A Case Study of Leiomyosarcoma
A Case Study of Leiomyosarcoma
'Somethin' Growin' in My Stomach'
By Tony V. Bevill, MPA, PA-C
Thirteen years since the last time she stepped into a clinic of any kind, Shirley had been doing pretty well for herself and thought she was fairly healthy--except for that lump in her belly. She didn't feel bad. But now the size of her abdomen was too big to continue to ignore, and her family and friends were beginning to voice a great deal of concern. She could no longer pretend she was just "gettin' fat" or that the oddly distinct, mask-like features of her face were just "age lines."
As I entered the examining room I encountered a strikingly tall, middle-aged woman who looked quite a bit older than
her 52 years. I would have guessed she was every inch six feet tall; the weight on the chart was 254 pounds. We introduced ourselves and the first thing out of her mouth was, "Doc, I think I've got something growin' in my stomach."
The obstetric and gynecologic history was unremarkable at G4P5A0 (all vaginal), and she related more than 10 years of alternating menometorrhagia and painful dysmenorrhea. There was no history of tobacco or alcohol use, she denied illicit drug use and she had been unemployed for about five years. Prior to that, she had worked odd jobs most of her life and was essentially unskilled; history of exposure to chemicals, caustic agents or hazardous wastes was negative. There was no history of nausea, hematochezia, hematemesis, melena, chest pain or dizziness, although she did note that she couldn't seem to catch her breath as easily as she once could and that her back hurt lately.
The swelling in her abdomen had first been noticed by a grandchild about four years earlier as a small "knot" in her lower abdomen near her bikini line. That area grew very slowly for the first couple of years but was now beginning to get a lot bigger, almost as if daily. Here was a lady that took pride in fitting comfortably in a size 10 three years ago; now she was having trouble just getting into a XXX-large with elastic waistbands. She could feel several "bumpy" areas all over her abdomen and one large one right in the middle near her belly button.
When I asked Shirley why she'd waited so long to see a doctor or come into the clinic, her eyes began to tear, and she said that she'd had no money and no ride.
Shirley's vital signs were as stable as one might expect for a middle-aged, moderately obese, African-American woman who had not seen a doctor for 17 years. Her blood pressure was 190/108 mm Hg, pulse mildly elevated at 92 beats per minute and her respirations were counted at better than 26 to 30 per minute and slightly labored.
The HEENT exam was unremarkable, and there was no indication of Horner's syndrome (unilateral ptosis, trismus, subclavian adenopathy, carotid bruit and ipsilateral facial palsy). I did note some filling of the subclavian spaces but no frank adenopathy. Chest sounds were very distant and diaphragmatic excursion nearly nonexistent; lateral costochondral retractions were noted. Heart sounds were also distant with normal S1 and S2, and no murmurs, gallops or rubs were auscultated. The breast examination was unremarkable, and there were no lumps, bumps or masses into the axillae.
The genitourinary examination was remarkable for moderate leukorrhea; moderately severe vaginal atrophy; a very large, multiparous uterus with significant adnexal tenderness to even light palpation. The rectal guiaic was negative. Several very large varicose veins were found on both lower extremities and she had +2 bilateral, pitting pedal edema. The pulses in the distal extremities were somewhat decreased from expected, but the color and temperature were both good. Neurologically, she was largely intact but with blunted abdominal reflexes in three out of four quadrants.
Most striking, of course, was the abdominal examination--a very large 15- to 16-week mass (larger than 15 cm); rubbery in consistency; a mid-abdomen nodule, largely centralized between the pubic symphysis and the xyphoid process; numerous smaller nodules throughout the abdomen measuring somewhere between 3 and 5 cm and a very prominent left kidney. These nodules were immobile and nonpulsatile with well-defined borders. There was tenderness everywhere.
My initial impression was, at the very least, a suspected disseminated form of leiomyomatosis (extrauterine fibroids). However, given her pattern of irregularity and general neglect of her health, I was also aware that the differential would have to include everything from uterine cancer to metastasis.
We did a basic set of screening labs including a CA-125, liver function tests and an erythrocyte sedimentation rate. Her white count was 6.7 with a hemoglobin of 13.2; blood urea nitrogen 10; creatinine 0.8. LFTs were well within normal range with an AST (SGOT) of 10, ALT (SGPT) of 10, GGT of 43 and a serum alkaline phosphatase of 85 IU/L. Electrolytes were all within normal limits, as well with a random blood sugar of 122 mg/dL. The lactate dehydrogenase was elevated at just over 360 (n = 100 to 250 IU/L), ESR of 58 (n = 0 to 30 mm/hr) and the CA-125 was normal at 21.6 (n = 0 to 35.0 U/mL).
