit in local disease control. In studies conducted thus far, improvement in survival has been small, yet present using doxorubicin either at the same time as radiation therapy or beginning after recovery (approximately one month following radiation therapy). The impact of chemotherapy may be diluted due to case selection bias in choosing chemotherapy for more advanced disease or high-risk patients. Further studies may help to elucidate the true efficacy of adjuvant chemotherapy.(10) Follow-up for VAS cases must focus on local disease control. Most failures are within the treatment site and most will occur within 6-9 months of the completion of therapy. Diligent palpation by the owner is the cornerstone, with further evaluation of suspicious changes by the veterinarian. Masses which show progressive growth should undergo biopsy. The need for periodic staging measures is unknown, but they are likely indicated prior to further major interventions for recurrent disease. The options for recurrent disease are dependent on prior treatment. Re-irradiation has not been evaluated, but is likely to result in unacceptable normal tissue complications due to the high doses used in primary therapy. Radiation could be considered for new growth outside of the original treatment field. Surgical removal may be an option for recurrence, the surgical dose dependent on prior surgery, local tissue involvement and the impact of irradiated tissues. Following aggressive first-line therapy, options for recurrent disease may be limited to palliative surgical resection of the mass. Due to the many concerns surrounding VAS, the AVMA formed the Vaccine Associated Sarcoma Task Force (VASTF). This task force is charged with assessing the impact of this disease, the responsibilities of owners, veterinarians and vaccine manufacturers, establishing research directions and funding as well as making recommendations for treatment and prevention. A number of clinical and bench research projects have been sponsored by the VASTF, through funding from vaccine manufacturers and veterinary associations in the areas of incidence and impact, etiology, prevention and treatment. Recommendations of disease prevention and treatment have also been made through the American Association of Feline Practitioners and pamphlets are available. In summary, these organizations recommend avoiding overvaccination and aggressive diagnostics for injection site reactions as well as aggressive treatment strategies. Vaccine site recommendations have been variable, but attempts been made to improve treatment options, especially surgical control. The details of all of these recommendations are evolving as more is learned about the disease and treatment response. In addition, adverse reactions to injectable agents should be reported through the Veterinary Practitioners Reporting Program of the US Pharmacopia. References:
ADVANCED ONCOLOGIC SURGERY
How to Save a Cancerous Limb Limb Sparing for Osteosarcoma A tentative diagnosis of osteosarcoma (OSA) is made by clinical presentation and radiographic changes with definitive diagnosis made by histologic evaluation. However, if the clinical and radiographic features are typical for OS, especially when there is little possibility of fungal or bacterial infection, confirmation by histologic diagnosis following surgical treatment of local disease (limb sparing) can be considered. Few diseases causing advanced destruction of the bone can be effectively treated without removal of the local disease. If the owners are willing to treat aggressively, surgical removal of local disease with biopsy submission following surgery can be considered. We recommend 3-view chest radiographs and, when available, nuclear scintigraphy. Although only 10-20% of cases will have positive results at the time of presentation, the finding of clinically evident metastasis greatly alters the prognosis and potentially the treatment options thus supporting aggressive staging prior to treatment.(1) Scintigraphy is also used to estimate resection margins for limb sparing.(2) Due to the aggressive biologic behavior of OSA, treatment for disease control involves local tumor therapy as well as therapy for micrometastatic disease. Options for local therapy of appendicular sites include amputation and limb sparing. Amputation is the traditional method for treatment of OSA. Function following amputation is excellent in better than 90% of dogs. Giant breed dogs, obese and those with a wide stance may have a longer adjustment period postoperatively, but amputation is still a viable treatment option. We have seen a number of dogs with cervical or lumbosacral instability lesions that were exacerbated following amputation. This may be due to the increased flexion and rotation of the vertebrae required for three-legged ambulation. Degenerative arthritis in remaining limbs is not a contraindication for amputation, as it rarely becomes a clinical problem. Local tumor recurrence following appropriate amputation is a very rare occurrence.(1) For dogs that are not candidates for amputation, or for owners that desire to avoid amputation, limb sparing may be a viable option. Although limb sparing does not compromise patient survival when compared to amputation, the complication rate is high. Tumor recurrence and postoperative infection as well as miscellaneous orthopedic and implant complications can occur, which do not exist for amputation patients. The cost and owner commitment for limb sparing is large when compared to amputation and if complications occur these factors can multiply exponentially. For these reasons, limb sparing cannot be considered as the treatment of choice for local disease control in most cases of appendicular bone tumors. Owners must be thoroughly informed of all factors involved with limb sparing before that commitment is made.(3) Limb sparing surgery generally involves a marginal resection of the involved tumor bone and replacement of the defect with a cortical allograft and stabilization with internal fixation. Dependent on location, arthrodesis of the joint may be necessary. In our experience, distal radius and ulna sites result in the best function following limb spare. Arthrodesis of the carpus is well tolerated by dogs of most any size. With arthrodesis of the shoulder, stifle or tarsus, function ranges from very poor to good and the complication rate is considerably higher than distal radius or ulna sites, especially in larger dogs. For these reasons, we generally recommend amputation (for amputation candidates) for OSA in sites other than distal radius or ulna.(4,5,6) Limb sparing should be questioned for dogs presented with metastatic disease due to the cost and commitment required for the procedure in light of a short-term survival outlook. Limb sparing candidates are those that show radiographic tumor involvement of 50% or less of the involved bone. Involvement of both distal radius and ulna will not preclude a patient from limb sparing, but the complication rate can increase. In these cases a radial allograft is used, but the ulna is not grafted. Ulna lesions are generally treated by ulnectomy without allograft placement since the radius is the primary weight bearing bone. Pathologic fractures increase the chances for soft tissue contamination with tumor cells locally and amputation should be considered.