|Second Steps: Making Decisions
written and compiled by doctordee
|Search LMS site|
|Adjuvant Treatment For Leiomyosarcoma?|
The following article is based upon the personal research of the author, a lay person. It should be used only as a general guidance in interacting with your doctors, and should not be considered a substitute for expert medical opinion.
This article defines adjuvant [or adjunctive] treatment as the administration of chemotherapy or radiation following surgical removal of the primary tumor with wide margins, when no secondaries are known to exist. Although there is some evidence that adjuvant treatment is useful for some soft tissue sarcomas, there is no hard evidence that it either prevents recurrence or prolongs survival for Leiomyosarcoma patients.
This section is meant to assist those who are faced with the question of whether to undergo adjuvant treatment after surgery.
There is Time To Decide: No matter what pre-surgical opinions one may have, there is no need to make a decision about adjuvant treatment before surgery. There will also be enough time after surgery to discuss the pros and cons. Even if the decision were to proceed with further treatment, most surgeons and oncologists would agree upon a significant recovery period (at least one month) following surgery before starting adjuvant treatment.
How to Make the Decision: After surgery ask for a copy of the operative report prepared by the surgeon (all surgeons prepare such a report). Read it carefully to determine whether the surgeon felt he/she had achieved clear margins and how large those margins were.
After reading the report, discuss it with your surgeon on your first postoperative visit. Make sure you understand what occurred with regard to margins. You may also want to ask the surgeon how successful he/she thought the surgery was with regard to eliminating the Leiomyosarcoma tumor(s). You may also want to explore whether there was any spillage while excising the tumor(s), although there is some disagreement over whether this factor influences future recurrences.
You should also ask for copies of any pathology reports. Do they offer any information about the virulence of your tumor(s)? Did they test your tumors for c-kit? If they did not test your tumors for c-kit, ask them to do so (although it is unlikely that Leiomyosarcoma originating outside of the abdominal cavity would be c-kit positive, ask for the test to be done anyway just in case--the results are critical to future decision making).
The next person you should see after your surgeon is a sarcoma specialist, at least for a consult. You should bring your operative and pathology reports with you.
Should you be c-kit positive, you may be eligible for treatment with a new drug called STI-571. People who are c-kit positive should be particularly cautious about adjuvant therapies, as there may be a much better alternative.
Let's turn to the pros and cons of adjuvant treatment:
What are the alternatives to adjuvant treatment? The main alternative is to monitor any recurrence on a frequent (every three months) and thorough (a minimum of a spiral CT Scan of the chest, abdomen and pelvis, with and without contrast) basis. Given that there is a likelihood of recurrence following surgery, early detection to permit prompt intervention is essential.
Norman, a former official of the Centers for Disease Control and a former New York City Assistant Commissioner of Health is a lay person married to a Leiomyosarcoma patient. Although he has done extensive research into the subject of this article he is not a physician and presents this material only as a guide for your own research and to assist you in discussing this issue with your own physicians. - April 2001
Questions and Answers About Metastatic Cancer
from CancerNet, NCI, NIH
"New cancer treatments are currently under study. To develop new treatments, the National Cancer Institute (NCI) sponsors clinical trials (research studies) with cancer patients in many hospitals, universities, medical schools, and cancer centers around the country. Clinical trials are a critical step in the improvement of treatment. Before any new treatment can be recommended for general use, doctors conduct studies to find out whether the treatment is both safe for patients and effective against the disease.
The results of such studies have led to progress not only in the treatment of cancer, but in the detection, diagnosis, and prevention of the disease as well. Patients interested in participating in research should ask their doctor to find out whether they are eligible for a clinical trial."
Information Above from National Cancer Institute Information Resources April 2001
|LMS, Metastases, and Treatment Decisions|
The best chance for a cure is an isolated LMS tumor that was surgically excised with wide, clear margins, while it was small. Even some of these patients have recurrences or metastases, though the 'still clear' rate may be as high as 80 or 90% at 5 years.
A larger, high grade tumor is much more likely to recur or metastasize. The rate of recurrence or metastasis may be as high as 80% or more for these tumors.
With a local recurrence, if you can have it surgically excised with wide, clear margins, you may again have a chance for cure. The oncologists often use radiation in the area as well, adjuvantly, in this situation. If you have a c-kit positive GIST , and if you respond to STI-571...it is possible that you might instead choose this option.
Recurrent Local Recurrence
is again treated surgically if possible, and/or radiation or chemotherapy as the oncologist and the patient decide.
With a metastasis, if you can have it surgically excised with wide, clear margins, you may again have a chance for a cure. However, you are likely to get more metastases. If you are c-kit positive, if you respond to STI-571...it is possible that you might instead choose this option.
Once the metastases present are either inoperable, or too numerous to operate upon, you will probably choose chemotherapy.
Doxorubicin, the chemotoxic agent that is most successful against LMS so far, is not that successful. About 30% of the patients will experience a partial success rate. A very, very few may go into what looks like complete remission. The rest will not respond to Doxorubicin. And the response does not last that long [months]. Doxorubicin is also very toxic to heart, bone marrow, and liver. Its cardiotoxicity is so powerful, that there is a lifetime dosage of doxorubicin that must not be exceeded.
Presently, in the literature, chemotherapy regimens containing Doxorubicin are the chemotherapeutic choices with the highest response rates. There are, however, other choices of agents, and many clinical trials of other treatments going on.
Why Clinical Trials?
When there are no GOOD treatments for a condition, there are often MANY treatments offered. There are other chemotherapy agents, and other treatment options...THAT is why the clinical trials sections of all the sites are so important for people with LMS.
BECAUSE you cannot depend solely upon your doctor, even if the doctor is a sarcoma oncologist. You must find out about these possibilities yourself.
BECAUSE, essentially, you are choosing to continue living, taking chemo trials as appropriate, until either you are very lucky and go into complete remission, or the tumors grow despite all chemo- or other therapy, or your bone marrow succumbs to myelodysplasia [effect of recurrent chemo and/or radiation on bone marrow].
BECAUSE the era of designer drugs is upon us. Those LMS patients who have GIST, have a drug which is a specific poison for their tumor. There are enzyme systems in LMS that are vulnerable to development of other, similar designer drugs. The idea is to stay alive until the drug is developed to which the majority of LMS tumors will respond.
Information from PDQ for Patients 208/03900
What is a clinical trial?
In cancer research, a clinical trial is an organized study conducted in people with cancer to answer specific questions about a new treatment or a new way of using a known treatment. Each study tries to increase medical knowledge and to find new and better ways to help cancer patients. Besides studying new anticancer drugs, clinical trials study new combinations of drugs already used in cancer treatment, new ways of giving treatment, and how changes in lifestyle can help cancer patients or prevent cancer from occurring. Other clinical trials compare the best known standard therapy with a newer therapy to see if one produces more cures and causes fewer side effects than the other.
Why are clinical trials important?
Before a new treatment is tested in patients, it is carefully studied in the laboratory. First, a drug is considered because it changes cells or parts of cells in a way that suggests it will destroy cancer or help the body to deal with the side effects of cancer treatment. Then, the new treatment is tested in animals to learn what it does in the body. But this early research cannot predict exactly how a new treatment will work in people or define all the side effects that might occur. Clinical trials are designed to help us find out how to give a new treatment safely and effectively to people. Each patient who participates in a clinical trial provides information on the effectiveness and risks of the new treatment. Advances in medicine and science are the result of new ideas and approaches developed through research. New cancer treatments must prove to be safe and effective in scientific studies with a certain number of patients before they can be made available to all patients.
Treatments now being used (standard treatments) are the base for building new, hopefully better, treatments. Many standard treatments were first shown to be effective in clinical trials. Clinical trials show researchers which therapies are more effective than others. This is the best way to identify an effective new treatment. New therapies are designed to take advantage of what has worked in the past and to improve on this base.
You may be interested in participating in a trial. You should learn as much as you can about the trial before you make up your mind.
** TYPES OF TRIALS **
What kinds of clinical trials are there?
There are many kinds of clinical trials. They range from studies of ways to prevent, detect, diagnose, control, and treat cancer to studies of the psychological impact of the disease and ways to improve the patient's comfort and quality of life (including pain control).
Cancer clinical trials deal with new approaches to the treatment of cancer. These treatments most often use surgery (cutting out the cancer), radiation therapy (using x-rays, neutrons, or other invisible beams to kill cancer cells), and/or chemotherapy (using cancer-killing drugs) alone or in combination. Surgery, radiation, and chemotherapy have cured many cancer patients and prolonged the lives of many others. A new area of cancer treatment is biological therapy that use substances that help the body to fight cancer.
Most clinical trials are carried out in steps called phases. Each phase is designed to find different information. Patients may be eligible for studies in different phases, depending on their general condition, the type and stage of their cancer, and what therapy, if any, they have already had. Patients are seen regularly to determine the effect of the treatment, and treatment is always stopped if side effects become too severe.
How can you find out about clinical trials?
The National Cancer Institute (NCI) has created a computer file about cancer and clinical trials called Physicians Data Query (PDQ). The information in PDQ is updated monthly and can give you or your doctor the latest information on clinical trials being offered around the country, as well as the names of doctors running the trials and the names of the hospitals treating patients on the trials. Patients can obtain PDQ information from their physicians or by contacting the Cancer Information Service (CIS). The CIS answers cancer-related questions from the public, cancer patients and their families, and health professionals. If you have questions, call the toll-free number 1-800-4-CANCER and you will be connected to the CIS office serving your area.
