CLL Complications el pt

Are You Dying to Get a Tan?

Date: March 26, 2024

by Chaya Venkat

Squamous Cell Carcinoma

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Best Practices

Squamous cell carcinoma (SCC) is the second most common skin cancer after basal cell carcinoma. In situ SCC is also known as "Bowen's disease". It typically occurs on sun-exposed areas of the body such as face, neck, the top of your no longer as luxuriantly endowed head, arms, etc. It is more common in light-skinned men, and seems to be more common in people older than 55 years. There is a correlation to the amount of UV present in sunlight, and therefore the  incidence of SCC increases as one gets closer to the Equator, all other things being constant. Some risk factors are a family history of skin cancer, smoking, old burn scars, immunosuppression because of chemotherapy or radiation therapy or AIDS, exposure to UV for long periods and chemical carcinogens.

If you have CLL, you are at a much higher risk of getting SCC too.

There is clear and unambiguous correlation between CLL and skin cancer, especially squamous cell carcinoma. Below is a table based on an ambitious study from Sweden and Denmark. 17,400 CLL patients were registered in this study, and incidence of SCC and malignant melanoma was recorded in this group.  As you can see, the actual rate of SCC in the CLL patient group was 120 cases, while the expected rate for the same size population without CLL is about 14. The break down by sex shows that male CLL patients are almost ten times as likely to have SCC than the general population (96 versus 9.8), the stats are a little less alarming for women, the relative risk is "only" six fold. While this study is based on very fair-skinned populations who are at more risk of skin cancer, do remember that the comparison is between Nordic people with CLL versus Nordic people without CLL. This is a huge risk factor, and I am deeply concerned that more oncologists do not read the  riot act to their CLL patients about UV exposure.

I guess after looking at the relative risk multiples close to double digits for squamous cell carcinoma, it is a relief to see that the relative risk of getting malignant melanoma on top of CLL is a mere three-fold higher!

 

Risk of skin cancers after an initial diagnosis of CLL (Denmark and Sweden, 1943-89)
Link: BMJ Journal Article

Cohort	Squamous Cell Carcinoma			Malignant Melanoma
	Observed	Expected	Relative Risk	Observed	Expected	Relative Risk
Overall	120	13.9	8.6	34	10.9	3.1
Men	96	9.8	9.9	22	6.4	3.4
Women	24	4.1	5.9	12	4.5	2.7

Why should we worry about SCC, it is easy to treat, right?

Wrong!

True, in otherwise healthy people SCC tends to remain localized and easy enough to treat. But aggressive forms of SCC can occasionally spread to other sites of the body. And when it does decide to metastasize, it generally does so through the lymphatic system. Aggressive forms of SCC are a lot harder to treat, and they can be a lot more dangerous. The abstract below from the Royal Marsden Hospital is dated 1996, and its message is quite clear. When SCC occurs in CLL patients, and the Swedish study above makes it abundantly clear that it is almost 10 times more likely to occur in CLL patients, it is likely to be much more aggressive and dangerous. 

My husband was diagnosed with CLL in 2024. Quite a few years after the Swedish report was published and 5 years after the Royal Marsden Hospital alarm was sounded. At the time of his diagnosis, we talked to our CLL Research Consortium expert who confirmed the diagnosis. We asked him what my husband should be doing by way of life style changes to maximize his chances of staying healthy. Our expert thought for a moment, and said PC should stay well hydrated. Good advice, as far as it goes – staying well hydrated is one way of protecting your kidneys and liver. But the expert did not say one word of warning about skin cancer or about lifestyle changes to minimize UV exposure. I have no doubt our story is not unique, that the majority of you have never been warned by your local oncologists or even CLL experts about the specific risk of squamous cell carcinoma. In fact, one more reason why I am delighted with the "Best Practices" list from Mayo Clinic. It sounds a clear and unambiguous warning to protect yourself from this malignancy risk.

Abstract:

Laryngol Otol. 1996 Jul;110(7):694-5. 

Aggressive cutaneous squamous cell carcinoma of the head and neck in patients with chronic lymphocytic leukaemia.

Hartley BE, Searle AE, Breach NM, Rhys-Evans PH, Henk JM.

Head and Neck Unit, Royal Marsden Hospital, London, UK.

