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Pigmented Lesions on the Lid/Conjunctiva and Vasovagal Syncope
Lesley L. Walls, OD, MD
CASE ONE-PIGMENTED LESIONS
What follows are two patients who presented with similar pigmented lesions in and around they eye.
SUBJECTIVE: First Case
The first case is a fourth year female optometry student who “dropped by” my office to show me a newly discovered pigmented spot on the lower left eyelid. She stated that she is certain that the spot is new and that she only noticed it 3 weeks ago and she thinks it is bigger now. She is otherwise completely healthy and on no medications. She has had no skin problems in the past and has otherwise noticed no new pigmented lesions elsewhere.
OBJECTIVE: First Case
Examination grossly and via slit-lamp revealed a 1-2 mm pigmented lesion near the lateral lid canthus. Under magnification the lesion was observed to be mostly flat with “slight” elevation in one area. It was unevenly pigmented with and irregular border. See Figure 1.
SUBJECTIVE: Second Case
The second case is the grandchild of one of my best friends from college. He contacted me for a third opinion on a pigmented lesion on the eye of his 2-year-old granddaughter. The parents noticed the lesion about a month earlier and took the child to their pediatrician. The pediatrician referred them to an ophthalmologist who informed the parents that the lesion is “innocent”, just a freckle and for them not to be concerned about it. The parents and grandparent consulted me for a third opinion.
OBJECTIVE: Second Case
Pigmented lesion approximately 2 mm in size near the limbus of the left eye. Under magnification the lesion was observed to be flat, unevenly pigmented with and with an irregular border. A few “satellite” lesions were also observed. See Figure 2.
Both cases were referred to an ophthalmologist who worked well with optometry and both had excisional biopsies of the lesions.
Recall the ABCDE “Rule of Thumb” for evaluating pigmented lesions:
A = Asymmetry
B = Border Irregularity
C = Color Variation within the lesion
D = Diameter greater than ½ Centimeter (about the size of a pencil eraser) -- but keep in mind that malignant lesions start as a spec and then increase in size
E = Evolving, which means the lesion is changing in size (growing), color, bleeding, shape, etc. See Figure 3.
QUESTIONS TO ANSWER:
What is the most likely diagnosis in each of these cases? Why?
What is the recommended treatment in each case? Why?
What is the role of the optometrist now?
DETAILED DISCUSSION OF CASES AND NEOPLASIA
A. Cancer is the real fear here and of concern are all the other disorders that may lead to cancer. These are all usually discussed as Neoplasia and New Cell Growth.
B. Cancer itself is the #1 killer of the U.S. population and a large number of people in this room will ultimately die of this disease unless some miracle happens soon. About 1/2 million people in the U.S. die of cancer each year and millions are diagnosed and on treatment at any given time.
C. Neoplasia: Abnormal new cell growth which is not subject to normal regulation (uncoordinated) and is at the expense of the health of the rest of the body. Neoplasia is: Autonomous (uncontrolled by normal body growth factors), rapidly reproduces (lots faster than normal cells), and is parasitic (gets its nutrition when the rest of the body is suffering for nutrition).
Now, we will discuss three categories of new cell growth, namely, Hyperplasia, Metaplasia, and Dysplasia as a prelude to our more extensive discussion of Neoplasia (benign and malignant).
A. Definition: an absolute increase in the cell number in a tissue or organ which occurs in a CONTROLLED fashion. Obviously, the size of the organ or tissue will increase but is different from hypertrophy!
B. This can occur in stable or labile tissues but not in permanent cell parenchymal tissue. The cells are quite normal morphologically UNLESS there is some pathological reason for the hyperplasia and then there may be some very subtle changes such as a little more prominent nucleoli.
C. Physiologic Hyperplasia - A normal increase in the number of cells in a tissue or organ in response to a body change.
1. Hormonal - the breast or testicle at puberty, etc.
2. Compensatory - the remaining kidney after loss of companion kidney for any reason, skin in a friction area (callous), etc.
