Skin tumors

Basal cell carcinoma
It is the most common malignant skin tumor. Its incidence has doubled in the last 15 years.

Occurrence
We observe an increased incidence after the age of 40, with the group over 60 being the most at risk. However, it can be at any age. It affects almost exclusively white individuals, if it occurs in pigmented races, it is associated with unusual etiological factors. The tumor arises from the keratinocytes of the epidermis.

Clinical picture, development
Typical cells are oval in shape and resemble the cells of the basal layer of the epidermis – hence the name. The tumor  almost never metastasizes - more than 200 cases of metastases have been described worldwide, mainly to the lymph nodes. It usually starts as a nodule, boil, or scab that does not change significantly at first. It grows slowly as if crawling on the surface. It consists of one solitary nodule with raised edges, parts may undergo ulceration that does not heal. Sometimes there is an illusory improvement, the ulcer almost heals, only to reappear before long and slowly enlarge. An inconspicuous course often results in the formation eventually increasing to dimensions that can be a treatment problem in some locations. On the other hand, basal cell carcinoma on the mucous membranes metastasizes very often.

The cause of the disease
As with other malignant diseases, the cause of the disease is unclear. The main etiological factor is chronic, long-term exposure of the skin to UV radiation.

Prognosis
With the exception of extensive or invasively growing tumors, basal cell carcinoma does not threaten the patient's life. However, if the tumor grows long enough, it can form extensive foci with destruction of neighboring tissues.

Therapy
Surgical removal. If it is not cut out completely, it recurs! Excision is then necessary until the entire bearing is removed. Due to the place of occurrence (face), the aesthetic side of the procedure cannot be neglected.

Spinal tumor
Squamous cell carcinoma is also classified as malignant epithelial tumors of the skin. It usually begins with intraepithelial growth, followed by destructive progression. It metastasizes mainly via the lymphatic route. The incidence in our population corresponds to about 11/100,000, compared to basal cell carcinoma which occurs less often (about 1:10).

Etiology
It usually develops from precancers (solar keratosis, leukoplakia, m. Bowen, etc.), especially in predisposed individuals with a lower amount of melanin in the skin (phototype I and II). Other risk factors are chronic degenerative skin changes (scars, fistulas, skin ulcers), immune disorders (immunosuppression), HPV infection, and long-term skin exposure to carcinogens.

Clinical manifestation
The clinical picture of the tumor develops over time.


 * 1) form: Diffuse infiltrating (inconspicuously elevated hyperkeratosis or hard, infiltrated focus with a bumpy surface, grows slowly, metastasizes late);
 * 2) form: Ulcerative (the center may break down and form an ulcer with swollen, hard edges);
 * 3) form: Exophytic (soft, aggressive, and rapidly growing formation with central disintegration and bleeding, metastasizes early).

Metastases to regional nodes occur in about 5-10% of patients. Nodules tend to be hard, and large in size, with the possibility of ulceration and fistula formation.

We recognize special forms with their typical precancer:


 * Spinal tumor of the lip (from leukoplakia and cheilitis)
 * spinalioma of the vulva (from lichen sclerosis et atrophicus)
 * penile spinalioma (from erythroplasia)
 * spinalioma of the tongue (from leukoplakia and erythroplakia)
 * aggressively growing exophytic form (from m. Bowen and chronic irritation)

Diagnostics
The decisive examination for determining the diagnosis is the histopathological examination. Tumor prognosis is correlated with the degree of cell dedifferentiation.

Therapy and prognosis
Radical excision with a border of healthy tissue (peripherally and deeply). For smaller bearings, an intact edge of about 1 cm width is recommended. Excision of larger tumors should have a border of healthy tissue of 2-3 cm, especially on the trunk, where the spinalioma behaves more aggressively and the solution of the resulting defect does not cause major difficulties. In the case of metastases to regional nodes, we also remove them.

If surgery is not possible (e.g. in the elderly), we perform radiotherapy. In the presence of metastases, we add chemotherapy.

Prognosis depends on location, tumor size and degree of dedifferentiation. Tumors in the solar area have the best prognosis, but are worse on the ear, lips, and scars. Tumors located on the mucous membranes have the worst prognosis.

Melanoma
Malignant melanoma is a cancer that arises from the neoplastic proliferation of melanocytes. It is classified as a neuroectoderm tumor. Malignant melanoma mainly affects the skin, but it can also affect the eye, ear, leptomeninges, GIT and mucous membrane of the mouth or genitals. The incidence of melanoma is increasing, affecting mainly the white population.