About an hour after sending her to the radiology department, I had a frantic phone call from the staff radiologist who was quite beside himself. The abdominal computed tomography scan revealed a large lobulated, heterogenous mass of various densities with a necrotic center extending from the pelvis to the upper abdomino-diaphragmatic border measuring 25.0 cm by 23.0 cm by 15.5 cm. There were innumerable smaller granular or semisolid masses (some larger than 13 cm in diameter) throughout the abdomen and extending into the lung parenchyma as might be seen or expected with metastasis.
Also noted were multiple retroperitoneal and subperitoneal masses compatible with extensive adenopathy of the pericaval and para-aortic lymph chains. Extensive pericaval adenopathy extended caudally down to the level of the aortic bifurcation and into the pelvis with compression of the inferior vena cava. The liver margins, surprisingly, were clear of involvement.
Adding insult to injury was the chest radiograph, which also showed innumerable rounded masses throughout the chest cavity and parenchyma, the largest about 5 cm and the smallest just under 1 cm diameter--highly suggestive of metastasis.
A suggestion made by the radiologist to perform a CT-guided needle biopsy was rejected in lieu of referral for endometrial biopsy, open resection or both.
At this point, the working differential diagnosis included non-Hodgkin's lymphoma, liposarcoma, lymphangioleiomyomatosis (LAM), disseminated leiomyomatosis and leiomyosarcoma. Of course, we wasted no time in referring Shirley to surgery. Within the next two weeks, pathology revealed large clusters of mixed degenerative or necrotic "spindle cells," and she was diagnosed with disseminated, or stage IVb, leiomyosarcoma. One week later she began receiving chemotherapy. She was scheduled to have surgery six weeks later, and this was to be a teaching case for the medical college's obstetrics and gynecology residents.
Nearly by mistake, I heard about Shirley's death one afternoon while in the process of referring another patient for surgery. Reportedly, she had begun some form of chemotherapy and contracted an infection in her Port-A-Cath. Though she had survived an insidiously invading cancer for years, it was something as simple and avoidable as a dirty wound site that ultimately resulted in her demise. Spiking a temperature of more than 103.5 degrees one Sunday around 3 a.m., she died of septicemia in the emergency room in a rural hospital just 30 minutes from the medical college--almost five weeks to the day since we first met.
Listed as the most common tumors in women, leiomyomas (fibroids) are typically composed of benign masses of smooth muscle cells. The incidence of uterine leiomyoma in women older than 30 years is approximately 20%.1
Leiomyomas may either be asymptomatic or associated with abnormal uterine bleeding, pain, urinary bladder disorders or a combination of the three. Malignant transformation of simple leiomyomas is extremely rare.2
Leiomyosarcomas, conversely, are uncommon. Most develop in skin and deep soft tissue. These tumors are usually quite large, soft, gray masses pathologically described as "spindle cells" with "cigar-shaped" nuclei. Although superficial lesions frequently can be excised fairly successfully, deep-tissue tumors are ostensibly invasive and rarely excisable.3
Benign metastasizing leiomyoma (BML) is a more rare form of this disorder occurring in younger women (20 to 40 years old) but is more common in African-American women. Although this form of rapidly spreading leiomyoma usually holds true to its descriptive name by displaying largely benign characteristics, the occurrence rate of mutated cells or malignancy is about 0.5%.
Intravenous leiomyomatosis (IVL), another form of leiomyoma, is characterized by nodular masses of smooth muscle growing into uterine and other pelvic veins. Extension to the vena cava and pericaval areas can obstruct venous return to the heart, resulting in complaints of dizziness, palpitations, near-syncope episodes and orthostatic hypotension.1,4
Leiomyomatosis peritonealis disseminata is a rare condition characterized by multiple smooth muscle or muscle-like nodules in a subperitoneal location throughout the abdominal cavity. It occurs in women late in the reproductive years, and more than 50% occur in pregnant women or others who are taking oral contraceptives. Nodules range from a few millimeters to several centimeters in diameter. Although described as a benign condition that usually regresses after pregnancy or on discontinuation of estrogen therapy, malignant change has been reported.5
Lymphangioleiomyomatosis (LAM) is a rare lung condition characterized by an unusual type of muscle cell invading tissue of the lungs, including the parenchyma, airways and blood and lymph vessels. Progressively, these muscle cells form bundles, become invasive and result in obstruction of bronchi and pulmonary arteries and veins, eventually spreading into the right atrium.6
Descriptive terms, such as "sharply circumcised," "discrete," "round" and "firm" have all been used to differentiate these gray-white nodules occurring either within the myometrium (intramural), beneath the serosa (subserosal) or immediately beneath the endometrium (submucosal). They may also undergo cystic degeneration, calcification and necrosis. They are monoclonal proliferations of connective tissue and smooth muscle cells. When subserosal leiomyomas become detached from their uterine surface, they may be transferred via visceral fluids or the circulatory system to other tissues and organs within the abdominal cavity. These migratory tumor cells are referred to as parasitic leiomyomas.4,7