We describe multiple cutaneous squamous cell carcinomas of the head and neck in five patients with chronic lymphocytic leukaemia (CLL). When associated with CLL, cutaneous squamous cell carcinomata behave in a much more aggressive manner than otherwise expected. Four patients developed local recurrence after primary treatment. All five patients developed lymph node metastases containing squamous cell carcinoma. Three of five patients (60 per cent) had multiple primary lesions. Whereas the increased incidence of second cancers in CLL and notably of skin cancers is documented, little has been written to describe the aggressive behaviour of these tumours. It is important, when treating these patients, to be aware of the high tendency towards local recurrence and lymph node metastasis and to consider an aggressive management plan and careful follow-up.

PMID: 8759553
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What Makes CLL Patients Such Easy Targets for Aggressive SCC?

CLL patients are not the only group singled out, patients who have gone through solid organ transplants, AIDs patients, patients with other types of cancers who have gone through immune suppressive chemotherapy, all of these folks are at increased risk. The reason is quite simple. CLL patients (and some of the other risk groups above) have damaged immune systems. We are quick to jump to the conclusion that since we are talking about B-cell CLL, only the B-cells are compromised. Not so. As we discussed in previous articles (Killer T-cells and the Risks of CTL Therapy), there is a great deal of cross-talk between the B-cell and T-cell lines: these two arms of the immune system work hand in glove with each other. A heavy load of damaged and screwed up B-cells, as in the case of CLL patients, takes its toll on the proper functioning of the T-cells as well. Much of the autoimmune disease seen in CLL patients is due to improper functioning of T-cells. When the immune system cells can no longer make the fine distinctions necessary to decide when to attack and what to attack, one side of the coin is autoimmune disease in which perfectly good and innocent cells of the body are attacked. The other side of the coin is when damaged and potentially malignant cells are not attacked and killed. Since the first line of defense in keeping squamous cell carcinoma contained is T-cells, it is easy to see why defects in T-cell function allows SCC to grow, metastasize and become a killer. 

It is not just the CLL that makes for a poorly functioning immune system, just about all the therapies associated with CLL also do a number on its proper functioning. The abstract below specifically cites fludarabine and 2-chlorodeoxyadenosine, but we can add just about all the standard chemotherapy drugs we are familiar with, including corticosteroids like prednisone and dexamethasone. Monoclonal antibody drugs are not exempt either. As we have seen in recent articles on Campath ("Campath Looking Better and Better"), this very important CLL drug is justly famous for wiping out all of your B-cells as well as T-cells, not to mention precipitating neutropenia in a large percent of patients using this drug. No one would dream of administering Campath these days without protective pre-medications to prevent opportunistic viral, fungal and bacterial infections. But how about skin cancer? How many Campath patients are warned to be extra vigilant to protect themselves from UV exposure? Are there preventive measures one can take to decrease the odds of a flare up of squamous cell carcinoma?

Abstracts:

Clin Lab Haematol. 1999 Jun;21(3):187-91. 

Impaired T-lymphocyte function in B-chronic lymphocytic leukaemia as measured by the local xenogeneic graft-versus-host reaction.

Stark P, Shohat B, Kadosh S, Shaklai M.

Institute of Hematology, Tel Aviv University, Israel.

The immunological dysfunction observed in B-chronic lymphocytic leukaemia (B-CLL) is often related to T-lymphocyte incompetence. The local xenogeneic graft-vs.-host reaction (XGVHR), an assay to evaluate T-lymphocyte function, was performed in 112 untreated B-CLL patients. The XGVHR results significantly correlated with clinical parameters: 37.1% of the patients in the stable phase (Rai stage 0-1-2) and only 13.3% of the patients in the progressive phase (Rai stage 3-4) had positive XGVHR results. Patients with negative results had a higher number and percentage of lymphocytes (25,247 vs. 17,071/microliter and 75.9% vs. 65.6%, respectively), much lower T/B lymphocyte ratio (0.37 vs. 0.93), higher WBC count (30,977 vs. 23,458/microliter), lower platelet count (158,068 vs. 181,684/microliter) and lower levels of IgA and IgM (115.6 vs. 200.5 mg/dl and 80.4 vs. 124.3 mg/dl, respectively) compared to those with positive results. Among those with negative XGVHR results, a higher mortality rate was found in those who had infections compared with those who did not (73.7% vs. 9.1%). In conclusion, the XGVHR assay significantly correlates with important characteristics of B-CLL and may be useful in the clinical evaluation of B-CLL patients.

PMID: 10448600
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Am J Hematol. 2024 May;70(1):48-50.