Melanoma occurs in four basic histological types: superficial spreading melanoma, lentigo maligna melanoma, acrolentiginous melanoma, and nodular melanoma. The basis of therapy is surgical resection of the tumor together with a sufficient margin of adjacent skin, or resection of lymph nodes. Adjuvant treatment with Interferons|interferon α, specific vaccines, BRAF inhibitors (Vemurafenib), and CTLA-4 blockers (Ipilimumab) is considered.

Epidemiology
The incidence of melanoma is increasing worldwide. In the white population in the United States, the incidence of melanoma has more than tripled over the past twenty years. The incidence of melanoma shows geographic variation. While in North America there are 6.4 new cases per 100,000 men and 11.7 new cases per 100,000 women, in Australia and New Zealand it is already 37.7 cases per 100,000 men and 29.4 cases per 100,000 women. In 2006, the incidence of melanoma in the Czech Republic was 18.4 per 100,000 men and 15.6 per 100,000 women.

Malignant melanoma accounts for approximately 4% of all skin cancers but is responsible for up to 73% of skin cancer deaths. Globally, survival is higher in developed countries (91% in the US, 81% in Europe) than in developing countries (approximately 40%). Lower mortality in developed countries is mainly due to greater awareness of the population, which leads to earlier diagnosis and treatment.

Malignant melanoma mainly affects the white population. The prevalence of melanoma in the Hispanic population in the United States is approximately six times lower than in the white population. The prevalence is even twenty times lower in African-Americans. However, Hispanic and African-American mortality from malignant melanoma is higher than that of the white population. The reason is the more frequent involvement of acral melanoma and the more advanced stage of the disease.

Up to the age of 39, the occurrence of melanoma is more common in women, and from the age of 40, it is more common in men. Overall, women are slightly more affected (male-to-female ratio, 0.97:1), but mortality is higher in men.

The median age of melanoma diagnosis is 59 years, however, in women aged 25–29 years, melanoma is the most common type of cancer, and among women aged 30–34 years, it is the second most common type of cancer after breast cancer. Malignant melanoma affects more elderly individuals, who are more likely to succumb to the disease. Therefore, the elderly should be the main target for the secondary prevention of melanoma.

Pathophysiology
The pathophysiology of melanoma development is not fully understood. Several pathogenetic mechanisms of melanoma development are hypothesized. Melanoma occurs not only on skin exposed to the sun, where UV radiation is the main pathogenetic factor, but also in places that are relatively protected from radiation (trunk).

Malignant melanoma is accompanied by mutations in the BRAF, NRAS and KIT genes. The individual representation of mutations depends on the method of exposure to sunlight. While a BRAF mutation occurs more with intermittent sun exposure and is more common in superficial spreading melanoma, a mutation in KIT occurs more with chronic exposure or in relatively unexposed skin and is more common in nodular melanoma.

Melanoma arises either by malignization of an already present melanocytic nevus or, more often, de novo (in more than 70% of cases).

Risk factors include :


 * age over 50
 * higher sensitivity to sunlight,
 * excessive exposure to sunlight in childhood, bullous dermatitis after sunburn in childhood,
 * increased number of atypical (dysplastic) nevi or large congenital nevus (larger than 20 cm in adulthood)
 * familial incidence of melanoma,
 * the presence of a changing pigment spot
 * immunosuppression
 * use of the solarium

Clinical picture and histopathological types
Melanoma occurs most often on the trunk in white men, while in white women it occurs on the lower leg or back. Melanomas in Hispanics, African Americans and Asians most often appear on the planta, then in the subungual location, on the palms and mucous membranes.

Melanoma can affect both the skin and mucous membranes (eg oral) or the eye.

Cutaneous melanoma is divided into four basic clinicopathological subtypes according to the nature of growth, the anatomical location of the lesion and the degree of sun damage:

Superficial spreading melanoma
Superficial spreading melanoma arising from a dysplastic nevus (marked by an arrow). A gray tumor regression can be seen in the lower left field.

This subtype accounts for approximately 70% of cutaneous melanomas and is the most common melanoma subtype in individuals between 30–50 years of age.

The tumor initially behaves as carcinoma in situ, which grows radially and does not tend to metastasize. Melanoma can remain in this stage for months to years. It occurs most often on the trunk of men or on the lower leg of women. It is caused by intermittent exposure to the sun.

