Testosterone Replacement Therapy & Risk of Prostate Cancer

Hormone sensitive metastatic prostate cancer is treated with androgen deprivation therapy, typically with gonadotropin releasing hormone analogues, which essentially turn off the pituitary release of luteinizing hormone through sustained stimulation (as opposed to pulsatile release, which is physiological). This results in chemical castration.

The issue assumes relevance when you consider the practice of testosterone replacement therapy (TRT). In recent years, TRT has become popular among primary care physicians, as a sort of panacea for fatigue, lassitude and muscle wasting, particularly in elderly subjects. The FDA recently mandated that preparations for TRT explicitly carry a warning against a higher risk of myocardial infarction and stroke in users. Nevertheless, a subset of subjects with low serum testosterone genuinely benefit from TRT, particularly when associated with diminished libido, or loss of morning or nocturnal erection despite being otherwise healthy, a condition known as adult onset hypogonadism. Such subjects have low total and free serum testosterone and normal LH levels.

When such subjects are elderly, as they often are, it is logical to ask whether such TRT increases the risk of causing hormone sensitive cancers in the future. In fact, TRT can increase the likelihood of developing breast cancer in those who have another risk factor such as BRCA1 or 2 or Cowden's syndrome. However, such cancers are very uncommon. A much more relevant concern is whether TRT stores up a future risk of prostate cancer.

In a disease which, when metastasised, is treated with surgical, or more commonly, chemical castration, it therefore came as a surprise to learn from RCTs that firstly, low testosterone levels were associated with a higher risk of prostate cancer. Secondly, subjects with adult onset hypogonadism had more advanced prostate cancer at diagnosis by stage, grade and volume. Thirdly, TRT was not associated with a higher risk of prostate cancer in any RCT.

Reference

Mayo Clinic Proceedings, Vol. 91, Issue 7, p908–926

Right Colectomy in Mucocoele of the Appendix to Prevent Pseudomyxoma Peritonei

Appendiceal mucocoele is most often caused by benign mucinous cystadenoma, and less commonly by mucinous adenocarcinoma. The commonest malignant tumour of the appendix used to be carcinoid. This is now changing, as mucinous adenocarcinoma becomes more common.

When mucocoele of the appendix is diagnosed, usually incidentally during cross sectional imaging, it mandates appendicectomy. Untreated, appendiceal mucocoeles can rupture, leading to pseudomyxoma peritonei (PMP), an incurable condition.

PMP caused by rupture of mucocoele is also called Disseminated Peritoneal Adenomucinosis or DPAM. Most authorities only use the term PMP when the underlying aetiology is DPAM. However, others use the term PMP to desribe the dissemination of mucin producing cells from carcinomas of the appendix or colon. The distinction is important, because the latter has a materially worse prognosis.

PMP has a striking appearance on imaging. On CT, mucin has the same appearance as water, but in addition, there is widespread calcification, scalloping of the liver and spleen, with a predominantly peripheral distribution of lesions.

PMP is difficult to treat. Repeated cytoreductive surgery (CRT) is required. An approach that is gaining in popularity among surgeons is cytoreductive surgery followed by Heated Intraperitoneal Chemotherapy or HIPEC. The latter involves intraoperative infusion of dialysis fluid containing mitomycin C, heated to 41 degree Celsius to increase penetration of tumour deposits. However, even with heating, the chemotherapeutic agent is unable to penetrate beyond a couple of millimeters.

Pioneering work in this area has been done by Sugarbaker & colleagues. They found that pre-operatively, the prognosis was worse when there was segmental obstruction of the jejunum or proximal ileum or if the peritoneal deposits exceeded 5 mm in size.

When CRT with HIPEC is used, it is standard to follow through with postoperative intra-peritoneal fluorouracil.

Untreated. PMP is fatal as intraperitoneal mucin accumulates inexorably and causes intestinal obstruction. The most well known victim was Audrey Hepburn, who succumbed to this condition.

PMP is more common in women. In the article in JAMA Surgery referenced below, the tumour (mucinous cystadenoma) involved the base of the appendix. To avoid spilling mucin intra-operatively and thus cause PMP, resection margins must be clear. Thus, right colectomy was opted for rather than a simple appendicectomy.

This is an example of a benign tumour behaving like a malignant one.

(Free access is available to most articles in all JAMA group journals through a single registration giving access to the JAMA Network Reader. Thank you, the American Medical Association).

References.

1. http://learningradiology.com/notes/gunotes/pseudomyxomacorrect.htm
2. http://jamanetwork.com/journals/jamasurgery/article-abstract/2601315
3. UpToDate