PDQ contains summaries of over 1,500 cancer clinical trials that are available to patients. Treatment studies are grouped by the site of disease (for example, lung, kidney, breast, or bone), by the type of treatment (surgery, radiotherapy, chemotherapy, biological therapy), by the study phase (I, II, III, adjuvant, neoadjuvant, Group C, or Treatment Referral Center), by the drug used in the study, and by the city where the study is done.
Supportive care studies are grouped by the cancer-related problem (for example, pain, anemia, infection), while prevention/early detection studies are grouped by the type of cancer like the treatment studies.
** TREATMENT OPTIONS **
What is best for you? Finding answers and making decisions are often hard for a cancer patient. The diagnosis of cancer followed by decisions about therapy can be confusing, and you may be frightened and upset. It is important to discuss your possible choices with medical experts, including your own doctor, and with those close to you. Your personal doctor and cancer specialists can advise you about your choices for standard treatment or clinical trials.
PDQ provides detailed information for patients and physicians about the recent, best, standard treatment for most types of cancer. When there is no standard therapy that works, PDQ advises that physicians and patients consider clinical trials.
What is informed consent? Anyone entering a clinical trial in the United States is required to sign a form indicating that they understand what will happen to them during the study. If the patient is a child, a parent or guardian must sign the form. This form will tell you what treatment will be given, what kind of problems might occur, and what other treatments might work for your condition. The amount of help expected from the study will be given. In phase I studies, it is usually not known whether any help will occur. The informed consent form also indicates which costs are covered by the study and which must be paid by you (or your insurance).
After you have signed the consent form, a copy of it is given to you. Included on the form is the name and telephone number of someone to call if you have questions. Informed consent also tells you that you have the right to leave the study at any time. You cannot be refused other treatment that may help you if you decide not to become part of the study. Before you sign the informed consent form, you need to ask the doctor questions about the study.
What are important questions to ask about a clinical trial? If you are thinking about taking part in a clinical trial, here are some important questions to ask:
Myelodysplasia, also known as Myelodysplastic [pronounced MY-eh-low dis-PLAH-stic] Syndromes, are conditions that affect the bone marrow.
The bone marrow makes blood cells. Red blood cells that carry oxygen. White blood cells that fight infection. Platelets that make clots and prevent bleeding.
The stem cells in the bone marrow are the "parent cells" of the cells [red, white & platelet] which are eventually released into the blood. The myelodysplastic syndromes are caused by damage to the stem cells of the cell line[s] affected. The damage is to the DNA of the stem cells.
Patients treated for cancers with high dose radiation have a higher incidence of therapy-related Myelodysplasia . Alkylating agents used in chemotherapy are known to induce Myelodysplasia, as well. There are other causes, too, but these are two causes that are important to LMS patients.
If the red blood cell line is affected, the patient becomes anemic, and requires transfusions. Eventually there is an iron buildup in the body, called hemachromatosis, which can cause further problems.
If the white blood cell line is affected, the patient is more prone to get seriously ill with infections. Sometimes some of the white cell line transforms to leukemia.
If the platelet cell line is affected, the patient is prone to hemorrhage, and internal bleeding.
The progress of the condition depends upon which cell lines are affected and how badly, and whether leukemia develops.
Development of Myelodysplasia puts a limit on how much radiation and chemotherapy a person can have. A patient might be cured of his or her cancer, but then succumb to myelodysplasia or leukemia as a result of the treatment for the cancer.
Above from p. 676-8 Harrison's Principles of Internal Medicine, 14th Edition. written by doctordee
|Special Uterine Leiomyosarcoma Section|
Because there are special issues for women with uterine leiomyosarcoma, we have included some extra information.
The question of adjuvant treatment for uterine LMS after surgical excision with clear margins seems to occur often, so we have included the abstracts of medical journal articles dealing with the results of studies of this question.
Hormone replacement therapy (HRT) may be dangerous for women with uterine leiomyosarcoma, even if their tumor is read as estrogen and progestogen receptor negative. The nature of the test for the receptors involves a skilled eye, and a cut-off point, which might be 10% or 20%.... It is best to proceed exceedingly carefully here.
But there is also the possibility of anti-hormone treatment for the uterine leiomyosarcoma.
Three of the women with Uterine LMS on the ACOR LMS list have a mother or sister who also has Uterine LMS. This has raised the question of inherited disorders. There are two medical journal articles included on this point.
The following abstracts of articles were compiled from Pubmed medical journal searches.[Parts of the abstracts have been emphasized by the compiler by placing them in bold type.
Compiler's comments will appear in brackets [such as this].]
Uterine Leiomyosarcoma: Whether or Not to have Adjuvant Treatment
Abstracts of Medical Journal Reference Articles
The following abstracts of articles were compiled from Pubmed medical journal searches. As you can see, the number of people with leiomyosarcoma (LMS) in each study is usually not large. Being abstracts, a lot of details are left out of the descriptions. However, in many of these studies neither adjuvant radiation nor adjuvant chemotherapy was effective in prolonging survival or the time interval before recurrence of LMS.
[Parts of the abstracts have been emphasized by the compiler by placing them in bold type. Compiler's comments will appear in brackets [such as this].]
These abstracts can be printed and taken to your doctor and discussed
Aust N Z J Obstet Gynaecol 1999 May;39(2):246-8
Uterine leiomyosarcoma--a Singapore experience.
Soh LT, Chew SH, Ang L Kandang Kerbau Hospital, Singapore.
Uterine leiomyosarcoma is an aggressive tumour. In our retrospective series of 27 patients, there were 25 with nonmyxoid high-grade leiomyosarcoma of the uterus. The stage distribution was Stage 1, 16; Stage 3, 5 and Stage 4, 4. In the patients with Stage 1 disease, 3 of the 8 patients who received adjuvant chemotherapy subsequently developed recurrent disease. In contrast, 6 of the 8 patients who did not receive adjuvant chemotherapy subsequently developed recurrent disease;
2 of the patients in the latter group also received adjuvant radiotherapy. Six of the 9 women with recurrences were distant 'failures' alone, 2 were both distant and pelvic 'failures' and 1 was pelvic 'failure' alone. All the patients with advanced-stage disease eventually succumbed to the disease despite the therapies given. This study is small and retrospective but it suggests that there might be a role for adjuvant chemotherapy in the management of the early stage of this disease.
Fetch PMID: 10755790
Aust N Z J Obstet Gynaecol 1999 Feb;39(1):93-8
Management of uterine leiomyosarcoma in Australia.
Gard GB, Mulvany NJ, Quinn MA Department of Obstetrics and Gynaecology, University of Melbourne.
Uterine leiomyosarcoma is an uncommon malignancy for which the management varies widely between individual gynaecologists and gynaecological oncology units. We have performed a retrospective review of patients treated at both the RoyalWomen's Hospital in Melbourne (1970-1997) and King George V Hospital in Sydney (1987-1993). In addition we have performed a survey of Certified Gynaecological Oncologists (CGO's) to assess the current management of uterine leiomyosarcomas in Australia. The results show varied management practices exist in Australia, many of which are not supported by evidence in the current literature.
Oophorectomy in the premenopausal patient appears unnecessary unless the ovaries are macroscopically involved. The role of pelvic lymphadenectomy is debatable. This practice was recommended by many CGO's, yet these nodes are rarely positive unless obvious extrauterine disease is present. Adjuvant chemotherapy appears not to have a role at present unless in a trial setting. Adjuvant radiotherapy does appear to have a potential palliative role as it prevents locoregional relapse, although survival is not prolonged. Until suitable phase 3 trials are available, gynaecological oncology units should be meticulous in prospectively recording the clinical course of their patients and critically analyzing their current management strategies. Publication Types: Review
Fetch PMID: 10099759
Am Surg 1998 Jan;64(1):53-60; discussion 60-1
Leiomyosarcoma: a 45-year review at Charity Hospital, New Orleans.
Hill MA, Mera R, Levine EA Section of Surgical Oncology, Louisiana State Univ Medical Center,New Orleans 70112,US
Approximately 2 to 9% of all soft tissue sarcomas are leiomyosarcomas (LMS). LMS arises nearly exclusively as tumors in adults, with peak incidence occurring in the fifth and sixth decades. The purpose of this study was to analyze disease-specific survival and define prognostic factors in patients with this disease who were treated and followed at a single institution. Fifty-eight cases of LMS were identified in the Tumor Registry of the Medical Center of Louisiana at New Orleans (charity Hospital) from 1950 to 1995. Charts were reviewed and tissue blocks reexamined to confirm the diagnosis. Follow-up information was available for 56 of 58 (96%) patients. Univariate and multivariate analyses wereperformed to analyze which factors predict outcome. The median survival time was 138 months. Univariate analysis identified age (> 48 years), location (retroperitoneal vs other sites), and extent of disease as prognostic factors.Multivariate analysis revealed that only age and the extent of disease at presentation are independent prognostic indicators. Race, sex, and adjuvant therapy were not significant prognostic factors. Surgical resection remains thetherapeutic mainstay for patients with LMS. The value of other treatment modalities is largely limited to surgical failures. The data show that the age of the patient and the extent of disease at presentation are the best predictorsof long-term survival. LMS has a good prognosis when complete resection of localized lesions can be achieved.
