Meet the Herpes Family, Warts and All

Herpes is a family of many different viruses, literally dozens of them, but only 9 of them are of importance in humans. Perhaps the most widely known members are Herpes Simplex types 1 and 2;  Epstein-Barr virus (EBV), which can cause infectious mononucleosis (“glandular fever”); Cytomegalovirus (CMV) which infects between 50% and 85% of adults in the United States by 40 years of age, and Varicella Zoster virus (VZV) which causes chicken pox — as well as shinglesHuman Papillomavirus (HPV) causes warts (including genital warts) and some varieties of HPV cause cervical cancer in women.

I have written before about EBV and CMV.  This article will focus on HPV - and its potential connection to secondary cancers in CLL patients.

Human Papillomavirus (HPV)

There are many varieties of HPVs. As a group, they can infect the skin and mucous membranes, causing different varieties of warts. Infection is often through direct contact but it is also possible to get  infected by touching a surface that is contaminated with the virus. It is also thought to be possible for a person to infect themselves, spread the virus from one location to another by touching.

Genital infection (leading to genital warts) is caused most often through sexual contact. In the last few years there has been breath-taking progress in our understanding and preventing majority of cervical cancers in women. Turns out some varieties of HPV are responsible for a large percentage of cervical cancers, and we now have a vaccine that can prevent infection. How cool is that! I do not know about you, but if I had a young daughter about to explore her sexuality, I would make sure she is protected from potentially deadly cervical cancer down the road due to HPV infection.

As with all members of the herpes family, once an individual is infected, traces of  HPV stay in the person’s body for the rest of his / her life. In healthy individuals the virus is kept under check by an active immune system. We know by now that CLL patients are very likely to be immune compromised, especially if they are late stage CLL patients or they have been through immune suppressing chemotherapy. T-cells are frontline troops for keeping pesky viruses under control. Drugs such as Campath and fludarabine cause massive reduction in T-cells counts and their efficacy, allowing viruses to use the window of opportunity and grow unchecked.

On a personal note, my husband PC had beautiful hands - well shaped with long, artistic fingers. Several years after his CLL diagnosis, I noticed he had these flesh colored bumps on the back of his knuckles. I had no idea what they were. Our dermatologist later told us they were common warts, caused by HPV. The picture alongside is what it looked like, more or less. If you don’t mind getting scared or grossed out, just type the word “warts” into Google and look for images.

Among the drugs used to treat genital warts are anti-viral drugs such as famcyclovir (“Famvir”) and imiquimod (“Aldara”). You should be familiar with both of these drugs by now. Famcyclovir (and its kissing cousins valacyclovir and acyclovir) are highly recommended as prophylactic medications to prevent a bad case of shingles (caused by Varicella Zoster virus) in at-risk CLL patients undergoing immune suppressive therapy. In addition to treating aktinic keratosis (pre-skin cancer), Aldara is also FDA approved for treating warts, the genital variety. PC was already taking daily Famvir. I bugged the doctor until we got a prescription for imiquimod (not a cheap drug by any stretch of the imagination!) and made sure PC put a tiny dab of the ointment on his knuckles. Over time, I was relieved to see the warts faded away.

HPV and Secondary Cancers

Below is the abstract of a very recent article from Ohio State University that makes a connection between HPV infection and secondary cancers (especially skin cancers) in CLL patients. Send me a personal email if you need help locating the full text of this article.

Br J Haematol. 2010 Mar 8.

Second malignancies in B-cell chronic lymphocytic leukaemia: possible association with human papilloma virus.

Flynn JM, Andritsos L, Lucas D, Byrd JC.

Division of Haematology and Oncology, The Ohio State University Medical Center, Columbus, OH, USA.

Second primary malignancies have long been associated with chronic lymphocytic leukaemia (CLL). We assessed secondary tumour samples from CLL and control patients for the presence of human papilloma virus (HPV). 132 CLL patients with 44 second malignancies were compared to a matched randomly-identified control population of 264 non-CLL patients with 54 solid malignancies. Polymerase chain reaction was performed with the highly conserved MY09/MY11 HPV primer. None of control samples were HPV-positive, while 53% of samples from the CLL group were positive. This report describes preliminary evidence for the presence of HPV in secondary malignancies, in patients with CLL.

PMID: 20230400

In this study a total of 132 patients with CLL were examined, compared to an age, gender and ethnicity matched population of randomly chosen control population. 44 out of the 132 CLL patients (33%) developed secondary cancers. This is consistent with many other studies done in more recent times. But I have to admit, the 33% number caught me by surprise as well.