Aggressive growth of epithelial carcinomas following treatment with nucleoside analogues.

Larsen CR, Hansen PB, Clausen NT.

Department of Internal Medicine F, Section of Hematology and Oncology, Hillerod Hospital, Hillerod, Denmark.

Two patients, one with B-cell chronic lymphocytic leukemia (CLL) and one with hairy-cell leukemia (HCL), were treated with immunosuppressive chemotherapy. The patient with CLL was a 54-year-old female, who had had a squamous cell carcinoma (SCC) excised from her forehead 5 months before receiving the first course of fludarabine. During the fludarabine treatment, the patient developed a local SCC relapse and metastases in the neck. The carcinoma was treated by excision and radiotherapy, and further fludarabine treatment was withheld. Nevertheless, the SCC metastasized aggressively and the patient died 3 months after the start of fludarabine treatment, primarily due to respiratory failure. The autopsy revealed heavy SCC infiltrations involving the lungs, pleura, mediastinum, pericardium, and liver. The patient with HCL was a 69-year-old male. At the time of diagnosis of HCL, the patient had two solid tumors in the liver containing poorly differentiated epithelial carcinoma cells of unknown origin. During treatment with 2-chlorodeoxyadenosine (2CdA), the tumors in the liver rapidly spread in multiple intrahepatic metastases, followed by liver failure and death within 1 month. Fludarabine and 2CdA cause a substantial suppression of all lymphocyte subsets, in particular the T-cell line. T-lymphocytes are believed to be responsible for the usually slow growth and the low metastatic rate of the SCC skin lesions. It is therefore assumed that fludarabine and 2CdA in these two cases triggered an exacerbation of both tumors due to the T-cell depletion.

Copyright 2024 Wiley-Liss, Inc.

PMID: 11994981
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Acta Haematol. 1997;98(1):44-6. 

Flare-up of squamous cell carcinoma of the skin following fludarabine therapy for chronic lymphocytic leukemia.

Davidovitz Y, Ballin A, Meytes D.

Department of Hematology, E. Wolfson Medical Center, Holon, Israel.

We present a 72-year-old patient with chronic lymphocytic leukemia (CLL). About a year following therapy with chlorambucil and prednisone, he suffered from anemia, thrombocytopenia and organomegaly. The patient received fludarabine with a favorable response. Concomitantly with the clinical improvement of the CLL there was a remarkable flare-up of scalp squamous cell carcinoma (SCC) lesions, initially noted 4 years previously. The lesions were multiple and grew rapidly. Fludarabine depresses the T lymphocyte population, cells that play a pivotal role in the regression of the SCC. We suggest, that the flare-up and exacerbation of the SCC lesions of the patient were triggered by the fludarabine therapy.

PMID: 9210914
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Some Simple Things You Can Do To Reduce Your Risk of SCC:

Back when I used to work for a living, my boss used to say  "Don't ever come into my office to tell me there is a problem, not unless you also have a recommendation on how to fix it".  Well, I am not sure I know how to fix SCC — that is way beyond my layperson reporter's abilities. But I think we can come up with a simple and sensible list of do's and don'ts, a list that most of us will recognize as sensible:

• Forget about that sexy dark tan, stay out of the sun especially during the mid-day periods when the UV is sleeting down at its worst.  Most people who live in the tropical regions of the world find it hard to understand why fair skinned people like to lay around in the sun. Back in India there was a saying that we heard as kids, "only mad dogs and Englishmen go out in the mid-day sun".  Remember, you are not a mad dog.
• Wear sun screen protection, preferably a high SPF value variety. Make it a daily part of your grooming before venturing out.
• Wear long sleeved shirts and blouses, long pants, and get into the habit of wearing a hat. Make a fashion statement, be outrageous in your choice of hats (PC wears this Aussie hat that has become his trademark. People in town are so used to seeing him with it that they comment when he forgets it in the car).
• This last one is important, in addition to checking yourself all over in the bathroom mirror, make sure you get professional checkup with a competent dermatologist on a regular basis. If you have already had an incidence of SCC, you should be doubly cautious on all these fronts.

