Congenital Anomalies. Endometrial Polyps

The uterus is formed from the paired mullerian ducts during embryogenesis. Uterine anomalies result from their defective migration, fusion, or absorption during embryonic life. The incidence of anomalies is difficult to estimate because many congenital anomalies do not result in clinical manifestations (Rock and Jones, 1977). Patients with symptomatic mullerian anomalies usually have signs of menstrual outflow obstruction or reproductive dysfunction. Diagnostic methods for determining the exact nature of a mullerian anomaly have evolved from bimanual examination, postpartum manual exploration, and D & C, to the more sophisticated techniques of hysterography, laparoscopy, hysteroscopy, ultrasonography, and MRI. Increased capacity of the latter techniques to yield complete information will undoubtedly be reflected in a higher reported incidence of the more subtle anomalies.

Retrospective studies reveal that approximately 25% of women with congenital uterine anomalies encounter re- productive difficulties, although conception rates are not different than they are among women in control groups (Abramovici et al, 1983; Harger, 1983). Spontaneous abortions, premature births, and fetal malpresentations are common in women with congenital uterine anomalies.

Anomalies can be classified as problems with hypoplasia or agenesis (American Fertility Society [AFS] class I) or as fusion defects (AFS classes II-V). Class I anomalies, also referred to as mullerian anomalies, usually are diagnosed in women who seek treatment for primary amenorrhea or for an inability to have vaginal intercourse. These defects are thought to occur developmentally when the mullerian structures fail to join with the structures arising from the vaginal bulb. There is a wide spectrum of defects ranging from isolated vaginal agenesis to hypoplasia of the vagina, cervix, ileus, and tubes.

Clinically important points of these anomalies include:

  1. In patients with complete mullerian agenesis, the possibility of complete androgen insensitivity (testicular feminization syndrome) should be considered because these women have Y chromosomes and must have their gonads removed because there is a high risk for neoplasia.
  2. The patient with an absent vagina can have one that is adequate for intercourse created through the use of progressive dilators or surgery.

Endometrial Polyps

Endometrial polyps are hyperplastic overgrowths of glands and stroma that are localized and that form a projection above the surface. Such polyps may be sessile or pedunculated and rarely include foci of neoplastic growth.

The prevalence of polyps has been estimated at 10% to 24% among women undergoing endometrial biopsy or hysterectomy. Endometrial polyps are rare among women younger than 20 years of age. The incidence of these polyps rises steadily with increasing age, peaks in the fifth decade of life, and gradually declines after menopause.

The most common symptom in women with endometrial polyps is metrorrhagia, or irregular bleeding; it is reported in 50% of symptomatic patients. Postmenstrual spotting is also common. Less common symptoms include menorrhagia, postmenopausal bleeding, and breakthrough bleeding during hormonal therapy. Overall, endometrial polyps account for 25% of abnormal bleeding in premenopausal and postmenopausal women (Van Bogaert, 1988).

Endometrial polyps can sometimes be seen prolapsing through the cervix. Often they are diagnosed by microscopic examination of a specimen obtained after dilatation and curettage (D & C) or after endometrial biopsy. As is the case with submucous fibroids, polyps can escape detection if the uterus is not distended. Increasingly these lesions are diagnosed by modalities such as ultrasonography and hysteroscopy.

Endometrial polyps usually are cured by thorough curettage. However, polyps or other structural abnormalities may be missed by blind curettage, and hysteroscopic-guided curettage is often useful.

Uterine anomalies may be congenital or they may be acquired after infection or mechanical trauma, and they may lead to reproductive or menstrual dysfunction.