(3) Following limb preparation and the use of impervious drape material, a marginal resection is performed with an attempt at obtaining one tissue plane between the tumor and the resection margin. Biopsy tracts are removed enbloc with the specimen. The proximal bone margin is determined by the radiographs to be 2-3 cm from any abnormal bone change. Alternatively, margins can be determined from the nuclear bone scan.(2) For distal radius sites, care must be taken in separation of the radius and ulna. Preferably, a portion of the medial ulna cortex is removed with the radius. If ulnar involvement is suspected, then both bones are resected. Reconstruction involves (preoperative) selection of a bone graft fitted to the defect followed by rigid fixation.(3) Filling the allograft with methyl methacrylate has been shown to decrease implant failure.(7) For large tumors, especially those with large soft tissue components, pre-operative down staging of local disease can improve the success of the procedure as well as the ease of resection. Our work has demonstrated that approximately 30 Gy of radiation (traditionally in 10 3 Gy fractions) combined with cisplatin as a radiation sensitize will result in 80% or better necrosis of the tumor. This degree of necrosis has been shown to significantly reduce local tumor recurrence. Higher radiation doses are required to obtain the same degree of necrosis if radiation is used alone; increasing the occurrence of radiation related complications.(8) A new technique for limb sparing has been utilized in a small number of patients with sites other than the distal radius or ulna. This technique involves osteotomy above or below the affected site and removal of soft tissues from the tumor bone. The neurovascular bundle is held away from the affected bone and the tumor is pivoted from the site on the intact joint tissues. A single dose of 70 Gy radiation is then directed to the tumor. The radiated bone is then anatomically replaced and fixed back into position using either an interlocking nail system or dynamic compression plating. The advantage to this technique is in sparing of joint function, the major limiting factor to the success of sparing in non-distal radius or ulna sites. To date, two proximal humeral sites, one distal humeral site, one distal femur and one distal tibia have been treated. All patients have had at least good function. Four patients have had to have implant revisions within 5 months of initial surgery, including 2 amputations. Local tumor recurrence has occurred in 2 patients and infection in 2 patients. Follow-up on this subset is relatively short and further evaluation as well as technique modification is indicated before this technique can be recommended routinely.(9) Complications following limb sparing include tumor recurrence, infection and implant failure. Without neoadjuvant or adjuvant therapy, local recurrence rates can be as high as 65%. As mentioned, preoperative down staging procedures can significantly lower this occurrence. In addition to this we have developed a method of local, intracavitary (in the wound bed) chemotherapy to help lower local recurrence. An Open cell PolyLactic Acid polymer (OPLAR, THM Biomedical, Duluth, MN), impregnated with cisPlatin (OPLA-Pt) is placed within the limb spare wound prior to closure. This results in high local concentrations of platinum yet low, non-toxic systemic levels. Platinum will penetrate tissue up to 3 mm and experimentally has been shown to be cytotoxic to OSA cells in this zone. Continuous release over a prolonged time (21 days) allows further tissue penetration and improved cytotoxicity. Using a combination of neoadjuvant therapy and local chemotherapy, limb spare recurrence rates are decreased to less than 20%. Local tumor recurrence can often be treated with a re-sparing procedure, especially if it occurs in the adjacent bone. As would be expected, success rates drop with successive local recurrence and salvage procedures. If further salvage is not feasible, amputation can be re-considered.(10) The largest single complication seen (outside of OSA disease) following limb sparing is infection. An infection rate approaching 50% is common. This is due to multiple factors including; extensive surgical field, large resection with compromise of arterial, venous and lymphatic flow, local and/or systemic chemotherapy with or without radiation, large allograft and metallic implants and lack of soft tissue covering (especially distal radius and ulna). Infection rate is high despite intraoperative and long-term postoperative antibiotic therapy. The majority of infections can be controlled with appropriate antibiotic therapy, but approximately 10% will require additional surgery to control. A small percentage cannot be controlled and end in amputation. We have been able to improve our treatment success of severe infections with the surgical implantation of aminoglycoside antibiotic impregnated polymethyl methacrylate beads, presumably due to overcoming bacterial resistance.(11) Bone tumors originating in proximal sites of the scapula can be successfully removed by partial scapulectomy. Dogs function well with partial scapulectomy; however gait abnormalities may occur after scapulectomy by disarticulation at the scapulohumeral joint.(12,13) In rare cases, internal pelvectomy with limb sparing can be performed for pelvic OSA sites. Cisplatin has been established as traditional chemotherapy for canine osteosarcoma metastases. Median survivals increase from less than three months to greater than one year when cisplatin is added to surgical treatment of primary disease. A recent Veterinary Cooperative Oncology Group study established carboplatin (ParaplatinR) as having equal efficacy to cisplatin (at 4 doses) for OSA patients following amputation.(14) Two recent studies have demonstrated efficacy for doxorubicin in OSA patients. These animals were treated preoperatively and postoperatively at 2-week intervals and one-year control rates were similar to dogs treated with cisplatin.(15) In attempts to overcome drug resistance, combination drug protocols have become commonplace in the treatment of OSA in people. Clinical trials have demonstrated significant improvement in disease control using combinations of agents (proven effective alone) when compared to single agent therapy. Combination protocols are now being evaluated in many institutions. One study using alternating courses of cisplatin and doxorubicin demonstrated equal disease control as with cisplatin alone. Another study demonstrated increased efficacy with cisplatin and doxorubicin given concomitantly.(16) Based on the success of our intracavitary use of cisplatin released from polylactide polymer systems in control of local recurrent disease, we have established the efficacy of this same slow release polymer system for systemic cisplatin administration in dogs with OSA. A single implantation of OPLA-Pt into the musculature at the time of closure following amputation resulted in similar disease control as dogs given 2 intravenous doses of cisplatin following amputation. This method of cisplatin release results in low peak, but sustained levels for up to 21 days following implantation. This results in an area under the time versus platinum concentration curve (AUC) up to 27 times that seen following intravenous injection of similar doses. We were able to demonstrate a significantly improved disease response for dogs with a 21 day AUC greater than 7, compared to those less than 7, indicating a response for this method of drug administration. The primary toxicity seen with the OPLA-Pt is local tissue reaction to the polymer or the cisplatin. This results in swelling and potentially drainage and secondary bacterial infection. This reaction is generally self-limiting with eventual dissolution of the polymer. Bone marrow suppression would be the most likely toxicity of a slow release system but is seen only at high doses of OPLA-Pt (120 mg/m2).