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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.

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 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.

Other special situations

Now what other special situations do you need to know about for the Boards, in terms of sarcomas? Well, desmoids which are mostly low grade, are mostly locally invasive. As I told you before, they are associated with the APC gene, Gardener’s syndrome. The treatment of choice is usually a wide excision with negative margins, if possible. But if you can’t achieve negative margins because there are vital structures in the area, then you ought to at least obtain the best margins you can and then the patient can either receive radiation therapy or, if the patient has a recurrence, they can then be re-resected and have radiation therapy. Then those who have further growth of tumor, you can treat them – there’s data for use with NSAID’s, with tamoxifen, low dose Velban with methotrexate or Adriamycin/DTIC. A recent article in your handout, for those patients who get into problems with neurotoxicity with Velban, you can substitute vinorelbine, Navelbine. That’s a recent article that came out in the American Journal of Clinical Oncology that’s in your handout.
Leiomyosarcomas, GI stromal, have an extremely poor response to chemo. I don’t know what to do for those. You need, if possible, to get them to a surgeon who does a lot of these the first time so that the tumor can be fully resected. Because if the tumor is not fully resected and the patient has positive margins, they are going to do extremely poorly. Those patients with uterine or extremity leiomyosarcomas, you may consider using Adriamycin/ifosfamide or specifically for the uterine sarcomas, continuous infusion DTIC at a dose of about 300 mg per meter squared over approximately seven days. Myxoid liposarcomas; you need to be aware that these have a very high incidence of extrapulmonary metastases and that for this specific sarcoma, soft tissue sarcoma, in addition to getting chest CT’s you need to get abdominal CT’s because they can have occurrences in the retroperitoneal area and other areas.

Clear cell sarcoma behaves more like a melanoma and is HB-45 positive, so they should be treated like a melanoma. Breast sarcomas; the treatment of choice is doing a total mastectomy, no axillary node dissection, because the incidence of lymph node metastasis is extremely rare.

So to review here, for soft tissue sarcomas, incisional or core biopsy. If you are at an institution that can do these, I would recommend core. To do a resection, wide if possible with at least 1-2 cm margins at minimum. Postoperative radiation therapy most of the time if the margins are not good, but there may be some patients now who don’t require postoperative radiation. That will depend on the location, grade, size, and margin status. Consider preoperative radiation for a very large tumor mass or possibly neoadjuvant chemo. Metastasectomy is beneficial in a select group of patients. In terms of chemotherapy, either the Adriamycin/ifosfamide regimen or MAID plus growth factors. There is an increased response rate but no survival advantage. If you are just palliating and it’s an elderly patient, just Adriamycin alone or Adriamycin plus DTIC, probably given as a continuous infusion where you are going to reduce cardiotoxicity and probably nausea and vomiting. Adjuvant therapy is unproven for soft tissue, except maybe for extremity, for large, deep, high grade extremity lesions. And neoadjuvant induction chemotherapy is now being looked at but certainly isn’t standard. We do it at our institution, but I would probably refer a patient into a center for that, if it’s a very large lesion that needs to be down-staged prior to surgery.