It often presents with warning signs of ABCD (see diagnosis). It is either flat or slightly elevated. It is usually larger than 6 mm. Histologically, a pagetoid distribution of atypical melanocytes is evident in the epidermis (similar to scattered buckshot after a shot from a shotgun, the so-called "buckshot scatter").

Nodular melanoma
It accounts for 15–30% of cutaneous melanomas.

Nodular melanoma lacks the carcinoma in situ stage, growing relatively quickly and invading deeper skin structures. The most common locations are the legs and torso of both men and women. It is caused by intermittent exposure to the sun.

It usually doesn't show ABCDE warning signs and can easily go unnoticed. It usually manifests itself as a brown-black papule or even a nodular formation that easily ulcerates and bleeds. In addition, the lesion can be amelanocytic, i.e. without pigment.

Lentigo maligna melanoma
The incidence of lentigo maligna melanoma is increasing. It mainly affects older individuals around 65 years of age.

Lentigo maligna is a carcinoma in situ with radial growth without a tendency to metastasize. The lesion is usually larger in diameter (1–3 cm) with dark brown to black pigmentation, although hypopigmentation is also not an exception. At this stage, lentigo maligna persists for at least 10-15 years before dermal invasion and the formation of lentigo maligna melanoma, which forms a raised blue-black nodule on the surface. Typical localization is the head, neck and arms. It is caused by chronic exposure to the sun.

Acrolentiginous melanoma
The least common subtype of melanoma in the white population, but the most common subtype of melanoma in the dark-skinned population (African Americans, Hispanics, Asians).

The tumor initially behaves as carcinoma in situ, which grows radially and does not tend to metastasize. Melanoma can remain in this stage for months to years. It most often occurs on the palms, soles or under the nail plate (subungual melanoma). Subungual melanoma manifests as a diffuse change in color or as a pigment band under the nail plate. Spread of pigment to the proximal or lateral nail plate is referred to as Hutchinson's sign, typical of subungual melanoma. Acrolentiginous melanoma is not linked to sun exposure like mucosal melanomas.

In terms of differential diagnosis, it is necessary to consider benign junctional melanocytic nevus, subungual hematoma and onychomycosis.

Rare subtypes of cutaneous melanoma
They occur in less than five percent of cases.


 * Desmoplastic melanoma is a rare but important subtype of cutaneous melanoma that occurs predominantly in older individuals (60-65 years of age). It mainly affects the skin of the head and neck exposed to the sun. Clinically, it is more reminiscent of non-melanocytic skin tumors and therefore there may be a delay in diagnosis. Desmoplastic melanoma often has perineural spread and tends to recur locally. Therefore, radical excision with adjuvant radiotherapy is recommended for therapy.
 * Mucosal (lentiginous) melanoma.
 * Malignant blue nevus.
 * Melanoma arising from a large congenital nevus.
 * Melanoma of soft parts (clear cell sarcoma).
 * Amelanocytic melanoma is non-pigmented and can occur simultaneously with any subtype of melanoma (mostly nodular or desmoplastic). It can mimic basal cell or squamous cell carcinoma, dermatofibroma or even hair follicle lesions.

Diagnostics
The most common warning sign of melanoma is a newly formed and changing pigment spot. Symptoms such as bleeding, itching, ulceration or pain at the site of the pigment spot may occur. For clinical needs, the ABCDE rule was created to evaluate the warning signs of melanoma:

Lesions that show these characteristics are evaluated as potential melanoma.
 * A – Asymmetry – the pigment spot is not symmetrical.
 * B – Border irregularity – the edges of the spot are uneven, jagged or vaguely defined.
 * C – Color variegation – coloring is not uniform, showing different shades of skin color, brown and black. The white, red or blue color of the pigment spot is a worrying finding.
 * D - Diameter - a diameter greater than 6 mm is characteristic of melanoma, although smaller diameters can also occur. Any growth of the stain deserves examination.
 * E – Evolution (development) – the pigment spot changes over time. This point is important mainly in nodular melanoma or amelanocytic melanoma (non-pigmented), which may lack ABCD points.

It is practical for the clinic to evaluate the warning sign of the "ugly duckling". It is a pigment spot that somehow differs from the others. It is convenient to combine this symptom with ABCDE criteria.