Fetch PMID: 9457038
J Gynecol Obstet Biol Reprod (Paris) 1997;26(3):256-62
[Uterine leiomyosarcoma. Nine case reports, review of the literature].[Article in French]
Razafintsalama T, Leveque J, Le Gall F, Paumier V, Pangui E, Kerisit J, Grall JY
Service de Gynecologie B, Hopital Sud, Rennes.
OBJECT OF THE STUDY: To evaluate management and outcome of the treatment of uterine leiomyosarcoma. PATIENTS AND METHODS: Retrospective study of a series of 9 patients treated for uterine leiomyosarcoma in this hospital from 1982 to 1994. RESULTS: The condition is rarely suspected preoperatively, diagnosis is usually made on histological examination of the operative specimen. The outcome is related to the mitotic activity of the tumour and to the infiltration of nearly structures. Surgery is the only effective treatment, chemotherapy is ineffective, adjuvant radiotherapy improves local control of the tumour but has no incidence on survival. CONCLUSION: In the absence of an effective adjuvant treatment uterine leiomyosarcoma bears a poor prognosis with the only exception of small non infiltrating tumours with a low mitotic activity.
Fetch PMID: 9265046
Eur J Gynaecol Oncol 1997;18(3):192-5
Uterine sarcoma: a clinicopathological study of 93 cases.
Gonzalez-Bosquet E, Martinez-Palones JM, Gonzalez-Bosquet J, Garcia Jimenez A, Xercavins J
Department of Gynecologic Surgery/Gynecologic Oncology, Hospital Universitario Materno-Infantil Vall d'Hebron, Barcelona, Spain.
OBJECTIVE: To evaluate the clinical outcome of patients suffering from primary uterine sarcoma diagnosed and treated in our Hospital. SETTING: Department of Gynecologic Surgery/Gynecologic Oncology, Hospital Universitario Materno-Infantil Vall d'Hebron de Barcelona, Barcelona, Spain. SUBJECTS AND METHODS: A retrospective review from 1967 to 1995 of clinical and pathological characteristics of 93 patients with primary uterine sarcoma was done. Patients were staged using the 1988 FIGO histological classification for uterine cancer. Clinical features, type of surgery, adjuvant therapy, recurrences, distant metastasis, and survival were recorded. RESULTS: Our study included three main histologic types: 44 patients with leiomyosarcoma, 26 patients with endometrial stromal sarcoma, and 18 patients with mixed Mullerian sarcomas. The mean age for all patients was 54.8 years, and the most common symptom was vaginal bleeding. Other clinicopathological features were examined. Although surgery was the most frequent treatment, adjuvant therapies have been analyzed and discussed. The overall three-year survival rate was 67.9% and the overall five-year survival rate was 64.5%. We found statistical differences (p < 0.001) between the stage I survival rate and other stage survival rates. CONCLUSIONS: Uterine sarcoma is an uncommon neoplasia diagnosed in the 6th decade of life. Leiomyosarcoma is the most frequent histologic type (47.3%). Stage I uterine sarcoma has a better prognosis than other stages.
Fetch PMID: 9174834
J Surg Oncol 1997 Jan;64(1):55-62
Uterine sarcoma in the south of Israel: study of 36 cases.
Piura B, Rabinovich A, Yanai-Inbar I, Cohen Y, Glezerman M
Department of Obstetrics and Gynecology, Soroka Medical Center, Beer-Sheva, Israel.
BACKGROUND: Uterine sarcomas are rare, characterised by rapid clinical progression and poor prognosis, and their management has been a challenge. The purpose of this study was to investigate the clinical and histologic findings, treatment, and outcome of patients with uterine sarcoma in the south of Israel. METHODS: Data from the files of 36 patients with uterine sarcoma who were managed at the Soroka Medical Center between January 1961 and December 1994 were evaluated. RESULTS: The 5-year survival rate was 32% overall; 63% for 9 patients with endometrial stromal sarcoma (ESS). 30% for 14 patients with mixed mesodermal sarcoma (MMS) and 18% for 13 patients with leiomyosarcoma (LMS): 41% for 22 patients with Stage I and 19% for 14 patients with Stages II, III, and IV. Only the difference in the 5-year survival rate between ESS and LMS was statistically significant (P < 0.05). Eleven patients (30.6%) were treated with surgery alone, 4 (11.1%) with surgery followed by pelvic radiotherapy, 11 (30.6%) with surgery followed by chemotherapy, 8 (22.2%) with surgery followed by pelvic radiotherapy and chemotherapy, one (2.8%) with chemotherapy alone, and one (2.8%) had no treatment. CONCLUSIONS: Uterine sarcomas are aggressive tumorswith a poor prognosis. The treatment is surgery generally followed by adjuvant pelvic radiotherapy and/or systemic chemotherapy.
Fetch PMID: 9040802
Bull Cancer 1997 Jun;84(6):625-9
[Uterine sarcoma treated by surgery and postoperative radiation therapy. Patterns of relapse, prognostic factors and role of radiation therapy]. [Article in French]
Coquard R, Romestaing P, Ardiet JM, Mornex F, Sentenac I, Gerard JP Service de radiotherapie-oncologie, Centre Hospitalier Lyon Sud, Pierre-Benite, France.
The objective was to evaluate the results of a combination of surgery and postoperative radiotherapy in patients with uterine sarcoma, to describe the patterns of relapse and to define prognostic factors. From 1980 to 1993, 29 patients (median age: 56 years) presenting with uterine sarcoma have been treated with surgery and postoperative irradiation. The histology was: leiomyosarcoma: 11; carcinosarcoma: 12; stromal sarcoma: 6. The distribution by stage was: pT1: 18; pT2: 5; pT3: 3; pT4: 3; pNO: 27; pN1: 2. Gross residual disease was present in 4 patients. External beam irradiation was performed in all the cases and brachytherapy in 19. Chemotherapy was given in 3 patients. The overall survival rate was 66% at 2 years and 57% at 5 years with a disease free survival of 54% at 2 years and 50% at 5 years. Seven patients relapsed locally and 8 developed metastases. One patient died of ileitis. In a multivariate analysis, the disease free survival was strongly influenced by the menopausal status. The survival in this study is higher than that described in series of patients treated with surgery alone. This study confirms the worse prognosis of uterine sarcoma in postmenopausal women. [Note: there is no mention of grading of tumors, which has a major effect on survival...one needs the entire paper to evaluate.] Publication Types: Review, multicase
Fetch PMID: 9295866
J Surg Oncol 1996 Nov;63(3):145-7
Malignant uterine smooth muscle tumors: role of etoposide, cisplatin, and doxorubicin (EPA) chemotherapy.
Resnik E, Chambers SK, Carcangiu ML, Kohorn EI, Schwartz PE, Chambers IT Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut, USA.
BACKGROUND: Nearly 80% of patients with malignant uterine smooth muscle tumor will suffer local relapse and/or distant metastases after initial surgical resection. There is no convincing evidence that the addition of pelvic radiation improves the outcome. However, adjuvant chemotherapy might be an appropriate therapeutic modality. METHODS: Between 1986 and 1991, 13 consecutive patients with malignant uterine smooth muscle tumors were treated at Yale-New Haven Hospital with a combination chemotherapy containing etoposide 100 mg/M2 on days 1 and 2, cisplatin 50 mg/M2 on day 1, and doxorubicin 50 mg/M2 on day 1, repeated every 28 days. Six patients had Stage I disease, one patient had Stage III disease, and six patients had Stage IV disease. The number of cycles ranged from 2 to 9. RESULTS: The median follow-up was 30 months (range 4-81). The mean overall survival for the group was 43.1 6.7 months, with the progression-free interval of 25.5 8.0 months. Of the seven patients with evaluable disease, one patient had complete response and one had partial response (total response rate of 28.6%). Of the six patients treated adjuvantly, three recurred at 9, 33, and 59 months (recurrence rate of 50%). CONCLUSIONS: Weconclude that this combination has only modest activity against malignant uterine smooth muscle tumors at the schedule and doses tested.
Fetch PMID: 8944057
Eur J Gynaecol Oncol 1993;14 Suppl:105-13
Different types and different prognosis-study of 310 uterine sarcomas.
Nickie-Psikuta M, Gawrychowski K Department of Gynaecological Oncology, Maria Slodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
Three hundred and ten cases of uterine sarcomas, among them, according to pathology: LMS (Leiomyosarcoma)--117, MMS (Mixed mesodermal sarcoma)--62, ESS (Endometrial stromal sarcoma)--56, CS (Carcinosarcoma)--27, RBMS (Rhabdomyosarcoma)--18 and other sarcomas--30, were retrospectively evaluated at the Maria Sklodowska-Curie Memorial Cancer Center between 1950 and 1985. These mesodermal tumors were divided into uterine corpus sarcomas (295) and the rarely occurring uterine cervix sarcomas. As the main modality of treatment 307 patients underwent surgery. Almost all patients received adjuvant radiotherapy but 51 cases of LMS. Overall 5-year survival was 34.5% and in particular subgroups the survivals were as follows: the best, 52% in LMS; lower, 30% in ESS; poor survival about 20% in CS and MMS. In spite of low curability in the majority of subgroups except LMS, the cases of CS with primary site in uterine cervix distinguished itself with better results. No significant survival advantage was found for surgery plus radiotherapy in LMS with low grade mitotic activity, (10 mitoses/10 HPF) compared with surgery alone (63% and 54%). These cases seem to have better prognosis in LMS with high grade mitotic activity (10 mitoses/10 HPF) and do not require adjuvant radiotherapy.
