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CTOS Op Ed: Questions, Comments & Counterpoint

Point & Counterpoint regarding the Leiomyosarcoma of the Uterus: A Review article

We received two letters regarding the article, Leiomyosarcoma of the Uterus: A Review, by Drs. Ghosh, Hecht, Ferzandi and Awtrey that appeared in the last issue of ESUN. The first letter, was received from Dr. Ian Judson of Royal Marsden Hospital, London, and reads:

Dear Bruce,

I should like to respond to one issue in the review on uterine leiomyosarcoma, in which it is stated that these tumours are unresponsive to oestrogen.

To the authors: This is an excellent and comprehensive review of a highly aggressive sarcoma and it is important that awareness be drawn to this disease entity. However, I would caution against the blanket statement that ULMS is unresponsive to oestrogen. I know of cases of ULMS that express oestrogen and progesterone receptors and have responded to oestrogen withdrawal measures. It has been assumed that this phenomenon is restricted to low grade endometrial stromal sarcoma. This appears not to be the case and there are grounds for believing that pathologists should examine all ULMS cases for ER and PgR expression.

with best wishes

Prof Ian Judson

Sarcoma Unit

Royal Marsden Hospital, London

The second letter was received from Shirley Collings, a leiomyosarcoma survivor who lives in the UK. It reads:

Dear Bruce and ULMS survivors

First of all may I refresh your memories about the article in the ESUN Apr 07 on Uterine Leiomyosarcomas

http://www.liddyshriversarcomainitiative.org/Newsletters/V04N02/ULMS/ULMS.htm

In particular the three following extracts:

"Benign leiomyomas (fibroids) and ULMS often coexist in the same uterus, but are genetically distinct entities. ULMS are much less common and not hormonally driven. "

"Fibroids rarely, if ever, degenerate into ULMS (12)."

"Certain uterine tumors are responsive to hormonal therapy because they express estrogen and/or progesterone receptors. However, this is not the case in ULMS and adjuvant hormonal therapy is not recommended for any stage of ULMS."

[My underscoring - Shirley]

I am sure I speak for a number of women on this and the Sarcoma UK lists, who disagree vehemently with these three statements. Through personal experience with diagnoses from fibroids, ER/PR positivity and subsequent treatment with aromatase inhibitors many of us can prove these statements wrong. I am shocked and disappointed that four such eminent doctors can attach their names publicly to these misleading statements in an otherwise very interesting article.

Bruce, would you kindly contact Drs Gosh, Hecht, Ferzandi and Awtry and ask them if they would be willing to respond to and comment on this email in the next edition of ESUN.

Shirley Collings, UK

Here is the authors' reply to these two notes:

We thank the Dr. Ian Judson for his thoughts and Mrs. Collings for her passionate comments and offer further data from the literature to clarify the issues raised.

The distinction between benign leiomyomata (fibroids) and smooth muscle sarcomas in the uterus is clear. (1) The genetic changes in sarcomas are more complex than in fibroids [many references over 20 years, available on request]. Interestingly, the specific genetic aberration detected may vary from cell to cell suggesting a high level of genomic instability. This instability can also be detected by techniques that measure allelic imbalance such as comparative genomic hybridization, and is not present in benign fibroids. (2) Some changes are unique to sarcomas such as a heterozygosity for the long arms of chromosomes 10 and 13 that is found in more than half of sarcomas.

Although hormone manipulation with agents such as leuprolide (a gonadotropin-releasing hormone –GnRH agonist) or aromatase inhibitors (an agent that reduces circulating estrogen) have a clear role in treatment of benign leiomyoma, the response of sarcomas is highly variable, and is not part of the primary therapy offered to women with sarcoma [treatment recommendations for sarcoma based on stage are available at the NCI website].

We could not find publications describing even anecdotal experiences with anti-estrogens for treatment of leiomyosarcoma. We suspect that such options are used when conventional therapy fails. There is no evidence that hormone receptor status correlates with response and those stains are not routinely performed. Rare reponses to antiprogestins has been reported. [Koivisto-Korander R, Leminen A, Heikinheimo O. Mifepristone as treatment of recurrent progesterone receptor-positive uterine leiomyosarcoma. Obstet Gynecol. 2007;109:512-4.]