Well, where are we going in the future

Well, where are we going in the future? I think where we are going in the future for sarcomas is further dose intensification with growth factor and stem cell support. Possibly reversing multi-drug resistance, like for Adriamycin, with PSC-833 and Incel. Possibly angiogenesis inhibitors to reduce the chances of metastasis. New work done in hormonal growth manipulation, one out of the Dana Farber. Dr. Dimitri looking at the peroxisome proliferator activating receptor gammon. It’s a ligand. Troglitazone is a ligand for this receptor which is an antidiabetic drug. Stimulating this receptor causes terminal differentiation of lipocytes and it may be helpful in inducing adipose differentiation. At the NCI a somatostatin analog, somatuline, is being looked at. This blocks the release of growth hormone which decreases the production of insulin-like growth factor 1, which is a growth factor for osteogenic sarcoma, and which is being looked at in the adjuvant setting. Also, as I mentioned, the work at Memorial with the possible use now of Herceptin in those osteogenic sarcoma patients who are HER2/neu positive, to possibly use in conjunction with platinum. Immune-modulation; worked on by Dr. Kleineman at the M.D. Anderson. LMTPE is one of the smallest components of the microbacterium and this causes stimulation of the pulmonary macrophages and in both a murine and a human model has … she has shown that there has been a reduction in the incidence of lung metastasis and a decrease in lung metastasis. So the intergroup, pediatric group now – which is the CCSG plus POG – is looking at the use of this agent after the patients have received adjuvant chemotherapy in osteogenic sarcoma. Possible use of immunotoxins. Our group and the NIHLBI are looking at the use of non-myeloablative allogeneic transplant. In other words, giving a somewhat lower dose chemotherapy regimen of Cytoxan and fludarabine in those patients who have a relative who is an HLA match. And in terms of giving them then their relative’s marrow, and in hopes of in addition to giving their relative’s stem cells back to them, also lymphocytes and in hopes of inducing a graft-versus-tumor response. This has already been tried now in renal cell and has been presented at the ASCO and they have some very high quality responses, specifically for renal cell. We have chosen sarcomas as well because they appear to have MHC class I and II antigens and HLA antigens where you may be able to induce an immune response.

Also utilizing oncogene products, modifying tumor suppresser genes, antisense oligonucleotides, using the fusion genes that I showed you earlier as molecular markers and possibly developing vaccines to some of these tumor-specific fusion peptides. And that’s work that’s being done at the pediatric branch at the NCI.

Well, in conclusion I want to emphasize that in order to advance the goals of local tumor control, limb-salvage with optimal function, to minimize treatment morbidity, and also to improve long term survival with the goal of maximum cure; that for the sarcomas because they are so rare and because they involve so many different disciplines, it’s really important if possible to have a multi-disciplinary team approach to treat these patients.

Which have incorporated not only Adriamycin

Two studies now, which have incorporated not only Adriamycin, methotrexate and cisplatin, but also looking at the use of higher doses of ifosfamide, one by Dr. Meiser where ifosfamide was incorporated with Adriamycin and high dose methotrexate, gave a very high limb-sparing surgery rate, very high tumor necrosis rate and very good relapse free and overall survival. Another institution, the Rizzoli Institute in Italy looking at two different studies. This was not prospectively randomized but retrospective, but in one where ifosfamide was given postoperatively and another where ifosfamide was given preoperatively. You can see that in the study where it was given preoperatively there is a much higher limb-salvage rate, much higher amount of tumor necrosis, local recurrence is the same and disease free survival is better.

So now for osteogenic sarcoma, I think what I’ve tried to show you is that in the 70’s and before the 70’s for historical controls, those patients who just received surgery or radiation, about 20% of patients survived. With the benefit of adjuvant and neoadjuvant chemotherapy with agents like platinum, Adriamycin and high dose methotrexate, that’s increased to about 60%. With ifosfamide now added to the regimens there is about another 10-20% benefit, but still approximately 30%, 20-30% of our patients, those with chondroblastic osteogenic sarcomas, those with metastasis on presentation still do very poorly. So we need new approaches.

So in overview now of osteosarcoma; a core or incisional biopsy, surgery – limb-sparing if possible – metastasectomy beneficial in select patients. In terms of chemotherapy, adjuvant is the standard. That’s been shown in two prospective studies of significant benefit, so that is the standard and has definite survival benefit. Whether tailoring is beneficial, the studies do not pan that out. It’s probably more important to give more aggressive chemotherapy as induction. Neoadjuvant, although there has been no study to show any definite improvement, it appears to be at least equivalent with probably more patients having limb-sparing surgery. This is favored, as I said, by most orthopedic oncologists and should include at least platinum and Adriamycin. Some regimens also include high dose methotrexate, but that has to be given properly. And probably now also to include higher doses of ifosfamide.