Fetch PMID: 8200360
Cancer 1993 Feb 15;71(4 Suppl):1702-9
Prognostic factors in early-stage uterine sarcoma. A Gynecologic Oncology Group study.
Major FJ, Blessing JA, Silverberg SG, Morrow CP, Creasman WT, Currie JL, Yordan E, Brady MF. University of Colorado School of Medicine, Denver.
BACKGROUND. A clinicopathologic evaluation of clinical Stage I and II uterine sarcoma was done by the Gynecologic Oncology Group from 1979-1988. METHODS. After all eligibility criteria were met, 453 cases were evaluable and analyzed for prognostic factors. RESULTS. Of the 301 mixed mesodermal tumors (MMT), 167 were homologous (HO), and 134 were heterologous (HE). Fifty-nine tumors were leiomyosarcomas (LM). The remaining 93 sarcomas were predominantly stromal cell and adenosarcomas. For this study, only the MMT or LM tumors were analyzed. The recurrence rate for all MMT was 53% (HO, 44%; HE, 63%). The recurrence rate for LM was 71%. The site of the first recurrence included the pelvis in 21% of MMT and 14% in LM. Factors significantly related to progression-free interval (PFI) by univariate analysis among MMT were adnexal spread, lymph node metastases, tumor size, lymphatic-vascular space involvement, histologic grade, cell type, age, peritoneal cytologic findings, and depth of uterine tumor site of invasion. The prognostic factors based on multivariate analysis were adnexal spread, lymph node metastases, histologic cell type (HO versus HE), and grade of sarcoma. For LM, the mitotic index was the only factor significantly related to PFI.
Fetch PMID: 8381710
Eur J Gynaecol Oncol 1990;11(3):225-31
Treatment of patients with sarcoma of the uterus.
Bokhman JV, Yakovleva IA, Urmanchejeva AF. Petrov Research Institute of Oncology, USSR Ministry of Health, Leningard.
In the present series of 156 patients with sarcomas of the uterus the therapeutic modalities employed were evaluated. The 5-year survival rate of 51.3% was obtained for this series including 41.2% for leiomyosarcomas, 57.1% for endometrial stromal sarcomas, 50.0% for mixed mesodermal tumors and 40.0% for carcinosarcomas. The prognostic significance of the extent of disease, histological type and the age of patients is emphasised. Clinical features of uterine sarcomas specific for different histological types were shown: leiomyosarcomas were characterized by a rapid tumor growth while uterine bleeding in the background of neuroendocrine disturbances similar to those observed in endometrial carcinomas were related to endometrial stromal sarcomas and mixed mesodermal tumors. In respect to early diagnosis of sarcomas an ultrasonic pelvic examination and studies of aspirate specimens taken from the uterine cavity are recommended to be performed for the groups at high risk. An individual treatment policy was developed for each sarcoma patient depending on the histological type, the stage of disease and general condition of the patient. Surgical approach varied ranging from a total hysterectomy and adnexectomy, done for leiomyosarcomas, to an extended hysterectomy and pelvic lymphadenectomy for mixed mesodermal tumors and endometrial stromal sarcomas. Postoperative distant and/or endovaginal radiation are indicated for all histological types of sarcomas excepting leiomyosarcomas. Application of adjuvant chemotherapy with carminomycin or adriamycin improves the results of treatment.
Fetch PMID: 2209643
Vopr Onkol 1989;35(10):1245-51
[Treatment of patients with sarcoma of the uterus]. [Article in Russian]
Bokhman IV, Urmancheeva AF.
The choice of treatment for uterine sarcoma should be determined by histological pattern and stage of tumor as well as by the patient's general condition. Operation should be withheld unless it is life-saving. The extent of surgeryshould vary from extirpation of the uterus with the appendages (leiomyosarcoma) to extended extirpation with pelvic lymphadenectomy for mixed mesodermal tumor, carcinosarcoma and endometrial stromal sarcoma. In the three latter cases, surgery should be followed by distant and/or endovaginal irradiation. Administration of such antitumor antibiotics as carminomycin and adriamycin assures a significantly longer survival in cases of recurrent and disseminated uterine sarcoma.
Fetch PMID: 2596071
J Clin Oncol 1985 Sep;3(9):1240-5
A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group Study.
Omura GA, Blessing JA, Major F, Lifshitz S, Ehrlich CE, Mangan C, Beecham J, Park R, Silverberg S
After hysterectomy, 156 evaluable patients with stage I (limited to the corpus) or stage II (limited to the corpus and cervix) uterine sarcomas were randomly assigned to adjuvant chemotherapy with Adriamycin (Adria Laboratories, Columbus, Ohio) for six months or to no further treatment. Pelvic irradiation (external or intracavitary) was optional before randomization. Of 75 patients receiving Adriamycin, 31 have suffered recurrences compared with 43 of 81 receiving no adjuvant chemotherapy. This difference is not statistically significant. Moreover, there is no difference in progression-free interval or survival. The optional radiotherapy did not influence the outcome although there was a suggestion that vaginal recurrence was decreased by pelvic radiotherapy. The recurrence rates in specific cell types (leiomyosarcoma, homologous mixed mesodermal sarcoma, or heterologous mixed mesodermal sarcoma) were not significantly different although the pattern of recurrence differed, with pulmonary metastases being more common in leiomyosarcoma and extrapulmonary recurrence being more common in mixed mesodermal sarcoma. The outcome with respect to chemotherapy was not altered even after adjusting for maldistribution of cases. Thus, we could not show a benefit for this dose schedule of Adriamycin as adjuvant treatment for uterine sarcomas.Publication Types: Clinical trial Randomized controlled trial
Fetch PMID: 3897471
Am J Obstet Gynecol 1985 Apr 15;151(8):1016-22
Uterine sarcoma: analysis of prognostic variables in 71 cases.
Wheelock JB, Krebs HB, Schneider V, Goplerud DR
The histories of 94 patients with a diagnosis of uterine sarcoma, treated from 1962 to 1982, at the Medical College of Virginia Hospital were reviewed. Histologic features were studied by one of the authors (V.S.), and cases that did not meet strict pathologic criteria were rejected. The 71 patients with uterine sarcoma accepted for this study had a survival rate of 22.5% from 1 to 11 years. Survival rates were similar for leiomyosarcoma, mixed mesodermal tumor, and endometrial stromal sarcoma. Clinical staging had some predictive value, since 45 patients with Stage I disease had a 27% survival rate, and 26 patients with Stages II, III, and IV disease had only a 12% survival rate (p less than 0.05). The type of treatment had no demonstrable effect on final outcome but did influence the recurrence patterns. Chemotherapy (used in 25 patients) was neither of benefit when used as adjuvant therapy nor effective inprolonging survival in patients with recurrence (mean survival, 5.4 months).
Fetch PMID: 2984936
Pathol Res Pract 1980 Oct;169(2):120-6
[Clinical aspects of uterine sarcomas (author's transl)]. [Article in German]
Uterine sarcomas constitute 1% to 3% of all uterine cancers. There are three main histological varieties: endometrial stromal sarcoma, leiomyosarcoma, and mixed mesodermal (Mullerian) sarcoma. The tumors are characterized by local aggressiveness and early dissemination. According to the literature, 5 year survival rates range from 3 to 75% (!). This wide range reflects great prognostic differences in the various histologic types. On the other hand it may be due to discrepancies in histopathological evaluation. Radical surgery is the most effective therapy. In early stages it leads to 5 year survival rates of up to 88%. Adjuvant irradiation may increase the control of disease in the pelvis but has proven to be of little influence on the final outcome. The histologic variants show great differences in radiosensitivity. In endometrial stromal sarcomas adjuvant radiation therapy apparently can improve the treatment results. By contrast mixed mesodermal sarcomas are highly radioresistant. There is poor knowledge on the effectiveness of cytotoxic agents on uterine sarcomas. Objective remission of distant metastasis has been observed following treatment with cytotoxic antibiotics (Adriamycin).
Fetch PMID: 7443570
compiled by doctordee
Uterine Leiomyosarcoma and HRT
Abstracts of Medical Journal Reference Articles
compiled by doctordee
Environ Health Perspect 2000 Oct;108 Suppl 5:779-84
Pathology and pathophysiology of uterine smooth-muscle tumors.
Robboy SJ, Bentley RC, Butnor K, Anderson MC. Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710,USA. firstname.lastname@example.org
Smooth-muscle tumors of uterine origin encompass a broad family of neoplasms. The leiomyoma, by far the most common of all the neoplasms, generally is hormone sensitive, with rates of growth semiquantitatively related to estrogen and progesterone receptor levels. Several forms of degenerative change can occur in the leiomyoma. The most common is hyaline degeneration, which is important in that it should not be mistaken for the coagulative tumor cell necrosis seen in leiomyosarcoma. Red degeneration (necrobiosis) is a form of degeneration that occurs characteristically but not exclusively in pregnancy, and the process is often the cause of pain and fever. Several forms of treatment have been used medically in the treatment of leiomyoma. Gonadotropin-releasing hormone analogs or agonists or selective arterial embolization with polyvinylformaldehyde particles may lead to substantial degeneration or infarction of the leiomyoma, respectively. Several variants of leiomyoma, the cellular and symplastic leiomyomas, are important to recognize, as they can be misinterpreted as sarcoma. In addition, there are two unusual growth patterns of leiomyoma that are important to recognize. Both the benign metastasizing leiomyoma and disseminated peritoneal leiomyomatosis are found outside the uterus, and neither is malignant.[the benign metastasizing leiomyoma has been postulated to be a low grade, slow growing leiomyosarcoma] Recent studies offer insights into their origin and hormonal influences. From a diagnostic and therapeutic point of view, the leiomyosarcoma, while rare, is clinically of great import. Coagulative necrosis, cytologic atypia, and mitotic counts are all important in diagnosing the condition. Publication Types: Review, tutorial
Fetch PMID: 11035982
Arch Pathol Lab Med 1999 Oct;123(10):960-2
Benign metastasizing leiomyoma of the uterus: histologic and immunohistochemical characterization of primary and metastatic lesions.