About 80% of uterine leiomyomas are multicellular with hemorrhagic, degenerative or ulcerative changes most common. Whether leiomyomas degenerate into leiomyosarcomas (LMS) spontaneously or insidiously is controversial. Current studies, however, suggest a malignant degeneration process is most likely, and most diagnosticians favor this hypothesis. Degeneration in this manner typically occurs in only about 0.5% of leiomyomas, and LMS occurs in only approximately 1.3% of all uterine malignant neoplasms.8
Histologically, differentiation is made possible by mitotic count. Lesions with more than 10 mitosis per 10 high-power field (HPF) are classified as leiomyosarcomas, and those with fewer than 5 to 10 mitosis per 10 HPF and no atypia are considered to be benign in some texts. However, the last group may also show substantial pleomorphism and often behave aggressively, resulting in gross metastasis or disseminated leiomyomatosis.7
Whereas the diagnosis of leiomyoma is made primarily by physical examination, the diagnosis of LMS is based almost entirely on the microscopic appearance. LMS appears microscopically as whitish gray or pale pink smooth muscle cells with a spindle-like appearance--"spindle cells." These lesions are often further described as cystic or including markedly necrotic areas. 8
Imaging techniques such as pelvic ultrasonography, magnetic resonance imaging or CT may be useful if physical examination fails to provide a clear diagnosis. Of these, only the pelvic sonogram is both highly effective and comparatively inexpensive.1,4
Evaluation of the leiomyoma should attempt to accurately determine the number, location and size of each tumor. The total leiomyoma size is usually estimated to the equivalent gestational size, i.e., 13 to 15 cm equals 13 weeks, etc.1,8
Other important preliminary studies include hematocrit or hemoglobin, coagulation studies (prothrombin time, activated partial thromboplastin time, platelets, fibrinogen) and endometrial biopsy in those patients susceptible to endometrial hyperplasia.1
As defined by at least one reference, treatment proposals for uterine leiomyosarcoma reflect an aura of frustration and often futility.
Total abdominal hysterectomy with bilateral salpingo-oophorectomy has been considered the gold-standard therapy, although this approach is frequently unsuccessful. Oncologists are in debate and no general consensus exists that extension to include regional pelvic lymphadenectomy has any higher prognostic value or success rate.4
Pharmaceutical treatment of choice is doxorubicin or doxorubicin plus dacarbazine. Adjuvant chemotherapy after surgical excision may be successful in leiomyosarcomas arising from sites outside the uterus. However, response rates to doxorubicin alone have only been about 18% in more than 200 cases of advanced and recurrent sarcomas and 25% with the combination regimen. Toxicity rates are much higher in combination therapies.
In those patients, such as Shirley, with stage IIIB or higher leiomyosarcomas, the prognosis is expectantly poor. Assisted comfort, pain management (occasionally requiring long-acting narcotics or opioids) and palliative care measures are highly recommended and may aid the family as much as the patient during this time.1,2
Leiomyosarcoma is a rapidly progressive disease of mutated, smooth muscle cells gone wild. In the middle-aged woman presenting with an unusual abdominal mass, particularly those of African-American descent and those with a history of previous leiomyomas or oral contraceptive therapy, leiomyosarcoma must not be discarded in the differential diagnosis. However, needle biopsy of any sarcoma with an unclear or indecisive diagnosis is specifically contraindicated because of the obvious risk of multilayer proliferation at the time of needle withdrawal.
As with any abdominal mass, close attention must be given to acquiring an accurate history and performing a thorough physical examination. Though several options exist for determining specific information about the origin or composition of a questionable mass, physical examination and history are still the cornerstones of primary care medicine in assessing a patient for potential pathology.
Every primary care provider must stress the need for regular, timely physical examinations to all patients and not just those with known chronic processes. Annual or periodic physical exams, based on nationally recognized life cycle recommendations, should be a matter of routine for PAs. Regular patient education in cancer prevention, digital rectal examination for fecal occult blood (in men and women alike), baseline and periodic mammograms and Pap smears and testicular exams are vital first-line mechanisms for early detection of treatable neoplasms.
Patients have to be encouraged and empowered to take an active part in their health care and report any changes in their health to their provider immediately. Whether indigent or fully covered, no patient should ever be afraid to call his or her provider to report an unusual development in health status for fear of inability to pay or embarrassment. *
Tony V. Bevill is the clinical coordinator at East Georgia Healthcare Center in Swainsboro, Ga. He is a member of the ADVANCE editorial advisory board.