(17) Renal toxicity has not been documented. We are presently evaluating serial OPLA-Pt implantation. We have also evaluated an injectable polylactic acid polymer system (AtriplatR, Atrix Laboratories, Fort Collins, CO) for sustained release of cisplatin. Pharmacokinetic studies have shown similar release kinetics to the OPLA-Pt and predictable (bone marrow) toxicity. We are presently evaluating efficacy against micrometastatic disease for appendicular osteosarcoma in a national trial. Local toxicity is still the primary complication to this method of treatment.(18) Large tumor size has been reported to be a negative prognostic factor for canine OSA as has young age and the presence of measurable metastases. Recently, elevated alkaline phosphatase (AP) has been associated with a poor prognosis for dogs with appendicular OSA. A preoperative elevation of either total (serum) or bone isoenzyme of AP is associated with a shorter disease free interval and survival. Likewise, dogs that have elevated preoperative values that do not return to normal following surgical removal of the primary lesion also fail earlier from disease.(19) In dogs, it has not been well established that there is a difference in the biological behavior of the different histologic subclassifications, however, recent work has shown a potential relationship between histologic grade, based on microscopic features, to be predictive for systemic behavior (metastasis).(20) The usual cause of death in dogs with osteosarcoma is diffuse pulmonary metastasis. Resection of pulmonary metastasis from osteosarcoma or other solid tumors has been reported in people. The criteria established for case selection for pulmonary metastasectomy in dogs, in order to maximize the probability of long survival periods are: 1) primary tumor in complete remission, preferably for a long relapse-free interval (> 300 days); 2) one or two nodules visible on plain thoracic radiographs; 4) cancer only found in the lung (negative bone scan); and perhaps 3) long doubling time (> 30 days) with no new visible lesions within this time.(21) For dogs with solitary bone metastases and no evidence of cancer elsewhere metastasectomy may be indicated although the subsequent disease free interval is generally short. An alternative is to treat metastatic bone lesions with palliative radiation. Up to 80% of dogs will respond positively (improvement in clinical evidence of pain and lameness) for an average of 3-4 months.(22) References
Pelvectomy involves removal of portions of the pelvis with or without amputation.(1) Pelvectomy is indicated for pelvic masses or proximal femur masses in an effort to obtain adequate resection margins. Partial pelvectomy (hemipelvectomy) indicates removal of a portion of the pelvis. This may or may not be combined with amputation dependent of the affect of the resection on weight bearing. Examples of hemipelvectomy without amputation would include ischial resections or acetabular resections in small dogs. A total hemipelvectomy indicates removal of one entire hemipelvis. This necessitates amputation of the limb. Pelvectomy has also been described for relief of pelvic canal narrowing.(2,3) Primary pelvic bone tumors such as OSA or CSA, proximal femur tumors such as OSA, CSA, synovial cell sarcoma or soft tissue sarcomas (femur or pelvis) would be the most common neoplastic indications for pelvectomy. Pelvectomy can also be considered for severe bacterial or fungal infections as well as irreparable traumatic injuries. Limitations to pelvectomy would include lesions that cross the midline, have extensive sacral involvement (beyond midline), or extension of disease into organs of the pelvic inlet. Full staging is recommended for pelvic masses suspected or confirmed to be malignant. Perioperative antibiotics are indicated due to the length of surgery as well as the potential for fecal contamination. Placement of a urinary catheter will assist in avoidance of injury in dissections close to the midline. Two cm margins are planned in bone and soft tissue. Portions of the illium, acetabulum, ishium and pubis can be removed. In addition, portions of the abdominal wall and epaxial muscles, as well as the sacrum can be removed if indicated. Up to 1/2 of the sacrum can be resected with maintenance of continence. Tail amputation can also be performed if needed and may be necessary with extensive sacral resection. Ligation of the femoral artery (if amputation planned) and the caudal gluteal artery will decrease blood loss during the resection. Closure involves re-attachment of the caudal abdominal wall to remaining sacrum, illium, pubis or to remaining pelvic musculature. Mesh implants can be used to fill larger defects if soft tissues are not available. An attempt should be made to reconstruct the pelvic diaphragm with remaining muscle or fascia. In some cases, only subcutaneous tissues remain for closure. Even with limited tissue reconstruction, herniation is rare. The use of negative suction drains is recommended to avoid seroma and hematoma formation. Aggressive analgesic management is indicated postoperatively with systemic opiods and epidural analgesia being helpful. Stool softeners to avoid constipation and straining during the postoperative wound healing period are recommended. Functional and cosmetic outcome are generally good to excellent. Pelvectomy amputation patients will function as well as a dog following amputation alone. In one study, 18% of dogs had local tumor recurrence with an overall one-year survival rate was 62%. References:
Perianal Tumors in the Male Dog Perianal tumors are common in the male dog. Benign perianal adenomas are the third most common tumor in the male dog, the intact male dog being at high risk presumably due to the influence of testosterone.(1) In the male, perianal tumors originate from the sebaceous cells of the perineum and can fall within a continuum of pathologic and biologic behavior from benign to malignant. The most common form is the benign adenoma; however, a small subset of these tumors can be locally invasive. A fine needle aspirate will help support the diagnosis of perianal tumor but will not usually differentiate between benign and malignant disease. Adenocarcinomas are also seen, which tend to be locally aggressive with a metastatic rate of approximately 15%, most commonly to regional lymph nodes.