Esteban JM, Allen WM, Schaerf RH. Department of Pathology, Providence/Saint Joseph Medical Center, Burbank, Calif 91505, USA.
Benign uterine leiomyoma metastasizing to the lung is a recognized entity that has been reported infrequently in the medical literature. There is persisting controversy regarding the pathogenesis and biology of these lesions. We report a well-studied and well-characterized case of benign leiomyoma metastasizing to the lung. The patient was a 72-year-old woman with an enlarged uterus that contained several leiomyomas with usual histology. Areas of fibrosis, hyalinization, edema, and focal infarction together with small foci with mildly increased cellularity and minimal nuclear pleomorphism were seen. Careful and repeated mitotic counts ranged from 0 to 2 mitoses per 10 high-power fields. In summary, based on histopathologic criteria, the neoplasm was determined to be a focally cellular benign leiomyoma. Four years later, the patient underwent surgical resection of a single nodule in the lung, which had been detected on routine radiographs. Histopathologic evaluation showed a low-grade leiomyosarcoma with moderate nuclear pleomorphism, necrosis, and brisk mitotic activity. Immunohistochemical studies performed on both neoplasms showed them to be of mesenchymal derivation with smooth muscle differentiation. Both neoplasms expressed estrogen receptors with moderate to strong intensity. The patient received no further treatment and, to date, shows no evidence of recurrent disease. The diagnosis of benign metastasizing leiomyoma can only be made with certainty after careful and extensive sampling of the primary tumor to exclude small foci of sarcoma and of the pulmonary tumor to rule out a primary neoplasm. Although it is biologically peculiar, benign metastasizing leiomyoma should continue to be recognized as a distinct entity because current morphologic criteria do not allow primary myometrial tumors to be reclassified as leiomyomas of uncertain malignant potential even if they have metastasized to the lung.
Fetch PMID: 10506455
Gynecol Oncol 1999 Oct;75(1):158-63
Leiomyomatosis peritonealis disseminata: does malignant transformation occur? A literature review.
Bekkers RL, Willemsen WN, Schijf CP, Massuger LF, Bulten J, Merkus JM. Department of Obstetrics and Gynaecology, University Hospital, St. Radboud, Nijmegen, 6500 HB, The Netherlands.
The following is a summary of the abstract...as the abstract is under copyright.
Leiomyomatosis peritonealis disseminata (LPD) is a rare smooth muscle tumor of which more than 100 cases have been described. It typically presents as multiple small nodules on the peritoneal surface, mimicking a malignant process with metastases. But the pathology reports are benign. Estrogen exposure has an etiologic role, and many patients have uterine leiomyomas as well, for which estrogen exposure also has an etiologic role. The diagnosis of LPD is made by biopsy. Reducing estrogen exposure is usually causes regression of LPD. Surgical castration or gonadotrophin releasing hormone agonists seem good alternatives if LPD progresses or recurs. In six patients a malignant leiomyosarcoma has been described shortly after the diagnosis of LPD was made. Five of these patients did not have uterine leiomyomas, exposure to exogenous estorgen, or increased endogenous estrogen, and the relationship with pregnancy in the sixth patient may be coincidental. Whether LPD undergoes malignant transformation is unknown. Characteristics of the LMS patients differ from those of LPD patients and may indicate a high malignant potential, needing a different approach. Copyright 1999 Academic Press. Review of reported cases
Fetch PMID: 10502446
Int J Gynecol Pathol 1999 Jan;18(1):20-8
Expression of steroid receptors, Ki-67, and p53 in uterine leiomyosarcomas.
Zhai YL, Kobayashi Y, Mori A, Orii A, Nikaido T, Konishi I, Fujii S. Department of Obstetrics and Gynecology, Shinshu Univ. School of Medicine,Matsumoto, Japan.
The expression of estrogen receptor (ER), progesterone receptor (PR), tumor suppressor oncogene p53, and Ki-67 was compared in uterine smooth muscle tumors, including leiomyosarcoma (LMS), tumor of uncertain malignant potential (UMP), cellular leiomyoma (CL), bizarre leiomyoma (BL), and usual leiomyoma (UL). ER and PR were expressed in all ULs. PR was expressed in UL irrespective of the phase of the menstrual cycle; this staining was also observed in CL, UMP, and BL, although BL showed variable staining for ER. Compared to these tumors, the expression of both ER and PR was markedly reduced in LMS. The results of ER and PR transcripts by reverse transcription-polymerase chain reaction were compatible with those of immunohistochemistry. The number of Ki-67 positive cells in LMS was significantly higher than in UMP, BL, CL, and UL. p53 immunoreactivity was seen in 10 of 14 LMSs, and missense mutation in the p53 gene was found in 4 of 10 LMSs. These results suggest that abnormal expression of ovarian steroid receptors, p53, and Ki-67 is frequently associated with LMS of the uterus.
Fetch PMID: 9891238
Mod Pathol 1999 Nov;12(11):1001-9
Comparative immunohistochemical and molecular analysis of uterine and extrauterine leiomyosarcomas.
Rao UN, Finkelstein SD, Jones MW. Department of Pathology, University of Pittsburgh Medical Center, Presbyterian University Hospital, Pennsylvania 15213-2582, USA.
Histologic criteria defining malignancy in smooth muscle tumors are currently site specific. This study was undertaken to determine whether, in leiomyosarcomas (LMS) occurring in different anatomic locations, there were differences in patterns of expression of molecules that have been demonstrated to be associated with biologically aggressive behavior in malignant neoplasms, and also to determine their diagnostic utility. Formalin-fixed paraffin-embeddedtissue blocks were selected from 16 extrauterine leiomyosarcomas (EULMS), 14 cases of uterine leiomyosarcomas (ULMS) and from five cases each of uterine and extrauterine leiomyomas (LM). Utilizing immunohistochemical (ABC) techniques with antigen retrieval, we assessed serial sections of each tumor for immunoreactivity with Glut1, CD44s, bcl2, cyclin D1, and estrogen receptor. Molecular genotyping for detecting k-ras-2 point mutation, p53 gene loss, and mdm2 gene amplification was performed on microdissected tumor samples from the same histologic sections. All of the uterine and extrauterine LM were diffusely positive for CD44s, bcl2, and cyclin D1, and uniformly negative for Glut1. In contrast, 50% of the ULMS and 25% of EULMS were Glutl positive. Moreover, Glut1 positivity closely correlated with aggressive biologic behavior reflected by distant metastatic spread. Eighty-percent of LM and 70% of the ULMS were estrogen receptor positive, whereas only one retroperitoneal tumor had focal weak positivity. Over 80% of the extrauterine and 50% of the uterine sarcomas showed absence of CD44s immunoreactivity. Percentage of cyclin D1 immunoreactivity was independent of tumor grade and inversely proportional to the percent of bcl2 positivity. An LMS of the male breast contained k-ras-2 exon 1 point mutation (codon 12 aspartate substitution of glycine). P53 allelic imbalance was present in 29% of ULMS and 57% EULMS. Mdm2 amplification was present in three of six EULMS but not in ULMS. In addition to clinical staging, Glut1 positivity together with patterns of immunoreactivity of CD44 and bcl2 may be helpful in identifying aggressive smooth muscle tumors of the uterus and some EULMS. The presence of estrogen receptor staining may be helpful in identifying uterine versus nonuterine LMS. Although sample numbers are too small for definite conclusions, this study suggests that there are differences in glucose transport, expression of adhesion molecules, and estrogen receptors in ULMS and EULMS, which in part may be due to the estrogen dependency of the ULMS. P53 mutations and mdm2 amplifications appear to be more frequent in EULMS. Publication Types: Clinical trial Randomized controlled trial
Fetch PMID: 10574596
Eur J Gynaecol Oncol 1999;20(5-6):379-82
Hormone replacement therapy after uterine leiomyosarcoma treatment. Case reports.
Ursic-Vrscaj M. Institute of Oncology, Ljubljana, Slovenia.
Uterine sarcomas are extremely rare uterine malignancies; with a review of the literature we could not find any data dealing with exogenous oestrogens or combined hormone replacement therapy (HRT) after leiomyosarcoma treatment. We report two cases of patients with leiomyosarcoma of the uterine corpus. Both patients were without pelvic irradiation or exogenous oestrogen treatment before the diagnosis. Leiomyoma of the uterus was found during surgery in both cases. Both patients were receiving HRT with non-conjugated oestrogens, after an intensive non-hormonal treatment had failed. No recurrence was established after surgical treatment in the patient with 12 mitoses per 10 high power fields (HPF). The patient is still on HRT (61 months). The other patient with a leiomyosarcoma with very high mitotic activity (40 mitoses per 10 HPF) received cytostatic and irradiation therapy after surgery because of locally widespread disease. Ten months after the diagnosis and 3 months after beginning HRT, recurrence was observed. The patient thereupon stopped HRT. After two additional operations, the patient is alive and without evidence of disease. We presume that the present case reports observations might suggest that HRT did not appear to have a pronounced adverse effect on the leiomyosarcoma outcome in our patients. Nevertheless, until more collected data determine that HRT is safe, caution is needed.