D. Pathologic Hyperplasia - Due to abnormal stimulation of the cells such as from exogenous hormones, e.g. male athletes abusing androgens, etc.
NOTE: Both physiologic and pathologic hyperplasia are reversible and controllable if the stimulus to the growth is removed. The concern is the "escape" to cancer if it is ongoing!
A. Definition: The adaptive substitution of one mature cell type for another mature cell type.
B. This is another form of adaptation (discussed earlier) to some form of stress on the cells of a tissue. The worry is when it is due to a stress that is known to have a relationship to causing cancer (carcinogenic) and the effect if not reversed or if prolonged.
C. Typical metaplasia: the cells substituted are "normal" in every way
D. Atypical metaplasia: The cells are morphologically altered (larger, smaller, darker, more prominent nucleoli, etc.) and indeed the worry is that there may be increasing abnormality such as dysplasia or even escape to malignancy. Example: Cigarettes. Again, this is controllable or reversible if the stimulus is removed.
A. Definition: The loss of the uniformity of individual cells and a loss of normal architectural orientation in the tissue. There is pleomorphism, that is variation in size and shape of the cells, combined with increased mitoses, staining, nucleus, nucleoli, etc.
B. Dysplasia is reversible but is very worrisome as to the higher possibility of it escaping to a cancer.
C. Dysplasia is caused by an abnormal stimulation which is somehow potentially cancer causing and leads to cellular changes. This is what was reported on biopsy from the conjunctival lesion in case 2. See Figure 4.
D. This is what the "pap" smear is designed to detect, i.e., changes that can be treated prior to a malignancy developing.
V. NOW FOR THE BIGGIE............NEOPLASIA
A. All the above cell types are controllable or reversible by removing the stimulus or with treatment. However, this is not true for cells that have become neoplastic as these cells have gone beyond the point of no return from that standpoint.
B. Definition: Abnormal new cell growth which is autonomous (not subject to normal growth control) and at the expense of the health of the rest of the body.
C. Benign Neoplasia: Not reversible but really does not mean to do harm to the body. It may harm the body due to location (intracranial, spinal canal, etc.), displacement of adjacent normal tissue (brain, etc.) or function (may elaborate hormones, etc.). Here the tumor cells are quite like the cell of origin, they stay in the area formed (they do not metastasize), they are often encapsulated, they tend to be slower growing than malignant neoplasias. See Figure 5.
Nomenclature: for benign just name the parenchymal cells of the tissue and use the suffix "oma", i.e., fibroma, chondroma, lipoma, squamous epithelioma. For glandular tumors the name of the gland and the word adenoma.
D. Malignant Neoplasia: The lay term here is "cancer". Not reversible and means to do great harm to the body. These cells rapidly reproduce, invade and destroy local tissues, are not encapsulated, can spread to distant sites and start another growth (metastasize - primarily by blood and lymphatics), and ultimately take over the tissues of a vital organ causing the organ to fail and leads to somatic death. The hallmark of malignant neoplasia is dedifferentiation that is termed ANAPLASIA. Here the cell will increasingly lose its resemblance to the cell of origin. Anaplasia is a series of steps beyond dysplasia and demonstrates marked pleomorphism and architectural disruption. This was the type of neoplasia seen in the eyelid lesion in case 1. See Figures 6-8.
Metastasis: A secondary site of growth away from the site of origin of the malignant neoplasm such as to the liver, lungs, brain, bone, etc.
Nomenclature: Again is named by the parenchymal cell of origin:
(1) If derived from mesenchymal tissue like bone, cartilage, hematopoietic, muscle, etc. just name the tissue and add the word sarcoma.
(2) If derived from epithelial tissue like squamous epithelium, renal cells, hepatocytes, etc. just name the tissue and add the word carcinoma.
NOTE: There are some misnomers like lymphoma or melanoma. So usually there is a modifier like malignant lymphoma or malignant melanoma but should be lymphosarcoma and melanocarcinoma.