What about neoadjuvant chemotherapy. Sarcoma

In addition to that, what about neoadjuvant chemotherapy? At the same time that these studies were being done, we had the development of prostheses and these prostheses took about 2-3 months to initially obtain from the companies. So Dr. Rosen, who was at Memorial Hospital at times, decided, “Well, if we are waiting this long for the prostheses and we are considering doing a limb-sparing procedure, maybe instead of waiting for the tumor to grow more, we should be giving some chemotherapy.” So he developed several protocols giving induction neoadjuvant chemotherapy for early treatment to possibly reduce tumor size, to facilitate the limb-sparing procedure and, as we talked about before, giving us an in vivo chemosensitivity test. Now there have been multiple institution studies done in institutions around the country looking at neoadjuvant chemotherapy with results that are at least as good for relapse free survival compared to adjuvant chemotherapy. There has been no definite randomized trial confirming that patients do any better, but I can tell you now that most orthopedic surgeons will not operate on a patient without the patient receiving induction chemotherapy first. The only randomized trial was done by the Pediatric Oncology Group and this is just to show you that in our adjuvant studies, which are mostly multi-institutional and cooperative groups, five year disease free survivals were between 46-61%. In single institution studies with neoadjuvant they were a little bit higher, but we know usually that single institution studies there is patient selection, so it could be a little bit higher. But in a randomized trial there was no difference between adjuvant or neoadjuvant plus adjuvant chemotherapy.

Here is the data. In 100 patients, again a small study – because these are rare tumors and the study took quite a long time – there was no difference in disease free or overall survival. So several oncologists in the community took this study to say that there is no benefit in neoadjuvant chemotherapy and you shouldn’t give it. Adjuvant chemotherapy is enough. But I think you really need to decide whether the cup is half full or the cup is empty. Another way of looking at this study is, yes there is no difference in survival but you have the benefit that you may be able to do much more limb-sparing surgery. So you could look at this study and say, “There are more patients who have had limb-sparing surgery and there has been no detriment in terms of survival in doing the limb-sparing surgery.”

Well, as part of Rosen’s study of giving induction chemotherapy, he also wanted to evaluate whether you could tailor chemotherapy afterwards. In other words, the in vivo chemosensitivity test. In other words, giving induction chemotherapy then looking at histologic necrosis and then, based on whether the patient had a good response – greater than 90% necrosis or less than 90% necrosis – either giving the same chemotherapy or if there was a very poor response to chemotherapy, giving other active drugs. In his initial studies, specifically protocol called the T-10 protocol, there appeared to be initial favorable outcome by changing the chemotherapy, giving a lesser chemotherapy preoperatively and then giving more aggressive chemotherapy postoperatively for those patients who were poor responders. Unfortunately, this concept has been tested in the Children’s Cancer Study Group, the German Group, the Italian Group, and they failed to confirm this concept. Other researchers at Memorial, Dr. Meyers, presented Dr. Rosen’s data with longer follow-up and it hasn’t held up. So I think what’s really important, in terms of induction chemotherapy, is that you need to use more intensive chemotherapy up front. That for the most part giving more intensive therapy postoperatively is not going to bail you out.

What about treatment now

Okay, what about treatment now, in terms of surgery? There has been a marked transition. If you remember Edward Kennedy’s son. He had an osteogenic sarcoma about 20 years ago. He had an amputation. It is rare now for a patient to require an amputation. About 80% of the time now limb-sparing surgery is done. It is probably based on improved diagnostic imaging. Also, it’s based on our orthopedic musculoskeletal surgeons having refined reconstructive techniques, with many new types of prostheses with better function and better materials that last longer. We now have intensive multi-agent chemotherapy which we can give beforehand to try to shrink these tumors down. And it’s been shown that with limb-sparing surgery and with a prosthesis there’s an improved quality of life, and probably it’s cost-effective as well.

When do we still have to do amputation? If there is neurovascular compromise, significant, where there’s really marked loss of limb function already. If it’s a very very young patient – although some of these prostheses now, you can go back in a change the size and stretch them out. If there is a pathologic fracture it’s somewhat of a contraindication, although at some centers now we do give induction chemotherapy. If you then have marked destruction of tumor – which sometimes you have – and you can then develop a new rim of bone, of new bone, around the tumor you can do a successful limb-sparing resection. If there is an improper biopsy site or a local infection, or an inadequate extremity function to begin with, then those would all be indications for doing amputation.