Many cases of leiomyosarcoma express hormone receptors and the association between hormone receptor expression and sarcoma growth has been examined. The largest study has com from Memorial Sloan-Kettering Cancer Center. They show that the expression of estrogen and progestin receptor was less frequent in uterine sarcoma compared with leiomyoma. Progesterone and androgen receptor expression appeared to be associated with disease-free survival but were not found to correlate with overall survival. [Leitao MM, Soslow RA, Nonaka D, Olshen AB, Aghajanian C, Sabbatini P, Dupont J, Hensley M, Sonoda Y, Barakat RR, Anderson S. Tissue microarray immunohistochemical expression of estrogen, progesterone, and androgen receptors in uterine leiomyomata and leiomyosarcoma. Cancer. 2004 Sep 15;101(6):1455-62.]

Another category of uterine sarcoma, uterine stromal sarcoma, may have some overlap in microscopic appearance and be confused with leiomyosarcoma. In addition, rare sarcomas have mixed differentiation (smooth muscle and stromal). Stromal sarcomas are more likely to express progesterone receptors and progesterone therapy may have some role in treating recurrent stromal sarcomas. [Katz L, Merino MJ, Sakamoto H, et al.: Endometrial stromal sarcoma: a clinicopathologic study of 11 cases with determination of estrogen and progestin receptor levels in three tumors. Gynecol Oncol 26 (1): 87-97, 1987.]

Given the importance of this issue, I elected to give Dr. Judson an opportunity to respond to the authors' reply, with the proviso that they would get one last opportunity to reply. Dr. Judson's response follows:

Thank you for giving me the opportunity to respond to the comments both of Mrs Collings and the authors of the review on uterine sarcomas.

Over the last 20 years there has been a gradual change in the approach to the hormonal manipulation of gynecological sarcomas. Progestogens have been used for more than 25 years, to my knowledge, in the management of the rare condition of metastasising leiomyoma, which is really low grade leiomyosarcoma. I first met a patient with the disease who had responded to medroxyprogesterone acetate (MPA) in 1983. She required pulmonary metastasectomy in the 1990s for progressive disease that was no longer responding but remains alive and well. I have other patients with the same condition whose disease fluctuates but remains essentially stable. We recently saw a case of grade I leiomyosarcoma of the vulva that had grown dramatically during pregnancy. Such lesions are acknowledged to be hormonally driven. We know that leiomyosarcomas represent a broad spectrum of malignancy from STUMP to high grade disease. It is assumed that hormonal dependence is lost with increasing grade. While there is no literature on the treatment of frankly malignant leiomyosarcoma with estrogen deprivation therapy, clearly in some cases it can be effective. What is particularly important is that doctors and patients alike should be aware of the potentially detrimental effect of hormone replacement therapy (HRT), suggesting that it might be helpful to know the ER/PgR status of all such tumours.

As acknowledged in the article, the position regarding endometrial stromal sarcoma (ESS) is clearer, although the literature is still sparse. Progestogens used to be the mainstay of hormonal therapy for these tumours. Since the advent of potent aromatase inhibitors it is much more logical, as well as highly effective, to use these agents that are better tolerated and provide a reliable way of reducing oestrogen levels in the menopausal / post-oophorectomy state. A brief review of our own experience of treating metastatic endometrial stromal sarcoma reveals 4 patients with response / prolonged stable disease on MPA, ranging from 4-10 years, 3 patients responding to withdrawal of HRT or oophorectomy lasting 18+months, 3 and 6 years respectively and 6 patients responding to an aromatase inhibitor (usually letrozole) of 1-5 years in duration. Recurrent well-differentiated ESS that expresses ER and PgR can be expected to respond to withdrawal of HRT (which should not be given in the first place), oophorectomy if this has not been performed, or administration of an aromatase inhibitor with a high degree of confidence. Tamoxifen should not be used since it is pro-estrogenic in the uterus and I have seen exacerbation of the disease with this agent.

It would appear that further research is required to address the true response rate of ESS to aromatase inhibitors and to examine their potential role in the treatment of a proportion of less agressive uterine leiomyosarcomas.

Ian Judson

Sarcoma Unit

Royal Marsden Hospital

And, finally, here is the authors' closing reply:

We appreciate the depth and insight of Dr. Judson's comments. As Dr Judson mentioned, the literature on this issue is sparse. In this review, we have attempted to outline guidelines for evidence-based standard of care for uterine LMS. We do recognize that in individual cases and case-series, there has been reponse to hormonal therapy, dependent on grade. Although in rare circumstances that the therapy may be indicated, until sufficient data exists, we were careful not to project this as routine treatment. However, the physician has a duty to serve his/her patients with the data available and that the patient must be given full informed consent thereof.

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