Some Things to Discuss with Your Doctor:

The short list above is pretty sensible stuff that you can implement yourself.  Below are some items you should discuss with your doctor before you act upon them.  Did you know that sulindac (like its better known counterpart aspirin, sulindac is also an NSAID) is a COX inhibitor too, and has shown interesting results as a protective agent in SCC? The first abstract below discusses a topical cream of 5% imiquimod and 200 mg of sulindac tablets twice a day as a therapy for SCC specifically in CLL patients. But do be aware that, like aspirin, sulindac also may irritate and damage the lining of your stomach. Something to think about and discuss seriously with your doctor, if you are prone to ulcers, have low platelets or other bleeding problems.

Abstract:

Dermatol Surg. 2024 Feb;27(2):143-6.  

Bowen's disease (squamous cell carcinoma in situ) in immunosuppressed patients treated with imiquimod 5% cream and a cox inhibitor, sulindac: potential applications for this combination of immunotherapy.

Smith KJ, Germain M, Skelton H.

Department of Dermatology and Pathology, National Naval Medical Center, Bethesda, Maryland 20249-5600

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) often have a protracted course. However, all these patients are immunosuppressed and may have a high incidence of cutaneous malignancies.
OBJECTIVE: To determine if combination therapy using topical imiquimod cream 5% and the oral cyclooxygenase (COX) inhibitor are useful in the therapy of squamous cell carcinoma in situ (SCC in situ)/Bowen's disease in patients with long-standing CLL.
METHODS: Five CLL patients with head and neck cutaneous SCC in situ, which met criteria for Bowen's disease, were treated with topical 5% topical imiquimod cream and an oral COX inhibitor, sulindac 200 mg twice a day.
RESULTS: All patients showed clinical resolution and histologic clearing of the tumors after 16 weeks of therapy.
CONCLUSION: The local immune modulator, 5% imiquimod, in combination with a COX inhibitor, with its many potential antitumor effects may stimulate the innate and possibly the adaptive immune responses to clear these malignancies.

PMID: 11207687
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If instead of pills and drugs, chemoprevention is more your style, below is an interesting article from Tucson, AZ, where they know a thing or two about high intensity sunshine. It is interesting that two of the compounds they are talking about, EGCG (from green tea extracts) and limonene (from lemon / orange peel oil) are natural compounds we have discussed before. The second abstract below talks about "Solaraze", a topical gel that has just been approved by the FDA for "Actinic Keratoses". AK can be thought of as a pre-skin cancer lesion, and it is much easier to treat at this stage than when it becomes full fledged SCC or some other form of skin cancer. AK has been shown to be treated effectively by topical application of a gel containing small amount of diclofenac, another NSAID. Solaraze can be purchased by getting a prescription for it from your doctor.

Abstracts:

Eur J Cancer. 2024 Jun;36(10):1292-7.

The state-of-the-art in chemoprevention of skin cancer.

Stratton SP, Dorr RT, Alberts DS.

Arizona Cancer Center, College of Medicine, University of Arizona, Tucson, AZ 85724

The incidence of skin cancer (both melanoma and non-melanoma) continues to grow at an alarming rate. Our chemoprevention strategies include the development of novel agents evaluated by (1) preclinical mechanistic studies in models of ultraviolet (UV) radiation-induced skin carcinogenesis; (2) clinical studies of immunohistochemical surrogate endpoint biomarkers in high-risk patients; and (3) randomised, placebo-controlled phase I, II and III clinical chemoprevention trials. Recent clinical results validate this development model. Molecular targets of chemopreventive strategies for melanoma and non-melanoma skin cancers include the ras and activator protein-1 (AP-1) signal transduction pathways. A transgenic murine melanoma model has been developed for evaluating potential agents in vivo. Agents at various stages of study include the green tea catechin epigallocatechin gallate (EGCG), the limonene derivative perillyl alcohol, the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO), selenium, retinoids and salicylates. New chemopreventive agents that can be used to complement sunscreens may result in decreased incidence, morbidity and mortality of skin cancer.

PMID: 10882869
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Skin Therapy Lett. 2024 Jan;9(1):1-3.

Topical 3% diclofenac in 2.5% hyaluronan gel for the treatment of actinic keratoses.

Rivers JK.

Division of Dermatology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

Actinic Keratoses (AKs) are epidermal skin lesions that have the potential to develop into squamous cell carcinoma. Many of the treatment options available can cause discomfort, pain or skin irritation. Topical 3% diclofenac in 2.5% hyaluronan gel (Solaraze, Bioglan Pharma) is a relatively new treatment that has been shown to be effective and well tolerated for the treatment of AKs.

PMID: 14716439
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