(2) Perianal adenomas can present as single, multiple or diffuse disease, and can extend over haired areas (tailhead, prepuce) where similar sebaceous cells are found. With the preponderance of metastatic spread to regional lymph nodes from carcinoma, aggressive staging is important with at least abdominal ultrasound and with the consideration of an exploratory laparotomy and node biopsy, especially if aggressive, involved treatment is elected. Thoracic radiographs are also important, although rarely positive. The treatment of choice for perianal adenomas is surgical resection. This can be combined with cryosurgery to improve local tumor control following marginal or close resections. For very small lesions, cryosurgery alone can be attempted.(3) For lesions that are highly suspected to be benign adenoma, excisional biopsy is indicated, especially with small lesions. Castration at the time of removal is recommended to decrease recurrent disease.(4) For large lesions and those suspected to be invasive adenomas, castration alone can be attempted to decrease the local tumor burden. This can be followed by resection if disease does not completely regress. Biopsy of the lesion at the time of castration is indicated to rule out carcinoma or invasive adenoma. The use of estrogens to decrease the size of large lesions or as a sole treatment is not recommended due to the potential for irreversible bone marrow suppression. Carcinomas require more aggressive resection and adjuvant therapy is dependent on the presence of metastasis and the ability to obtain a complete resection of local disease. Removal of up to one-half of the anal sphincter can be performed and fecal continence still maintained. Incomplete resection can be followed by external beam radiation with some success. Positive lymph nodes denotes a poorer prognosis, but if elected, removal of nodes and adjuvant radiation to the node bed can lead to reasonable remission times. Even large nodes are usually easily removed. Chemotherapy is unproven for perianal carcinomas, although may be elected for cases presenting with metastasis. Regimens including cisplatin and doxorubicin have been reported. Complete surgical removal of benign adenomas is up to 90% curative. Carcinomas in the male dog are often slow to metastasize and adequate control of local disease will often result in long term remission. Surgery alone for non-metastatic lesions less than 5 cm has resulted in average remission times of greater than 2 years. Perianal Tumors in the female dog In general, perianal tumors are uncommon in the female dog, appearing most commonly as adenocarcinoma of anal sac origin in the spayed female dog.(2) These tumors are locally aggressive with a metastatic rate of up to 50%, most commonly to regional nodes but also to lungs. Hypercalcemia is a commonly seen paraneoplastic finding and may persist following perianal mass excision if metastatic disease persists. With the preponderance of metastatic spread to regional lymph nodes, aggressive staging is important with at least abdominal ultrasound and with the consideration of an exploratory laparotomy and node biopsy, especially if aggressive, involved treatment is elected. Thoracic radiographs are also important, although rarely positive. Since the female dog lacks the sebaceous cells of the perineum, the appearance of benign adenomas in that sex is suspected to be due to the secretion of androgens (like testosterone) commonly from the adrenal gland. A clinicopathologic 'search' for cushings disease is warranted with the diagnosis of perianal adenoma on the female dog. Surgical removal of perianal carcinomas in the female is indicated, dependent on the status of metastatic disease. These tumors require aggressive resection. Removal of up to one-half of the anal sphincter can be performed and fecal continence still maintained. Adjuvant therapy is dependent on the presence of metastasis and the ability to obtain a complete resection of local disease. Incomplete resection can be followed by external beam radiation with some success. Positive lymph nodes denotes a poorer prognosis, but if elected, removal of nodes and adjuvant radiation to the node bed can lead to reasonable remission times. Even large nodes are usually easily removed and can help return a hypercalcemic dog to normocalcemia. Chemotherapy is unproven for perianal tumors, although may be elected for cases presenting with metastasis. Regimens including cisplatin and doxorubicin have been reported. Anal sac origin perianal carcinoma in the female caries a guarded prognosis. Aggressive treatment has resulted in a median survival of only 1-year with failure equally divided between local tumor recurrence and metastasis. Metastasis present at the time of presentation and the presence of hypercalcemia has been associated with poorer prognosis for his disease. References
Maximum Mandibulectomy and Maxillectomy Mandibulectomy, maxillectomy and orbitectomy are most often performed for the treatment of oral and orbital neoplasia. Surgical resection should be considered as a first line of treatment for all oral neoplasms. However, limited soft tissue excisions for attempted cure of oral tumors often fail because of recurrence of the tumor at the primary surgical site. Mandibulectomy, maxillectomy or orbitectomy accompanied by soft tissue resection for tumors has the potential for prolonged remission or cure in certain malignancies. If nothing else, the quality of life can be dramatically improved even though distant metastasis may ultimately occur. These techniques can also be applied for the treatment of severe infection or following irreparable trauma to regions of the oral cavity. This text focuses on the more advanced surgical techniques of mandibulectomy, maxillectomy and orbitectomy. For a more detailed description of pre and postoperative considerations and specific treatment recommendations for individual tumor types, the reader is referred to other publications.1,2 When mandibulectomy or maxillectomy are performed for treatment of an oral neoplasm, at least a 1-cm grossly visible tumor-free margin should be obtained on all cut surfaces. Boundaries for partial hemimandibulectomy for benign neoplasms with or without evidence of cortical bone penetration into the medullary cavity should be determined radiographically and by oral examination. Cortical bone penetration by malignant neoplasms with suspected bone marrow involvement is the main indication for total hemimandibulectomy versus partial hemimandibulectomy. If tumor cells are found following the neurovascular bundle within the medullary cavity of the mandible, the entire hemimandible (minimally the mandibular body rostral to the vertical ramus) must be removed to completely excise the tumor. Malignant disease without radiographic evidence of cortical bone penetration can be treated similarly to benign disease. Hemorrhage during mandibulectomy and maxillectomy should be controlled with cautery and preferably ligation for larger vessels including the mandibular alveolar and branches of the palatine artery. Bone wax can be used to control hemorrhage from the medullary cavity of the mandible or form the hard palate. Temporary unilateral or bilateral carotid artery occlusion has been found to decrease blood volume loss and improve visualization of the surgical field during maxillectomies, especially hemimaxillectomy and caudal maxillectomy. After removal of the tissue to be excised, blood flow is reestablished to allow maximum circulation to the surgical site. The blood flow to the nasal cavity and palatal mucosa originates from terminal branches of the maxillary artery, the main continuation of the external carotid artery. These branches include