A. Definition - an agent capable of inducing cancer. This is for the most part not well understood from an actual molecular basis except in some limited number of cases.
B. Chemical Carcinogens - The very first identified carcinogens were chemical and it is still thought that chemicals are the number 1 underlying cause for cancer, in fact, some estimates are that 80-90 % of cancers are induced by chemicals as the key factor. Recall polygenic as a concept too!! 200 years ago Dr. Perciville Pott associated the soot from chimneys to be the cause of scrotal cancer in chimney sweeps. He proved it by inducing cancer in rabbits ears from rubbing coal tar on them. Now there are thousands of chemicals listed by the FDA as carcinogens and these chemicals are in foods, drugs, food additives, etc.
Asbestos, cigarette smoke (tars, etc.), smokeless tobacco, various hydrocarbons, etc. are known chemical carcinogens due to mutagenic (works on the genetic apparatus) activity. These chemical mutagens are usually dose dependent, additive, and induce irreversible changes in the affected cell that are all transmitted to the progeny of the cell.
C. Oncogenic Viruses - A host of viruses are proven to be carcinogenic and are of both RNA and DNA varieties. Worthy of mention includes the Human Papilloma Virus which causes venereal warts and Herpes Simplex type 2 which causes genital herpes. Both have been associated with cancer of the cervix and prostate. It is thought that oncogenic viruses are mutagenic as they affect the genetic apparatus as part of their life cycle.
D. Radiation Carcinogenesis - Exposure to radiation has been clearly linked to the development of cancer. It is thought that it does so by the effects radiation has directly on the genetic apparatus. However, exposure to radiation causes rapid acceleration of the aging process and therefore may lead to increased incidence of spontaneous mutations as well. Sunlight, X-rays, nuclear reactions, exposure to radionucleotides, etc. are significant in todays society in this regard. Again, it is thought that the effects are additive and passed on to the progeny of the affected cells in an irreversible manner.
E. Other Carcinogens - Chronic irritation itself in some tissues may induce a cancer. That is why moles in friction areas are sometimes of concern, etc. Hormones in unusual or large amounts may be carcinogenic like the male androgens, and female estrogen or progesterone.
VII. EFFECTS OF TUMOR ON THE HOST
A. Benign Neoplasia - Here are rather "innocent" but can harm due to location or functional activity, i.e., like hormone production. There are a few other possible complication as they are more likely to hemorrhage plus there is a concern that escape may occur into a malignant neoplasia.
B. Malignant Neoplasia - These are obviously much more serious for the host. Invasion and destruction of local tissue, taking over a vital organ, metastatic disease to distant tissues, production of circulating ill defined products that lead to depression, fatigue, and cachexia (weakness, loss of appetite, weight loss and wasting of body tissues), which often leads to Hippocratic facies in the patient with advanced cancer. Death ensues with loss of vital organ function.
VIII. DIAGNOSIS OF CANCER
A. As of this moment, the gold standard for diagnosis of neoplasia both benign and malignant is a tissue biopsy with review by an experienced pathologist for morphology and differentiation.
The hottest area for early detection is in biochemical assays. The new PSA (prostate specific antigen) for prostate cancer, and the time tested CEA (carcinoembryogenic antigen) and Alpha-fetoprotein are examples for GI, breast, gonadal, liver, and other kinds of tumors. It is important to consider that CEA is not a invalid laboratory test for patients who smoke. This fact seems to indicate that there a message here for smokers! The newest item is genetic phenotyping for some specific tumor predispositions such as breast, ovary and prostate, and other kinds of cancers, i.e., BRCA1 for predisposition to Breast Cancer.
C. Cancer Genomics
Lung cancer – A predisposition to lung cancer has been observed in those with p53, p16, MYCL1 and FHIT genetic abnormalities and these are associated with the development of Small Cell Carcinoma of the Lung. This appears to be especially true with exposure to high levels of air pollutants and in the presence of tobacco smoke
Prostate cancer – Genetic markers including NKX3A, PTEN, RBI, p53, p27, p21, PCA3 AND KA11 have been associated with this type cancer but to date the associated environmental triggers have not been identified, however, it is thought that perhaps sexually transmitted diseases such as the Human Papilloma Virus could be a culprit.