Fetch PMID: 10609499
Pathol Res Pract 1996 Mar;192(3):215-23
Immunohistological detection of estrogen and progesterone receptors in multiple and well differentiated leiomyomatous lung tumors in women with uterine leiomyomas (so-called benign metastasizing leiomyomas). A report on 5 cases.
Jautzke G, Muller-Ruchholtz E, Thalmann U. Institut fur Pathologie, Universitatsklinikum Rudolf Virchow, Berlin, Germany.
Seventy-four cases of so-called "benign metastasizing uterine leiomyomata" are reported in the literature. In these cases, well differentiated, leiomyomatous lung tumors developed, usually after a period of several years. Histologically, these tumors appear to be benign. We report on five more such cases in which we investigated the contents of estrogen and progesterone receptors in the pulmonary tumors by immunohistological procedures. All the lung tumors exhibited a high content of progesterone receptors, and in 4 out of the 5 cases a high estrogen receptor content was also found. Modern immunohistological techniques permit the investigation of routinely fixed tissue blocks, and it is thus recommended that the contents of these hormone receptors should be determined in well differentiated, leiomyomatous lung tumors from women. This would both provide information on the pathogenesis of these tumors and establish a basis for possible later institution of hormone treatment. It is likely that the majority of these lung tumors are in fact metastases of extremely well differentiated leiomyosarcomas of the uterus. The possibility that lung tumors of this type may constitute a small group that develop in situ as hormone-sensitive proliferations cannot, however, be fully excluded. Publication Types: Review of reported cases
Fetch PMID: 8739468
Cancer 1996 Feb 15;77(4):717-24
Exogenous sex hormone use, correlates of endogenous hormone levels, and the incidence of histologic types of sarcoma of the uterus.
Schwartz SM, Weiss NS, Daling JR, Gammon MD, Liff JM, Watt J, Lynch CF, Newcomb PA, Armstrong BK, Thompson WD. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center,Seattle,Washington,
BACKGROUND: We analyzed data from a population-based, multi-center, case-control study to determine whether the occurrence of histologic types of uterine sarcoma is related to exogenous hormone use and/or to two correlates of endogenous estrogens: excess weight and cigarette smoking. METHODS: One hundred sixty-seven women with newly-diagnosed uterine sarcoma (56 leiomyosarcoma, 85 mixed mullerian tumors, and 26 endometrial stromal sarcomas) were interviewed by telephone regarding possible risk factors for these neoplasms, For comparison, 208 women identified at random from the general population of the study areas were interviewed as controls. RESULTS: Use of oral contraceptives was positively associated with the risk of leiomyosarcoma (odds ratios [OR] = 1.7, 95% confidence interval [CI] = 0.7, 4.1), primarily among women who last used these medications 15 or more years prior to diagnosis. Use of noncontraceptive estrogens was directly associated with the risk of mixed mullerian tumors, but only among recent and long-term users of these medications. Women in the highest quantile of body mass index (> or = 27.5 kg/m2) one year prior to diagnosis were at increased risk of each type of uterine sarcoma (leiomyosarcoma, OR = 2.5, 95% CI = 1.1, 5.7; mixed mullerian tumors, OR = 2.9, 95% CI = 1.3, 6.7; stromal sarcoma, OR = 3.5, 95% CI = 1.1, 10.9). Women who had ever smoked cigarettes were at reduced risk of leiomyosarcoma (OR = 0.6, 95% CI = 0.3, 1.1) and stromal sarcoma (OR = 0.5, 95% CI = 0.2, 1.2), but the relationship was not more pronounced among heavy smokers; no association with smoking was observed with mixed mullerian tumors. CONCLUSIONS: Several of these findings parallel those from studies of endometrial carcinoma and may indicate a role for unopposed estrogen in the etiology of histologic types of uterine sarcoma.
Fetch PMID: 8616764
Surg Today 1996;26(2):138-41
The effectiveness of medroxyprogesterone in the treatment of multiple metastasizing leiomyosarcomas: report of a case.
Uchida T, Nakakawaji K, Sakamoto J, Kojima H, Murakami H, Kato J, Yasue M. Department of Surgery, Aichi Prefectural Hospital, Kakemachi, Okazaki, Japan.
A 51-year-old woman was admitted to our hospital for further investigation of chest X-ray films which showed multiple shadows that had been growing slowly over 2 years. Her only symptom was hemosputa. The lesions were suspected of being metastasizing leiomyoma due to her past history of uterine leiomyoma. Just 1 week before undergoing scheduled open lung biopsy, the lung lesions increased remarkably in size and number. A thoracotomy was performed and six of the numerous nodules were removed. The resected specimens were pathologically diagnosed as metastasizing leimyosarcoma which was positive for the progesterone and estrogen receptors. Thus, 1 month postoperatively, a course of medroxyprogesterone (MPA), 600 mg daily, was commenced. The residual lesions in her chest started to diminish, shortly afterward. She has remained well on this MPA regimen for 45 months. The prognosis of patients with metastasizing leiomyosarcoma is poor because of its low sensitivity to chemotherapy; however, some types of leiomyosarcoma are hormone-sensitive. It is therefore important to examine the hormone receptors of excised tumors from patients suspected of having metastasizing leiomyoma or leimyosarcoma.
Fetch PMID: 8919287
Gynecol Oncol 1994 Jan;52(1):74-9
Uterine leiomyosarcomas coexistent with cellular and atypical leiomyomata in a young woman during the treatment with luteinizing hormone-releasing hormone agonist.
Lee WY, Tzeng CC, Chou CY. Department of Pathology, National Cheng Kung University Hospital,Tainan,Taiwan,RepofChina.
We report a case of a 28-year-old woman who had received 2 months of intranasal buserelin (a luteinizing hormone- releasing hormone agonist; LH-RH agonist) therapy for presumed uterine leiomyomata. In addition to no reduction of the tumor size evaluated by sonography, heavy vaginal bleeding and abdominal pain recurred and worsened during the therapy. Pathological examination of the myomectomy and hysterectomy specimens revealed leiomyosarcomas coexistent with cellular, atypical, and classical leiomyomata. We suggest that this is a case of leiomyosarcomas arising in preexisting leiomyomata rather than de novo from the smooth muscle fibers of the myometrium. Furthermore, the potential of LH-RH, agonist therapy to delay the surgical treatment of an unsuspected leiomyosarcoma is high-lighted. Close monitoring of the treatment response by improvement of clinical symptoms and sonographic assessment of tumor size may be helpful in early diagnosis of an underlying malignant tumor. Review of reported cases
Fetch PMID: 8307505
Nihon Kyobu Shikkan Gakkai Zasshi 1993 Jul;31(7):890-5
[A case of so-called benign metastasizing leiomyoma responsive to progesterone].[Article in Japanese]
Motegi M, Takayanagi N, Sando Y, Ubukata M, Imai S, Suzuki T, Nakajima T,Yoshida I. Second Department of Internal Medicine, Gunma University School of Medicine,Japan.
A 47-year-old female, who had undergone hysterectomy and unilateral oophorectomy in 1975, was admitted to our hospital in 1989 because chest X-ray films revealed an increase in size and number of pulmonary nodules for two years. On admission, a left inguinal tumor was found and histologically it consisted of smooth muscle cells with nuclear atypia arranged in interlacing fascicles. An open-lung biopsy was performed. Pulmonary tumors revealed similar histology to the inguinal tumor. They were diagnosed as metastatic low-grade leiomyosarcoma, so-called benign metastasizing leiomyoma (BML), on the basis of location and history, reinforced by mild histologic atypia. The tumor contained a high progesterone receptor level (400 fmol/mg). Therefore, medroxyprogesterone acetate, 600 mg daily, was administered orally. At two years the pulmonary lesions had regressed. BML is a rare condition, considered to be pulmonary metastasis from low-grade leiomyosarcoma of the uterus. Measuring estrogen and progesteronereceptors in lung biopy material may help determine the most appropriate therapy.
Fetch PMID: 8366630
Acta Cytol 1986 Mar-Apr;30(2):93-8
Comparison of cytohormonal status of postmenopausal women with cancer to age-matched controls.
Cassano PA, Saigo PE, Hajdu SI.
To determine whether the cytohormonal status of postmenopausal women with cancer involving the uterus and vagina differs from that of women free of cancer, 100 women 60 years of age or older with positive cervicovaginal smears were compared with an age-matched control group without malignant neoplasms. Epidermoid carcinoma was identified in 64 patients (average age: 67 years) and adenocarcinoma in 34 patients (average age: 69 years). One patient had leiomyosarcoma, and another had bladder carcinoma. The paucity of benign squamous cells in the smears precluded hormonal evaluation in 32% of the index cases; the smears from 10% of the controls were also indeterminate. Of the evaluable cases with epidermoid carcinoma of the cervix, a high maturation was noted in 46% as compared to 11% for the matched controls. In addition, high maturation was noted in 69% of those patients with endometrial adenocarcinoma as compared to 19% for the matched controls. None of the index cases were atrophic; 31% of the controls were. A history of exogenous estrogen usage was obtained in three patients with endometrial adenocarcinoma, all with high maturation, and in five controls, none with high maturation. These data appear to indicate a difference in the cytohormonal status of patients with cervical or endometrial carcinoma as compared to those without; consequently, cytologists should be especially attentive to smears showing high maturation from postmenopausal women.