the sphenopalatine, major and minor palatine, infraor-bital, and dorsal and lateral nasal arteries. Experimentally and clinically, the common carotid artery has been permanently occluded both unilaterally and bilaterally in dogs without causing neurologic or ischemic deficits. This may not be true, however, in the cat. Mandibulectomy is the resection of variable portions of the mandibular symphysis, body and vertical ramus and closure of the resulting defect with a labial mucosal-submucosal flap. The resultant defect fills with fibrous tissue, eliminating the need for bone replacement. For caudal mandibular resections, function of the remaining cranial portions are by connection to the contralateral side through the symphysis. Closure of the mandibulectomy site is limited by the availability of normal labial and lingual mucosa. Tumors that extensively involve the labia or the labial mucosa may not be resectable. Ap-pearance and function generally are excellent after mandibulectomy. Total Hemimandibulectomy (THM) is the most aggressive form of mandibulectomy and entails removal of the entire hemimandible on one side. It is indicated for tumors or injuries involving a large segment of the mandible or for those tumors (e.g. malignant melanoma, fibrosarcoma, and osteosarcoma) that appear to have penetrated into the medullary cavity. For rostrally located masses with marrow involvement, the body of the mandible can be resected at the rostral edge of the masseter muscle (the marrow cavity ends at this level) and the vertical ramus and the Temporomandibular joint (TMJ) joint left intact. Incising the commissure of the lip at its midpoint to the rostral edge of the masseter muscle will aid in caudal dissection. Closure is specific to each case, depending on the amount of soft tissue excised, but in all cases dead space must be closed, followed by mucosal apposition in the caudal third of the incision. A three-layer suture closure is recommended with a continuous suture pattern in the mucosa to obtain a watertight seal. If this does not inadequately close the dead space, a negative suction drain may be placed to exit close to the incision. Exiting passive drains away from the incision could potentially contaminate a larger area with tumor cells if the resection is microscopically incomplete. This could compromise adjuvant radiation therapy by considerably enlarging the treatment field. Because removal of the entire hemimandible results in loss of lateral support for the tongue, lateral drifting of the tongue often occurs. Closing the commissure of the lip farther rostrally can help maintain the normal position of the tongue. To do this, the margin of the upper lip, where it previously met the lower lip to form the commissure, is incised full thickness along its margin to the level of the first premolar or canine tooth. A three-layer suture closure consisting of the mucosa, subcutaneous tissue, and skin is then performed. Because of excess tension at the rostral extent of the suture line when the mouth is opened, a vertical mattress suture with buttons or rubber stent may be considered. Vertical Ramus Mandibulectomy (VRM) is indicated for tumors or injuries involving the angle or vertical ramus of the mandible. This procedure is versatile enough to allow preservation of the temporomandibular joint or excision of the entire hemimandible caudal to the last molar. The procedure can be combined with resection of the zygoma (orbitectomy) for lesions with more extensive tissue involvement. Depending on the extent of the lesion to be removed, one may preserve the temporomandibular joint or include the joint in the excised bone. Exposure is similar to that performed during THM, followed by resection of the desired portion of the vertical ramus. For closure, replacement of the osteotomized zygoma is not necessary. Maxillectomy is the resection of variable portions of the maxillary, incisive, and palatine bones and closure of the resulting oronasal defect with a labial mucosal-submucosal flap. The remaining bony structure of the muzzle maintains stability and contour, eliminating the need for bone replacement. Closure of the maxillectomy site is limited by the availability of normal labial and buccal mucosa. Tumors that extensively involve the labia or cross the midline of the hard palate may not be resectable. Ap-pearance and function generally are excellent after maxillectomy. Hemimaxillectomy (HM) is the most aggressive of the described maxillectomy procedures and is indicated for tumors that involve the majority of the hard palate on one side without crossing the midline. It involves removal of the oral mucosa, teeth, and portions of the incisive, maxillary, palatine, and zygomatic bones. The degree of resection is dictated by the size of the lesion, its location, the degree of tissue involvement and the expected biologic behavior (of the tumor). Any portion of the maxilla can be excised unilaterally and still result in normal function and adequate cosmetics. Caudal maxillary resections can be combined with resections of portions of the inferior orbit, zygoma and/or vertical ramus of the mandible depending on degree of tissue involvement. For tumors that have a large lateral or dorsal component, the dog can be placed in lateral or ipsilateral recumbancy and a dorsal incision made over the skin of the dorsal maxilla, to assist in dissection, in addition to the mucosal incision. Closure is similar to premaxillectomy. Interrupted sutures at each end of the mucosal closure which encircle the remaining teeth can be placed in addition to the continuous closure to combat tension, which is often most evident in these locations. Orbitectomy is a viable option for treating various solid tumors of the periorbital area in dogs and cats. Long disease-free intervals and survival times can often be achieved. The surgical procedure, although technically demanding often results inmaintenance of good function and cosmetics appearance with minimal complications.2 Performing an orbitectomy requires detailed knowledge of the regional anatomy and experience in performing combined procedures such as orbital exenteration, maxillectomy, mandibulectomy, rhinotomy, and craniotomy. To determine the types of procedures that might be required, the extent of neoplastic disease has to be assessed in each case. Computed tomography has been found to be subjectively better in identifying the presence of tumor in the periorbital soft tissues, as well as invasion into the nasal cavity, paranasal sinuses, and the calvarium. In general, if the tumor does not appear to invade a vital region of the brain and extensive metastatic disease is not evident, a surgical resection can be attempted. The surgical approach varies with the location of the tumor. Incisions are centered over the tumor and in-clude any biopsy tracks or previous surgical scars. An attempt is made to remove the tumor intact and surrounded by at least 1-2 cm of normal tissue. Care is taken to protect the eye if it is to be preserved. A temporary tarsorrhaphy can be performed to cover the globe. A total orbitectomy involves a combination of individual approaches. The bones that comprise the orbit include the maxilla, and the frontal, zygoma, palatine, lacrimal, and sphenoid bones. A dorsal approach is used to expose the frontal bone overlying the nasal cavity