The authors point out that CLL patients have poor immune function, similar to patients who have been through organ transplant and treated with immunosuppressive drugs to prevent graft rejection. Organ transplant patients are also more prone to development of secondary cancers while they are on immune suppression drugs. This is particularly true for squamous cell carcinoma of the skin, which occurs much more frequently in CLL patients as well as solid organ transplant patients.

Now for the interesting part: human papilloma virus (HPV) has been associated with skin cancers in solid organ transplants than in otherwise healthy patients diagnosed with squamous cell carcinoma of the skin. Can the same thing be happening in CLL patients as well? Are our guys more likely to get skin cancer because their immune compromised state allows HPV to flourish unchecked? This is an important question because if we know the root cause of the increased incidence of secondary cancers, we can hope to do something about it.

There were 9 cases (7%) of localized skin cancer in the CLL patient group. A similar percentage of skin cancer patients were identified in the control group as well. Five of the skin biopsies of CLL patients with skin cancer were also positive for local HPV infection, while none of the control group had skin cancer that was HPV positive. The difference between CLL and normal control patients for HPV association with squamous cell carcinoma of the skin was highly statistically significant.

By the way, there were also two prostate cancers and one colon cancer as secondary cancers in the CLL patient group that also tested positive for HPV. So, it seems the risk of HPV driven secondary cancers in CLL patients is not restricted to just the skin. Remember, HPV is capable of attacking all mucous membranes, not just skin. There are well over 120 different types of HPV capable of infecting people and their ability to cause ano-genital cancer, laryngeal papillomas, head and neck cancers, carcinoma of the uterine cervix etc has been well documented.

Studies looking at kidney transplant patients have shown that up to 79% of viral warts, 42% of premalignant keratoses, and 43% of invasive squamous cell carcinoma contain tell-tale signs of HPV infection. Many of our guys are in the same boat as these kidney transplant patients, with similar or even worse levels of immune suppression.

For  now, here are some thoughts buzzing around my head after reading this article, ideas I would like to bring to your attention:

  1. Many thousands of patients with genital lesions and even “cold sores” have been on daily Valtrex, Famvir etc for many years now, to control of these viraly driven lesions. These drugs have a long track record of safety and efficacy.
  2. Should “at-risk” CLL patients be on these medications as well, to prevent shingles and herpes simplex inspired sores on lips and genetalia?  Perhaps protect against HPV driven secondary cancers?  There is no evidence that  Valtrex and its kindred are active against HPV.  I am just asking…
  3. It is interesting that imiquimod (Aldara) is FDA approved for actinic keratosis (pre-skin cancer) as well as HPV driven genital warts. Hmmm. A drug that is good for HPV driven warts as well as skin cancer.  Makes you think.  Like, you know, the same thing that is causing the warts is also likely to cause skin cancer - and what is sauce for the goose is sauce for the gander as well?
  4. As the authors of this study point out, immune modulating drugs (drugs that modify how the immune system works, not just deaden it as do many conventional chemotherapy drugs) may become more important in preventing deep immune suppression and therefore increased risk of secondary cancers. I was not an early fan of Revlimid - but I am really beginning to change my mind about this immune modulating drug. I especially like it that T-cell and NK cell function is thought to be improved due to Revlimid therapy.
  5. As most of you are aware, there is already a vaccine that protects young women against majority of cervical cancers driven by HPV. Hopefully researchers will continue to develop vaccines against other forms of HPV that trigger secondary cancers in immune compromised folks like CLL patients.
  6. Here is a quote from a recent article in Scientific American:
    Researchers have for the first time shown that as many as 1.3 million cases of cancer a year may one day be successfully treated or even prevented by targeting and destroying the viruses that cause them” 
  7. In the mean time, do sit up and notice if you develop warts on your hands, soles of your feet etc. Make sure your dermatologist gets told about it.  Look up “warts” on Google images so you know what they look like, more or less.

How much of an impact do second cancers have on overall survival?  How many patients die from the second cancer triggered by CLL, even if they get a ‘pass’ from the CLL itself?  That, my friends, is the subject of my next article.  Writing this article has been a nice diversion from the chore of packing. I am surrounded by dozens of half-filled packing boxes and mounds of paper that needs to get shredded. Out of chaos comes order, I tell myself., and it is time I got back to restoring order in my chaotic  home and life.