Fetch PMID: 3457512
Acta Obstet Gynecol Scand 1984;63(6):505-8
Estradiol and progesterone receptors in gynecologic sarcomas.
Lantta M, Karkkainen J, Wahlstrom T, Widholm O.
We report the concentrations of estradiol and progesterone receptors found in the tumor tissue of 5 patients with leiomyosarcoma, 4 of uterine and one of ventricular origin, and of 5 patients with uterine or ovarian carcinosarcoma. Steroid receptor positive and negative tumors were present in both groups of sarcoma. One uterine leiomyosarcoma had a high concentration of estradiol and progesterone receptors, 37 fmoles/mg protein and 156 fmoles/mg protein, respectively. We suggest that steroid receptors should be analysed in all gynecologic sarcomas.
Fetch PMID: 6507052
Arch Surg 1980 Mar;115(3):244-8
Estrogen receptor proteins in diverse human tumors.
Stedman KE, Moore GE, Morgan RT.
One hundred three diverse benign and malignant human tissues have been assayed for estrogen receptor proteins. Receptors were detected in many endocrine and nonendocrine tumors. Tissues with estrogen receptor activity included four of five male breast carcinomas, 11 of 14 malignant melanomas, four of eight colon carcinomas, five of seven renal carcinomas, and various sarcomas and benign and normal tissues. Some tumors also had progesterone, androgen, and/or glucocorticoid receptors. These results suggest the use of hormones and hormone antagonists for therapy of a broad range of human cancer. Clinicians of diverse expertise should be aware of, and responsive to, potential endocrinological involvement in many dissimilar disease states.
Fetch PMID: 7356378
Cancer 1980 Mar 1;45(5):932-7
Metastasizing leiomyoma of the uterus. S-phase fraction, estrogen receptor, and ultrastructure.
Cramer SF, Meyer JS, Kraner JF, Camel M, Mazur MT, Tenenbaum MS.
A 33-year-old woman had a metastasizing leiomyoma in which mitotic figures could not be found. The tumor was composed of well differentiated smooth muscle indistinguishable from uterine leiomyoma or normal myometrium by light and electron microscopy. The S-phase fraction of the tumor, measured by in vitro tritiated thymidine labeling, was near the upper limit of the range seen in seven ordinary uterine leiomyomas and was distinctly lower than that in a uterine leiomyosarcoma. The content of estrogen receptors in the cytosol was within the range seen in uterine leiomyomas. Metastasizing leiomyoma is an actively proliferating neoplasm of mature smooth muscle that appears to be hormonally responsive. The tumor in our patient showed no clear differences from ordinary leiomyomas in findings relating to the rate of cellular proliferation, morphology, or estrogen receptor content.
Fetch PMID: 7260844
Am J Surg Pathol 1979 Aug;3(4):325-42
Pulmonary metastases (with admixed epithelial elements) from smooth muscle neoplasms. Report of nine cases, including three males.
Wolff M, Silva F, Kaye G.
This study pertains to an entity characterized by the presence of multiple intrapulmonary nodules, which consist of an admixture of bundles of well-differentiated smooth muscle cells and epithelial-lined spaces. These lesions have been frequently interpreted as a variant of hamartomas. However, in this review of the literature, and careful analysis of nine cases of this entity, we concluded that they should be considered metastases from smooth muscle tumors which incorporate some structures of mature lung parenchyma as they slowly expand. We affirm that the designation "fibroeliomyomatous hamartoma" should be discarded. Our cases occurred in six female and three male patients. In all but one female the primary source for lung metastases was uterus, while the male patients had primary lesions in the saphenous vein,diaphragm, and soft tissues. These lung lesions increase in size and number and are potentially fatal, though this may take many years. Even though the smooth muscle cells of the lung nodules appear bland on light microscopy, we were always able to demonstrate mitotic activity; electron microscopy indicated immaturity of the cells. For these reasons, we believe the tumors to represent metastatic leiomyosarcomas. Publication Types: Review
Fetch PMID: 395847
Uterine Diagnostic Error
Abstracts of Medical Journal Articles
compiled by doctordee
Am J Obstet Gynecol 1990 Apr;162(4):968-74; discussion 974-6
Leiomyosarcoma in a series of hysterectomies performed for presumed uterine leiomyomas. Leibsohn S, d'Ablaing G, Mishell DR Jr, Schlaerth JB. Department of Obstetrics and Gynecology, University of Southern California School of Medicine, Women's Hospital, Los Angeles 90033.
The incidence of leiomyosarcoma in uterine leiomyomas is estimated to be between 0.13 to 0.29%. However, the exact incidence of leiomyosarcoma in uteri removed with a preoperative diagnosis of benign uterine leiomyomas has not been previously reported. Between 1983 and 1988, a total of 1432 patients in Women's Hospital, a self-referred indigent population, had a hysterectomy planned because of abnormal uterine bleeding or abdominal pain associated with the presence of uterine leiomyomas, or because of a pelvic mass thought to be uterine leiomyoma of sufficient size or character to warrant surgical exploration. The ages of these women ranged from 36 to 62 years and the presence of leiomyosarcoma in the hysterectomy specimens increased steadily from the fourth to seventh decades of age (0.2%, 0.9%, 1.4%, and 1.7%, respectively). Preoperative histologic examination of the endometrium was performed in eight patients. Three of the eight patients had a preoperative tissue diagnosis of leiomyosarcoma that was clinically confined to the uterus. After the hysterectomy in the 1429 patients with presumed benign disease, histologic diagnosis of leiomyosarcoma was made in seven (0.49%). There was no evidence of malignancy in the endometrial sampling of any of these seven patients and the diagnosis was suspected intraoperatively in only three. Preoperative uterine size ranged from 8 to 20 weeks' gestational size and postoperative uterine weight ranged from 120 to 1100 gm. Seven of the 10 patients had symptoms of abnormal uterine bleeding. Between the ages of 40 and 60 years, 1% (8 of 817) of women with presumed uterine leiomyomas producing symptoms that necessitated hysterectomy in this series had leiomyosarcoma diagnosis postoperatively. Such treatments as gonadotropin-releasing hormone agonists, endometrial ablation, myomectomy by hysteroscopy or laparotomy instead of hysterectomy in such women could delay the diagnosis and definitive treatment of leiomyosarcoma.
Cancer 1978 May;41(5):1902-10 A reassessment of uterine neoplasms originally diagnosed as leiomyosarcomas. Hart WR, Billman JK Jr.
Twenty-eight uterine tumors originally diagnosed as leiomyosarcomas were histologically reclassified without prior knowledge of follow-up or clinical data. Thirteen (46%) neoplasms were reinterpreted as cellular or pleomorphic leiomyomas. They had sparse mitotic activity with three or fewer mitotic figures per 10 high power microscopic fields (MF/10 HPF). None recurred or metastasized, and all patients were alive from 6.3 to 23 years after operation (median of 14.2 years). In 15 cases the diagnosis of leiomyosarcoma (LMS) was confirmed. All showed hypercellularity, nuclear atypism and high mitotic activity. Mitosis counts ranged from 6 to more than 50 MF/10 HPF with 93% of LMS having at least 15 MF/10 HPF. These patients all died of LMS after post-operative intervals of 3 months to 7.5 years (median survival of 13 months). No consistent correlation was found between length of survival and the patient's menopausal status or histologic grade of LMS. The degree of mitotic activity is the single most reliable diagnostic criterion of malignant potential, albeit not the only one. Surgery alone is ineffective treatment for LMS and combination therapy with radiation therapy and/or chemotherapy should be considered.
Fetch PMID: 647634
J Reprod Med 1992 Dec;37(12):980-2
Incidental finding of endolymphatic stromal myosis during luteinizing hormone releasing hormone agonist therapy for suspected benign uterine myomata. A case report.
Smith S, Cooper M, Schinfeld JS. Department of Obstetrics and Gynecology, Temple University School of Medicine, Abington Memorial Hospital, PA 19001.
A 39-year-old woman with an enlarging myomatous uterus underwent a three-month course of luteinizing hormonereleasing hormone (LHRH) agonist treatment. Despite a 50% reduction in uterine size, pathologic examination after uncomplicated hysterectomy revealed a low-grade endometrial stromal sarcoma. As the use of LHRH agonists for myoma reduction increases, delay in the diagnosis of sarcomatous disease will become more widespread. With current available diagnostic modalities, differentiation between sarcomatous and myomatous growth within the uterus is difficult. The possibility of delay in the diagnosis of unsuspected sarcoma when using LHRH agonists is an inherent and apparently unavoidable complication in some cases.
Fetch PMID: 1287209
Zhonghua Fu Chan Ke Za Zhi 1992 Jul;27(4):206-8, 249
[Diagnostic errors in dysfunctional uterine bleeding. Analysis of 24 cases]. [Article in Chinese]
Long L. Capital institute of Medicine, Xuanwu Hospital, Beijing.
This paper reports 24 cases of genital organic diseases which were misdiagnosed as dysfunctional uterine bleeding during 1984-1990. These include small submucous uterine myoma 5 cases, Granulosa cell tumor of ovary 2 cases, leiomyosarcoma of uterus 1 case, ectopic pregnancy 7 cases, carcinoma of endometrium 4 cases, abortion 3 cases, choriocarcinoma 2 cases, altogether there were 9 patients with malignant tumors in the series. The author point out that it is possible to reduce the misdiagnosis rate by emphasizing history, diagnostic curettage, ultrasonography, hysteroscopy and blood hCG determination.