and frontal sinus. For periorbital tumors extending into the oral cavity an intraoral approach is used to isolate the caudal hemimaxilla. The exposure of the maxilla is then continued dorsally to join the exposure of the frontal bone. The lateral orbit is defined by the zygomatic arch and the orbital ligament. If the tumor extends lateral to the orbit, portions of the masseter muscle ventral to the zygomatic arch are removed with the tumor. If the tumor involves the coronoid process of the mandible, the vertical ramus is exposed ventral to the tumor and a transverse osteotomy of the ramus is performed. The coronoid process is then removed with the entire mass. On occasion, the entire vertical ramus and a portion of the mandibular body is also removed. The zygomatic arch is osteotomized at its caudal-most border. If the tumor extends caudally to involve the temporomandibular joint, it is excised along with the zygomatic arch. If the maxilla is involved, a caudal hemimaxillectomy is performed. The hemimaxillectomy is continuous with the rhinotomy over the nasal cavity and frontal sinus. This excision can be extended into a craniotomy if necessary. The medial orbital wall is removed by osteotomy of the lacrimal and frontal bone to complete the resection. The optic nerve is severed as it exited the optic foramen. Partial orbitectomy consists of either removal of the superior orbit (e.g., frontal bone) or the inferior orbit (e.g., zygoma and maxilla). Inferior orbitectomy consists of excision of the zygomatic arch or both the zygomatic arch and the caudal hemimaxilla. As with the total orbitectomy procedure, if the vertical ramus of the mandible is involved, it is removed with the zygomatic arch. A superior orbitectomy involves excision of a portion of the frontal bone and removal of the medial aspect of the orbital wall. Enucleation is only performed if the eye or its neurovascular supply, or a significant percentage of the eyelid is infiltrated with tumor or are in close proximity to the tumor border. The surgical defect is closed by apposition of subcutaneous tissues using absorbable sutures. Care is taken to reestablish the compartments of the oral and nasal cavities. If a caudal maxillectomy is performed the oral and nasal cavities were reestablished by suturing the labial mucosa of the upper lip to the hard and soft palate. Attachment of soft tissues to the palatine bone can be facilitated by predrilling holes in the bone through which sutures can be passed. If a craniotomy has been performed, a temporalis muscle flap is sometimes used to cover and protect the exposed brain. References
Thoracic Wall Resection Thoracic wall resection is indicated for tumors which originate from or invade into the tissues of the chest wall. Primary bone tumors of the rib, such as osteosarcoma (OSA) or chondrosarcoma (CSA) and soft tissue sarcomas originating from fascial or vascular tissues would be the most common. In addition, chest wall resection can be indicated for severe bacterial or fungal infections of ribs, severely displaced rib fractures or other severe traumatic injuries to the thorax.1 Complete staging is indicated for chest wall tumors, especially those originating from rib since systemic metastasis is common. Three view metastasis evaluation thoracic radiographs are indicated. Thoracic films may demonstrate intrathoracic spread of disease. Lung technique may be adequate to evaluate the extent of local (rib) disease, however special 'rib-technique' views may be helpful in discerning subtle changes. For larger masses, or those that may have intrathoracic extension, computed tomography may be of benefit. Margins for chest wall resection are not necessarily dependent on histology. Therefore a biopsy is indicated if knowledge of the disease state would alter the owner's decision, based on prognosis. Excisional biopsy following chest wall resection is appropriate if the owner is willing to treat, despite the pathology of the mass. For lesions where infection is suspected, a preoperative biopsy may avoid overtreatment of the lesion. Incisional biopsies are preferred due to the increased likelihood of positive identification of the mass with larger samples. The biopsy must be placed in a location that will not compromise the definitive resection, as the biopsy tract must be removed at the time of definitive surgery. The maximum number of ribs that can be safely resected with a chest wall resection is unknown. We have removed (portions) of 7 ribs without major postoperative complications. Limitations to chest wall resection would include disease that extends into the vertebrae dorsally. However, laminectiomy in combination with rib resection could be considered for small lesions. Lesions that extend bilaterally across the sternum may also limit resection due to instability of the ventral chest wall, however, this is not known. Ribs 1-8 are termed sternal ribs, due to their articulation with the sternum. Resection of parts of these ribs requires reconstruction with muscle, fascia, implants or a combination in order to maintain chest wall stability. Ribs 9-12 are termed asternal ribs as they articulate with the costochondral junction of cranial ribs and not directly with the sternum. Resection of these ribs does not affect chest wall stability and repair can be through diaphragmatic advancement alone. Since the majority of chest wall masses are malignant, margins for resection should be liberal. A minimum of one (freely moving) tissue plane surrounding the mass is necessary, however, 2-3 cm of soft tissue (normal) margin are preferable. If the skin is freely moveable over the mass, then it need not be removed with the mass, with the exception of the biopsy tract. In general, obtaining one non-affected rib cranial and caudal to the affected rib or ribs is preferred. This will often assure adequate soft tissue margins beyond the affected rib. If involved, portions of the sternum, vertebrae or diaphragm can also be removed. It is not uncommon to have attachment of lung lobe to a chest wall mass. This may indicate invasion from the chest wall to the lung, or extension of a lung mass to the chest wall. If lung tissue is attached to the chest wall, it must be resected. Once the thorax is entered, palpation of the deep limits of the mass is performed to evaluate for thoracic extension. If attached lung tissue is found, the entire lung lobe or a portion can be resected prior to or following completion of the chest wall resection. Rib can be cut using manual rib cutters or an oscillating saw, dependent on the size of the patient. Small defects (1-2 ribs) can usually be repaired by apposing the remaining ribs with encircling suture or through a hemicirclage technique. Larger defects (2 or greater ribs) require a more stable closure as mentioned above. The preference at our institution for closure of sternal rib defects is through the use of muscle flaps. Although the literature would suggest that muscle flaps are restricted to smaller defects, defects up to 7 ribs have been effectively repaired with this technique without major complication at our institution.2 The latissimus dorsi muscle is the most useful for chest wall closure. If the primary vascular pedicle, (just caudal to the shoulder joint), is maintained, dorsal and ventral attachments can be severed and the muscle belly rotated to