Breast Cancer – It is well documented that the genetic abnormalities of BRCA1, BRCA2, BRIPI, HER2, CCND1, p53 and Ras are involved in the development of these cancers. It is not understood how, but somehow estrogen plays a critical role in stimulating predisposed cells in the breast for the development of this cancer (NOTE: the BRCA 2 and BRIPI added together are considered to account for about 25% of breast cancers that are due to having breast cancer “run” in the family)
Leukemia – There are several gene abnormalities associated with this cancer but one has gotten quite a bit of attention is the NF1 gene on Chromosome 17. Again, the triggering environmental factor is to date unknown but several viruses are suspected to be possible triggers.
Colon Cancer – There is a high correlation with the MLH1 Gene Mutation for predisposition to this cancer. However, again a triggering environmental agent has not been identified.
Genes have also been identified for, lymphoma and many other forms of cancer. In these cases again an environmental trigger has not be identified.
Malignant Melanoma – Mutation in the MC1R Gene is associated with this type cancer. This is especially true in patients with light-skin and for freckled individuals, however, in patients who have the MC1R gene and red hair the incidence is the highest! This particular genetic defect leads to an increase in free-radicals in the deeper layers of the epidermis which is where the melanocytes reside.
Patients who develop retinoblastoma have a very high incidence of an abnormal gene locus on Chromosome 13. The abnormality is a mutation in the RBI gene. There are numerous laboratories with the capability to perform testing for this particular abnormal gene locus.
IX. SKIN TUMORS BOTH BENIGN AND MALIGNANT
A. Skin cancer is the most common form of malignant neoplasia world wide but is not all that common as a lethal form of neoplasia. Most skin cancers are curable if detected early and most occur in sun exposed areas of skin. It is important for optometrists to examine the skin around the eyes, the face and other easily visible areas of the head and neck as these are high sun exposure areas. An example is actinic keratosis, which is not a skin cancer but is a precursor to it. Actinic keratosis is manifested by reddened, scaly, hypopigmented areas with atrophy. See Figure 9.
Squamous Cell Carcinoma – Definitely a malignant skin tumor derived from the stratified squamous epithelial cell type, i.e., skin, conjunctiva, mouth, cervix, etc. Occurs in sun damaged skin (termed actinic keratosis) and is more common in light skinned people. See Figure 10.
Squamous cell carcinoma itself appears as a scaly sore that won't heal and it slowly increases in size and ultimately has an strong tendency to ulcerate in the center. Squamous Cell Carcinomas are best treated by wide surgical excision in order to assure “getting it all.” The actinic keratosis lesions are easily treated by freezing with liquid nitrogen or by the application of topical anti-tumor medication (5FU). Squamous Cell Carcinomas definitely can metastasize and when this occurs there is a high incidence of mortality. These types of cancers are of special concern when they are near the eye as they may spread to the orbit!
C. Basal Cell Carcinoma - These are indeed malignant but usually are so slow growing that they are not taken seriously. Take them seriously, especially if they are near the eye! These are very common and occur mostly in sun-exposed skin with extensive sun related damage. Recall that the predisposing lesion due to sun damage is termed Actinic Keratosis. Actinic Keratosis lesions tend to be easily identified and very characteristic. When a Basal Cell Carcinoma develops, the lesions begin as a small nodule that slowly progresses to a waxy appearing, raised lesion with a rolled border that ultimately leads to “dimpling” in the center of the nodule along with the rolled border manifesting small dilated red threads of new blood vessel growth termed telangiectasia. See Figures 11-13.
It is important to note that there very commonly is “central dimpling” and with time the dimpling leads to central ulceration due to necrosis of the tumor in the central area. Basal Cell Carcinomas should be treated early by surgical excision, freezing with liquid nitrogen if very small, or complete cauterization as a form of “burning it out.”