1. Rock J. Obstetrics and gynecology. Uterine leiomyomas. In: Rakel RE, ed. Conn's Current Therapy 1998. Philadelphia, Pa: WB Saunders Co; 1998:1104-1117.
2. Leiomyoma of the uterus (fibroid tumor). In: Tierney LM Jr, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis & Treatment. 38th ed. Norwalk, Conn.: Appleton & Lange; 1999:712-714.
3. Female genital tract and breast. Tumors of smooth muscle: leiomyoma and leiomyosarcoma. In: Cotran RS, Kumar V, Robbins SL, eds. Pathologic Basis of Disease. 5th ed. Philadelphia, Pa: WB Saunders Co; 1995:500-501.
4. The Division of Gynecologic Oncology, University of Washington. Uterine sarcoma [tutorial]. Available at: http://gynoncology.obgyn.washington.edu/tutorials/Uterine%20Sarcomas.html. Accessed March 24, 2000.
5. Royal College of Pathologists of Australasia. Histopathology Case Database Web page. Diagnosis and discussion. Case 2: diagnosis: leiomyomatosis peritonealis disseminata." Available at: http://www.rcpa.edu.au/pathcase/Grace%20Building/1998/february/gbfeb98case2.html Accessed March 24, 2000.
6. The LAM Foundation Web page. What is pulmonary lymphangioleiomyomatosis (LAM)? Available at: http://lam.uc.edu/html/body_disease.html. Accessed March 24, 2000.
7. Female genital tract and breast. Tumors. Leiomyoma. In: Cotran RS, Kumar V, Robbins SL, eds. Pathologic Basis of Disease. 5th ed. Philadelphia, Pa: WB Saunders Co; 1995:417-418.
8. Forney JP, Buschbaum HJ. Classifying, staging, and treating uterine sarcomas. Contemporary Ob/Gyn. 1981;18(3):47-69.
The FIGO (International Federation of Gynecology and Obstetrics) staging system for carcinoma of the corpus uteri, carcinoma of the endometrium and uterine sarcoma also has been applied to leiomyosarcoma.
Stage I: Confined to the corpus uteri. Accounts for 50% of presentation.
IA: Tumor limited to endometrium
IB: Invasion to less than half of the myometrium
IC: Invasion to greater than half of the myometrium
Stage II: Cancer has involved the corpus uteri and cervix but has not extended outside the uterus.
IIA: Endocervical glandular involvement only
IIB: Cervical stromal invasion
Stage III: Extension outside the uterus but confined to the true pelvis.
IIIA: Tumor invades serosa and/or adnexa and/or positive peritoneal cytology
IIIB: Metastasis to pelvic and/or para-aortic lymph nodes
Stage IV: Involvement of the urinary bladder or bowel mucosa or metastasis to distant sites.
IVA: Tumor invasion of bladder and/or bowel mucosa
IVB: Distant metastasis, including intra-abdominal and/or inguinal lymph nodes(integral)
Smoke Added, Saccharin Dumped
from Government Carcinogen List
The National Institute for Environmental Health Sciences (NIEHS) has added 14 substances to its list of known carcinogens.
NIEHS, which issues a report twice a year, included tobacco smoke and alcohol on the list as known carcinogens while removing saccharin from the list of suspected carcinogens.
The report listed 218 substances known to cause or suspected to cause cancer in people. Fourteen substances have been upgraded to the known category or added to the list.
Secondhand smoke was one substance upgraded to a known cancer cause. The NIEHS report cited studies showing that secondhand smoke can cause lung cancer, and cited other studies showing that nonsmoking wives and co-workers of smokers have higher rates of lung cancer than people not exposed to as much secondhand smoke.
Tobacco smoke, as a whole, was also listed as a known cause. Separate chemicals contained in tobacco smoke had been listed previously.
Alcohol was cited for its association with cancers of the mouth, pharynx, larynx and esophagus. It may also be associated with liver and breast cancer. Chewing tobacco and snuff were cited for their association with cancers of the mouth and nose.
The using tanning beds or sunlamps, along with "too much sun," also were included on the list.
Other substances on the list of known carcinogens for the first time were:
* Crystalline silica dust small enough to breath, which is a byproduct of mining.
* Dyes metabolized to benzidine.
* Strong inorganic mists containing sulfuric acid, which are produced in the manufacture of alcohol, lead batteries, phosphate fertilizers, soap and detergents, synthetic ethanol and in other acid treatments of metals.
* 1,3-Butadiene, which is used in the making of synthetic rubber.
* Cadmium, which is used in batteries, coating and plating, plastic and synthetic products and alloy.
* Ethylene oxide, which is used to sterilize medical devices.
* The breast cancer drug tamoxifen, which can increase the risk of endometrial or uterine cancer.