In terms of radiation; we use radiation much less often for osteogenic sarcoma. It’s usually for palliation and an unresectable pelvic lesion or an unresectable vertebral lesion. Occasionally we also use it if there is a tumor of the maxilla or the mandible where you can’t get very good margins. Now our active chemotherapeutic drugs are Adriamycin, high dose methotrexate, platinum and ifosfamide. There is a dose response for all these active agents. You need to be aware that for methotrexate that you need to give industrial strength methotrexate, 8-12 gm per meter squared. You want to achieve serum concentrations of greater than 10 micro-molar. You want, for the first 24 hours, to limit the initial hydration so that the urine output is less than 1400 cc per meter squared for the first 24 hours, so that you can obtain these concentrations. Because if you don’t obtain these concentrations the response rates are much lower. In the past we used a combination of bleomycin, Cytoxan and actinomycin-C in some of the earlier regimens that were used in induction chemotherapy later on. Its use for metastatic disease was looked at again and really this regimen does not have much activity for osteogenic.

Okay, what about adjuvant chemotherapy for osteogenic sarcoma? Well, between the 1940’s and the 1970’s pretty much only surgery or radiation therapy was done and the survival was approximately 20%. There were then uncontrolled trials, single institution studies of adjuvant chemotherapy in the 1970’s which showed a relapse free survival of 35-60%. It appeared then people were starting to use adjuvant chemotherapy. The Mayo Clinic then in the 1970’s looked at a group of patients with osteogenic sarcoma that just had surgery alone and they appeared to have a survival of 42% and they felt that this was related to better diagnostic imaging and better surgery. They then performed a study at their institution looking at adjuvant chemotherapy versus surgery alone, and there was no difference in survival. But the dose of methotrexate that they used at that time was much much less than 8-12 gm per meter squared that we now recommend. So after that study was done, the multi-institutional osteosarcoma group and UCLA performed two randomized studies looking at the use of surgery alone versus surgery plus adjuvant chemotherapy. Both relapse free survival and overall survival they showed significant benefit for adjuvant chemotherapy.

Probably our most important prognostic factors

Probably our most important prognostic factors, specifically if you are going to be giving neoadjuvant induction chemotherapy, is histologic tumor necrosis. That’s probably the gold standard. In those patients who have at least 90% necrosis or a Houvus score of IV – which I will show you what that is – have an extremely good prognosis. Surgical margin quality is important. You want to have negative margins. Those patients who have positive margins have a high incidence of local recurrence and then have a worse prognosis. So again, this is where pathology becomes important and you want, if we are going to give neoadjuvant induction chemotherapy at our institution we have a pathologist, Barry Schmukler, who samples multiple areas in a grid fashion of the bone, and looks in all these areas for the amount of necrosis and then gives us a number of the amount of tumor cells that are destroyed. This is based on work by Dr. Houvus who was a pathologist at Memorial Sloan-Kettering who developed the Houvus classification of I-IV, IV being no histological evidence of any tumor. This is now at many institutions been changed to greater than 90% being a good response.

In terms of work-up now. What kind of a work-up do you do for osteogenic sarcomas? Well, on plane x-ray you can see a sunburst sign. You need, as I talked to you before for soft tissue, you have to have a properly placed core on incisional biopsy. We usually obtain alkaline phosphatases and LDH’s as markers because they can be elevated, but they are not always elevated. We want to obtain an MR or a CT scan of the bone area plus a chest CT scan because this metastasizes to lung, plus a bone scan because it can metastasize to other bones. We use angiograms and thallium scans to assess the response to induction chemotherapy. If limb salvage is contemplated, if possible you want to have the surgeon who is going to perform the definitive operation do the incision placement, because if it’s not placed properly that may unfortunately mean that the patient will require an amputation. This is the sunburst sign that I was talking about. There can be elevation of the periosteum, which we call Codman’s triangle. This is this paraostial osteogenic sarcoma, which is low grade, which has the better prognosis.

In terms of staging, our staging again is a bi-gradal system, as for soft tissue sarcomas. Whether the tumor is in the cortex or beyond the cortex, size although important is not part of the grading system. And then metastasis. So it’s actually I, II, IV with nothing in the stage III group. So this is very similar to the previous Enneking staging system I showed you.