fill most defects.3 Care must be exercised during the resection to avoid removal of the muscle. This is dependent on the potential need to include portions of this muscle in the resection margins. As the wound heals, the majority of this muscle belly is replaced with fibrous tissue resulting in a stable chest wall replacement. An additional option for muscle flaps would include the external abdominal oblique, especially for caudal defects. For full thickness chest wall defects, myocutaneous free flaps could be considered. If muscle and fascial flaps are inadequate for repair, implant materials can be used to repair chest wall defects. The most commonly used material is polypropylene mesh (MarlexR).4 This is an inert, knitted material with a crystalline molecular structure. As the defect heals with Marlex in place, fibrous tissue grows into the interstices and will eventually create a stable chest wall. For defects of 2-4 ribs, a single layer of Marlex is usually adequate. This can be combined with muscle or fascial tissue to improve the stability. For defects greater than 4 ribs, a double layer of marlex can be used. In addition, the placement of a thin layer of polymethyl methacrylate or attachment of a lubraplate to every second rib can aid in stability.5 Additional prosthetic meshes include expanded polytetraflouroethylene (GortexR), polyethylene terephthalate (MerseleneR), plastic (ProxplastR) as well as biodegradable mesh constructed of polygalactin 910 or polyglycolic acid. The use of a negative suction drain is recommended following chest wall resection, especially after the implantation of prosthetic meshes due to the increase in fluid production secondary to the foreign body reaction. Seroma and hematoma formation increase the risk of infection, which will persist due to the presence of the mesh. The advantages to mesh implants are the immediate rigidity and strength of the repair. The major disadvantage is also the most serious complication, that of infection. Once a mesh implant becomes infected, conservative management with drainage and long-term antibiotic therapy is indicated in order to maintain the mesh for a minimum of 6 weeks.6 This allows a fibrous capsule to form, allowing removal of the implant without the creation of chest wall instability. Caudal rib resections (asternal ribs 9-12) can be repaired by diaphragmatic advancement. The pleural recesses between the lung periphery and the diaphragm are not fully utilized in animals and advancement uses this space. Following diaphragmatic advancement, some compromise of respiratory capacity does occur, however it rarely results in a clinical problem. Diaphragmatic advancement entails re-suturing the cut edge if the diaphragm to the newly created caudal extent of the thoracic wall. The free edge is sutured to the epaxial musculature, the intercostal muscles or around the caudal most rib. Following advancement and closure of the thoracic cavity, a muscle flap of the abdominal muscles or closure with local tissue is performed to fill the soft tissue defect. The major advantage to diaphragmatic advancement is the avoidance of foreign material in the wound. However, the technique is limited to caudally located masses. Infected chest wall resections, or those with compromised blood supply to the local tissues, closure can be assisted by an omental pedical flap. A pedicle of omentum can be tunneled or laid in directly from the abdomen and sutured into the defect. A muscle flap or other implant can be used in combination. Pain management following chest wall resection should be aggressive. Options include systemic narcotics, either intermittently given perenterally or given as a constant rate infusion. The use of local anesthetics to block intercostal nerves or to infiltrate wound tissues can be helpful, especially with long acting local anesthetics. Intraplueral installation of local anesthetics through the thoracic drain tube can also be helpful. Drain tubes should be maintained until a trend of decreasing fluid production is documented. Thoracic drain tubes as well as mesh implants will increase fluid production at the site. Three large retrospective studies7-9 have evaluated outcome for dogs treated with chest wall resection for neoplastic disease. The primary mode of failure was local tumor recurrence. Survival ranges were 5 to 32 weeks for osteosarcoma, 4 months to 1.5 years for CSA and only 3 to 12 months for hemangiosarcoma. A positive effect on patient survival was seen when systemic chemotherapy was given for osteosarcoma patients. In these studies, all patients reported good functional and cosmetic outcomes. In conclusion, chest wall resection is the treatment of choice for locally aggressive cancers, which originate from or invade into the ribs or soft tissues of the thoracic wall. Complete surgical removal can result in a long-term remission and survival, dependent on the tumor type. Wide resection margins are essential for success. Defect repair can be performed through the use of muscle flaps, mesh implants or a combination for sternal ribs and diaphragmatic advancement for caudal, asternal defects. The functional and cosmetic outcome following resection is generally good. References
Oncologic Applications of Rigid Endoscopy The use of rigid endoscopy for evaluation of body cavities and other non-accessible sites is increasing in popularity and availability in veterinary medicine. The primary advantage of these techniques over surgical exploration and manipulation is decreased patient morbidity. Much of the explosion of this technology and technique comes on the heels of similar instrumentation and procedures in people. Techniques now commonly employed include cystoscopy, laparoscopy and thoracoscopy. The focus of this proceedings is the application of these techniques in the small animal oncology patient. Cystoscopy Rigid cystoscopy only applies to the female dog, as the tortuosity and diameter of the male urethra does not allow passage of the scope. In addition, even female cats are too small to allow passage of any rigid scopes presently available. The primary application of cystoscopy is for the diagnosis and staging of bladder tumors. Since all bladder disease can present with similar clinical findings, differentiating between bacterial cystitis, urolythiasis or neoplasia relies heavily on imaging. Contrast cystograms or ultrasound can identify bladder masses, however, in some cases a more definitive diagnosis is needed. Biopsy and visualization through laparotomy and cystotomy is definitive, however this is associated with morbidity. In addition, even complete surgical resection is not thought to be curative for bladder malignancy and the role of surgery is controversial. Cystoscopy allows visualization and biopsy of bladder masses with minimal morbidity. Cystoscopy can often be performed under sedation alone. This technique also allows assessment of mass location and extent, which can aid in deciding if surgical resection may be feasible (and safe) in an effort to downstage local disease prior to adjuvant therapy. If secondary bacterial cystitis is suspected, bladder mucosal biopsies can also be obtained for culture. Laparoscopy The primary application of laparoscopy is for limited exploration of the abdomen, with biopsy of suspicious structures. Newer imaging techniques, specifically