Fetch PMID: 1291214
Zhonghua Zhong Liu Za Zhi 1990 Nov;12(6):441-3
[Bizarre leiomyoma of the uterus--a clinicopathological analysis of 21 cases]. [Article in Chinese]
Zhao ZS. Hangzhou Hospital of Traditional Chinese Medicine.
Twenty-one patients with bizarre leiomyoma of uterus treated in the Obstetrics and Gynecology Hospital, Zhejiang Medical College from 1968 to 1988 are reported. These accounted for 1% of patients with uterine myogenic tumors in the same period. All were multipara. Their age ranged from 25 to 59 years with an average of 41.3 years. Of these 21 cases, 7 had taken oral contraceptives, 3 had had IUD, 8 had undergone tubosterilization and 3 had concurrent pregnancy. Twelve cases were diagnosed as bizarre leiomyoma of uterus by pathology and 9 as leiomyoma with sarcoma-like changes in limited areas or leiomyosarcoma. Among these 21 cases, 9 had limited focal bizarre leiomyoma and 12 pseudosarcomatoid tumor. The bizarre leiomyoma of uterus is of benign nature. Its treatment is similar to that of the common leiomyoma. Its occurrence might be related to the primary leiomyoma of uterus under constant influence of high level sex hormone or being of bizarre cell type at the very beginning. The differentiation between the bizarre leiomyoma of uterus and leiomyosarcoma is discussed.
Fetch PMID: 2076641
Am J Obstet Gynecol 1988 Oct;159(4):826-7
Comment in: Am J Obstet Gynecol. 1990 Jan;162(1):293
Diagnosis of a tumor with an unusual presentation in the pelvis.
Sloan D. Department of Obstetrics and Gynecology, New York Medical College, Lenox Hill Hospital, NY.
A 47-year-old multiparous woman was first seen with signs and symptoms of sudden, copious vaginal bleeding. The pelvic examination revealed a classic-appearing aborting leiomyoma. Subsequent operation and histologic examination, however, revealed a rare pelvic tumor. The diagnostic evidence and management are outlined.
Fetch PMID: 3177529
South Med J 1988 May;81(5):651-2
Calcified uterine leiomyoma simulating metastatic disease on bone scan.
Rohrer DG, Williamson BR, Teates CD. Department of Radiology, University of Virginia Medical Center, Charlottesville 22908.
We have reported a case in which focal uptake in a uterine fibroid simulated a sacral metastasis on bone scanning. CT suggested the correct diagnosis. However, a repeat bone scan using single photon emission computerized tomography (SPECT) was definitive in correctly localizing the abnormality. This method should be used when more precise localization is required than can routinely be obtained.
Fetch PMID: 2835820
Geburtshilfe Frauenheilkd 1975 Dec;35(12):919-28
[Uterine myoma in geriatric surgical cases (author's transl)]. [Article in German]
The following is a report on 189 cases involving surgical treatment of uterine myoma in women who were at least 60 years old. The cases were collected from 18 gynecological departments in West-Berlin over a 10-year period (1960-1969). 66 of these patients (38,1%) have never been pregnant, 17 (9,8%) had only abortions, while 90 (52,1%) had given birth to one or more children. In only 89 women (47,0%) the pre-operative diagnosis had been uterine myoma. The number of correct diagnosis prior to surgery decreased with increasing age of the patients. 47 patients had been completely asymptomatic; an additional 20 had shown no gynecological symptoms. Total hysterectomy including removal of the tubes and ovaries, which we consider the preferential method of treatment, was done in 105 cases (55,5%). Other surgical procedures were performed in 84 instances (44,5%). 8 registered deaths equal a post-operative mortality rate of 4,2%. Analysis of our cases contradicts the hypothesis regarding postmenopausal involution of uterine myoma. Removal of the uterus for myoma should not be considered a typical geriatric gynecological operation. In many instances it could have been performed at an earlier date; in some cases it even could have been avoided if all diagnostic procedures presently available had been utilized.
Fetch PMID: 1213256
Thorac Cardiovasc Surg 1994 Dec;42(6):361-3
Intravenous leiomyomatosis extending into the right ventricle: one-stage radical excision during hypothermic circulatory arrest.
Okamoto H, Itoh T, Morita S, Matsuura A, Yasuura K.
Division of Thoracic and Cardiovascular Surgery, Yokkaichi Municipal Hospital, Japan.
A case of intravenous leiomyomatosis with extension into the right ventricle is described. A tumor in the inferior vena cava was detected 5 years after a hysterectomy had been performed for a myomatous uterus, but was misdiagnosed as an intracaval thrombus. Three years later this tumor was discovered after it had enlarged and intruded into the right ventricle. The correct diagnosis was made after a complete evaluation. The patient underwent surgery employing simultaneous sternotomy and laparotomy. Radical excision was achieved using cardiopulmonary bypass with hypothermic circulatory arrest. The diagnostic and surgical approaches are reviewed and discussed.
Publication Types: Review Review of reported cases
Fetch PMID: 7534959
Acta Obstet Gynecol Scand 1993 Jul;72(5):374-6
Prehysterectomy curettage in women with uterine fibromyomata is not worthwhile.
Moller LM, Berget A.
Department of Obstetrics and Gynecology, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.
OBJECTIVE: To study the value of prehysterectomy curettage in women referred on the suggestion of uterine fibroids. DESIGN: A retrospective study. SETTING: Gentofte Hospital, University of Copenhagen. SUBJECTS: Four hundred and eleven patients with a curettage prior to hysterectomy on suspicion of uterine fibroids. MAIN OUTCOME MEASURE: Histological accuracy, frequency of (pre)malignancies and clinical consequences due to routine curettage. RESULTS: Curettage disclosed two cases of endometrial cancer and four cases of CIN. It missed two cases of CIN and one case of endometrial cancer in a postmenopausal women. In no case did the final histology disclose diseases that had not been taken care of during the laparotomy. CONCLUSION: Curettage in women with a preoperative diagnosis of uterine fibromyomata is not worthwhile.
Fetch PMID: 8392269
Uterine Leiomyosarcoma & Inherited Susceptibility
Two medical journal abstracts.
compiled by doctordee
Proc Natl Acad Sci U S A 2001 Mar 13;98(6):3387-3392
Inherited susceptibility to uterine leiomyomas and renal cell cancer. Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, Sistonen P, Herva R Aaltonen LA.
Department of Medical Genetics, Haartman Institute, University of Helsinki, P. O. Box 21, FIN-00014, Helsinki, Finland; Department of Clinical Genetics, Oulu University Hospital, Kajaanintie 50, FIN-90220, Oulu, Finland; Institute of Medical Technology, University of Tampere, FIN-33014, Tampere, Finland; Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Finnish Cancer Registry, FIN-00170, Helsinki, Finland; Finnish Red Cross Blood Transfusion Service, Kivihaantie 7, FIN-00310, Helsinki, Finland; and Department of Pathology, Oulu University Hospital, Kajaanintie 52, FIN-90220, Oulu, Finland.
Herein we report the clinical, histopathological, and molecular features of a cancer syndrome with predisposition to uterine leiomyomas and papillary renal cell carcinoma. The studied kindred included 11 family members with uterine leiomyomas and two with uterine leiomyosarcoma. Seven individuals had a history of cutaneous nodules, two of which were confirmed to be cutaneous leiomyomatosis. The four kidney cancer cases occurred in young (33- to 48-year-old) females and displayed a unique natural history. All these kidney cancers displayed a distinct papillary histology and presented as unilateral solitary lesions that had metastasized at the time of diagnosis. Genetic-marker analysis mapped the predisposition gene to chromosome 1q. Losses of the normal chromosome 1q were observed in tumors that had occurred in the kindred, including a uterine leiomyoma. Moreover, the observed histological features were used as a tool to diagnose a second kindred displaying the phenotype. We have shown that predisposition to uterine leiomyomas and papillary renal cell cancercan be inherited dominantly through the hereditary leiomyomatosis and renal cell cancer (HLRCC) gene. The HLRCC gene maps to chromosome 1q and is likely to be a tumor suppressor. Clinical, histopathological, and molecular tools are now available for accurate detection and diagnosis of this cancer syndrome.
Fetch PMID: 11248088
Int J Gynaecol Obstet 1988 Oct;27(2):289-91
Recurrent uterine myomata in three sisters--an uncommon occurrence. Kulenthran A, Sivanesaratnam V. Department Obstetrics and Gynaecology, University Hospital, Kuala Lumpur,Malaysia.
Three sisters who developed recurrent uterine myomata from a very young age are presented. Despite repeated attempts at myomectomy, all three cases had hysterectomies ultimately. Complications encountered during surgery were severe hemorrhage, inadvertent injury to bladder and bowel in two patients and a rare complication of colonic-uteric-cutaneous fistula occurring post-operatively in one patient. Histology of the final hysterectomy specimens in two cases showed low grade leiomyosarcoma and cell ular myoma, respectively.
Fetch PMID: 2903099
|The information on this site is not a substitute for professional medical advice. You should not use this information to diagnose or treat a health problem or disease without consulting with your doctor. Please consult your doctor with any questions or concerns you may have regarding your condition. Copyright © 2001-2010 LMSWEBSITE|