D. Nevi (moles) - These lesions of the skin are developmental anomalies of melanocytes and virtually everybody has a number of these skin lesions! There is usually, but not always, increased melanocyte activity within the lesions and therefore they are pigmented in color. Most authorities on the subject agree that there are three (3) distinct kinds of nevi but for clinical purposes only two (2) will be described:
1. Common Acquired Nevi - The lay term is a "mole" and virtually every on has these and in fact, the average is 20-30 per person. These benign lesions are absent at birth, appear in early childhood, peak during middle adult life and then often tend to slowly disappear! They begin as a small tan-dark brown area and slowly enlarge to full size. Some become elevated and even pedunculated, and are then commonly called “skin tags”. See Figures 14-15.
This kind of Nevus is usually less than 1/2 centimeter in diameter, is evenly pigmented, and has a smooth, round or oval border. These lesions are at very low risk for malignant degeneration.
2. Dysplastic Nevi - These usually begin as dysplastic nevi but can develop over time due to dysplasia occurring in a common acquired nevus. Here there is cellular "atypia" with the characteristics of dysplasia including pleomorphism and some microscopic architectural changes in cellular alignment. These lesions tend to be larger than 1/2 centimeter in diameter, have irregular borders often with "notching", and the pigmentation within the lesion being uneven, i.e., there are light and dark areas of pigmentation within the nevus). Dysplastic Nevi are considered to be at risk for malignant transformation and, indeed, about 1/3 of all malignant melanomas originate within a pre-existing dysplastic nevus. This was the type of nevus seen on the upper lid in case study one. See Figure 1.
E. Malignant Melanoma – The term “Malignant Melanoma” is a misnomer as it is a malignant lesion and should have been named melancarcinoma. There is a frightening increase in the incidence of these malignancies possibly due to more sun exposure in today’s recreation minded population, tanning parlor use, increased incidence of radiation exposure, etc. Malignant Melanoma can be highly agressive and these types of cancers occur in two important varieties:
1. Superficial Spreading Melanoma – With cases of this type the increase in size is radially manifested superficially on the skin. Melanomas of this type definitely have a lower incidence of metastases until much later in the course of the cancer. This melanoma was seen in Figure 3 and can be seen in Figure 16, below.
2. Nodular Melanoma – With cancer of this type, there is vertical growth with more penetration deep into the skin and underlying tissues. This type of cancer tends to be much more aggressive and more highly malignant which leads to a tendency to manifest metastases early in their course.
NOTE: Therefore, any change in a mole due to size, color, nodularity, notching, easy bleeding etc. is a possible indication for excisional biopsy. The rule for pigmented lesions being at higher risk for malignancy is the pneumonic ABCDE. The “A” is for asymmetry, the “B” for border irregularity, the “C” for color variation, the “D” for diameter greater than ½ centimeter and the “E” for evolving, i.e., change in color, nodularity, bleeding, size, shape, etc.
X. CANCER THERAPY CONSIDERATIONS
A. Surgical excision - Here the cancer is either totally removed or hopefully at least debulked in mass for higher chance of cure.
B. Radiation - High energy is "focused" on the tumor that is usually very lethal to the cells and this is often successful in debulking the tumor or even completely curing some cancers.
C. Chemotherapy – There are a number of medications that inhibit cellular reproduction and are toxic or even able to kill cancer cells in many types of cancers. The idea is to be much more toxic to the tumor cells than to host cells, however, all these agents have side effects which leads to hair loss, diarrhea, vital organ damage, etc. Side effects of chemotherapy agents such as hair loss, etc. is due to the fact that these cells, like cancer cells, have a more rapid “turnover rate” and it is the reproducing cells that are most subject to the medication effects.
D. Immunotherapy – The idea behind this type of therapy is to enhance tumor rejection by the hosts own immune system “rejecting” the tumor cells and thus eliminating them.
E. Unorthodox therapy - No proven scientific benefit like Laetrile, vitamins, various diets, coffee enemas, etc.