ultrasound, can often confirm the presence of suspected abdominal masses. Ultrasound (as well as other non-invasive diagnostic tools) is, however, often imprecise, especially for masses associated with the spleen or liver. Regenerative lesions of the spleen and liver cannot be differentiated from neoplastic masses without biopsy. In addition, cases with suspected multicentic disease cannot be thoroughly staged without visualization. Ultrasound can be used to guide fine needle aspirate cytology or needle biopsy. Unfortunately, small samples from many of the more common abdominal neoplasias are often nondiagnostic. Larger, definitive biopsy samples as well as visualization can occur through laparotomy, however, this is associated with increased morbidity. If solitary, potentially respectable masses are suspect, an exploratory laparotomy is generally recommended. Exceptions would include unstable patients or if owners desire definitive diagnoses prior to proceeding. Laparoscopy allows visualization of most of the abdominal cavity with the exception of dorsal structures such as the mesenteric root, terminal portal vein and the left limb of the pancreas. Visualization is greatly improved with gas distension, however, bowel motion and interference of the omentum can be complicating factors. These factors can be more easily compensated for once the clinician gains experience. Laparoscopy can often be performed under sedation and local anesthetic. Newer techniques allow retrieval of bowel with extrusion through limited openings for palpation, surgical biopsies and potentially resection. Additional techniques allow laparoscopic-guided cystoscopy for patients with urethral openings either too small or too long for cystoscopy (see above). This technique involves a standard laparoscopic approach and once the bladder is visualized, it is grasped and punctured sharply, followed by placement of the scope through the puncture. Repair of the bladder portal is rarely necessary.(1) Thoracoscopy Thoracoscopy also affords limited thoracic exploration and biopsy of suspicious structures. As well, newer 'endosurgical' techniques are constantly being developed.Although at the present time, intrathoracic oncologic surgery is most often performed through standard thoracotomy exposure, techniques of thoracoscopy may offer comparable results in select circumstances with the marked advantage of limited morbidity. This review discusses oncology applications of thoracoscopy.(2) The most predictive prognostic factor for canine primary lung tumors is the presence of lymphatic or intrapleural metastasis. Advanced cases of disease can often be predicted from findings on plain thoracic radiographs or ultrasound. Subtle cases, however can be missed by imaging and must be visualized at surgery. In some instances, confirmation of metastasis can render primary tumor resection unreasonable or an owner may chose to decline resection based on the poor prognosis. Staging of lymph node status or the discovery of advanced intrapleural disease through less invasive means offers a lower complication rate and a faster return to normal function. Most dogs recover rapidly and uneventfully following thoracoscopy with less of a need for intensive post-operative monitoring than patients following thoracotomy. A thorough thoracic exploration with biopsy of suspected nodes or lesions can be performed using a two or three portal system. Samples can be obtained for cytology as well as histology. If available, frozen section histology can be performed intraoperatively to decide if further surgery is warranted or to help the owner decide if intraoperative euthanasia is appropriate in advanced cases.(3) Newer techniques are available for resection of intrapleural disease, specifically lung masses. Endoscopic suture devices (endoloop) are available to allow guillotine-type suture placement for biopsy or removal of small lung (serosal or subserosal) lesions. Endoscopic stapling devices are available to allow removal of larger lung lesions. This technique involves stapling across the lung lobe (or portion) containing the mass, followed by excision. One excised, the specimen can either be pulled through a limited, intercostal incision or can be pulled into a plastic bag, homogenized with a specialized instrument and then extracted through a normal thorascopic portal. These techniques are most applicable for smaller lesions. Larger lesions would be better removed through full thoracotomy incisions to avoid compromise of oncologic margins. Single lung ventilation, with collapse of one hemithorax can greatly assist more advanced thorascopic procedures such as lung lobectomy. Another application of thoracoscpy is evaluation and treatment of pericardial effusion. The creation of a pericardial window as well as performing a modified subtotal pericardectomy using thorascopic techniques has been described. Pericardial windows can be performed either from a lateral or ventral (dog in dorsal recumbency) approach. Subtotal pericardectomy is best performed from with the dog in lateral recumbency. Visualization of the heart base (outside of the pericardium) as well as thorough exploration within the pericardial sac is limited from portals arranged with an animal in dorsal recumbency. Better visualization is afforded from a lateral approach with the obvious limitation of only being able to fully visualize one side. A thorough evaluation preoperatively with echocardiography is important to help guide and focus the thorascopic procedure. Biopsy of suspected lesions and of the pericardium itself can be performed as well as obtaining pericardial fluid following aspiration with the suction instrument. An excellent application of thoracoscopy is evaluation of cases with pleural effusion. If non-surgical diagnostic efforts are unsuccessful in defining the cause of the effusion, thoracoscopy is a logical follow-up step. Idiopathic effusion, pleuritis, and neoplastic disease such as mesothelioma or carcinomatosis cannot be definitively treated with surgery. Therefore, obtaining a diagnosis is the primary reason for entering the thorax and this can be achieved with considerably less morbidity with thoracoscopy than with open thoracotomy. A thorough exploration of the thorax is performed, with biopsy of suspected lesions and collection of fluid for examination. More complete evacuation of the chest can be performed with thoracoscopy than with external methods of thoracic drainage. This will potentially facilitate follow-up treatment, as well as prolong the interval between subsequent drainage. If neoplasia is suspected, biopsy of even subtle lesions on the pleural surface is warranted, as these may well yield the diagnosis. Both mesothelioma and carcinomatosis (from unknown primary) will often 'seed' the pleural surfaces with small plaque-like lesions. If intra-pleural follow-up chemotherapy is contemplated, standard placement of a thoracotomy tube with tunneling beneath the subcutaneous tissues is necessary. This is in contrast to placement of the tube through the thoracoscopy portals. As well, the portals need to be sutured tightly closed. With these steps, leakage of chemotherapeutics into the subcutaneous tissues or out of the thorax will be minimal following instillation through the chest tube. References
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