When melanoma is suspected, a biopsy of the suspected lesion on the skin or mucous membrane (excision with a 1-3 mm margin of healthy tissue) and subsequent histological examination are important. In the biopsy report, we will then read five basic pieces of information:

In the case of ambiguities in the histology, immunohistochemical staining, for example for S-100, HMB-45 (homatropine methyl bromide 45), melan-A/Mart-1 or markers of proliferation such as Ki67 (proliferating cell nuclear antigen), can help the diagnosis.
 * 1) Tumor thickness in millimeters (Breslow) – is the most important prognostic factor, it is measured from the upper border of the stratum granulosum to the deepest point of tumor invasion. The greater this thickness, the higher the potential for metastases and therefore the worse the prognosis.
 * 2) Ulceration – is the second most important prognostic factor, its presence shifts and increases staging.
 * 3) Cutaneous number of mitoses – the number of mitoses per 1/mm 2 increases the probability of metastasis and worsens the patient's prognosis.
 * 4) Microsatellite
 * 5) Anatomical grade of invasion (Clark) – only for tumors smaller than or equal to 1 mm and if the mitotic index cannot be evaluated; optional for tumors larger than 1 mm. According to statistics, ulceration, mitotic index, age, gender or location of the lesion do not have such a prognostic significance for the survival of patients as Breslow.

If the tumor is greater than (or equal to) 1 mm or if a thinner tumor shows unfavorable prognostic factors such as ulceration or a higher number of mitoses, a sentinel node biopsy is performed to help us determine the staging of the disease.

Increased values ​​of serum LDH in the biochemical examination are a negative prognostic marker, they are associated with a shorter survival time.

Indications for imaging examinations such as X- ray, CT, MRI or PET are considered individually, for example to evaluate the presence of metastases.

Staging
Melanoma is divided into stages 0–IV according to histology:

In addition, the individual stages have subgroups according to the presence of various signs, for example the presence of ulceration, the number of mitoses or the value of LDH (lactate dehydrogenase). For example, a lesion 2.01–4 mm wide without ulcerations is graded as stage IIA, but the same lesion with ulcerations is graded as IIB.
 * Stage 0 is carcinoma in situ.
 * Stage I and II have the depth of invasion as a criterion.
 * Stage III affects the regional lymph nodes.
 * Stage IV represents distant metastases in the skin, subcutaneous tissue, nodes, visceral area, skeleton or CNS.

Surgery
The basic method of therapy for a localized form of malignant melanoma is surgical resection of the tumor site with a sufficiently wide border of healthy skin. For carcinoma in situ, this border is 5 mm wide. For "low risk" melanomas with a depth (Breslow) of 1 mm and less, it is recommended to excise a border 1 cm wide. A 2 cm border is recommended for melanomas 1 mm deep or more. According to the studies, a wider hem than 2 cm did not bring clinical benefit. Elective lymph node dissection can improve the prognosis of patients with malignant melanoma, according to WHO studies.

Previously, the problem of whether to perform a regional lymphadenectomy for melanomas 1 mm deep (Breslow) or less than 1 mm, but with negative prognostic features such as ulceration, lymphovascular invasion or a higher number of mitoses, was addressed. In the 1990s, sentinel node biopsy (SLNB) methods began to be used for malignant melanoma, which solved this problem. Peritumorous injection of 99m Tc is used to visualize the sentinel node. The radiopharmaceutical is drained by the lymphatics into the draining lymph node. Intraoperatively, this nodule can be identified with a gamma camera. Another option is the application of dyes such as methylene blue or lymphazurin, which colors the cascade node. When both methods are combined, the probability of capturing the sentinel node is approximately 95% (influenced by anatomical location). The sentinel node located in this way is removed and examined histologically, or immunohistochemically for the presence of micrometastases. If the biopsy sample is positive, a complete lymph node dissection (CLND) is performed. If the findings are negative, the nodes are left.

Adjuvant therapy
Adjuvant therapy in the form of chemotherapy (dacarbazine therapy), radiotherapy, biological therapy, non-specific immunomodulation or vitamin therapy has no effect on patient survival and is still the subject of research.

One hope may be high-dose interferon α therapy, which statistically reduces the incidence of relapse. The disadvantage is long-term therapy with high doses and the resulting side effects. These can be flu-like symptoms, manifestations of intolerance to therapy or induction of autoimmunity with the formation of autoantibodies (antithyroid, antinuclear, anticardiolipin). The prognostic significance of induced autoimmunity in malignant melanoma is still under study.

The second hope may be the application of specific vaccines that contain the antigenic structures of melanoma. These vaccines, as we might expect, have no value in prevention, but act as a stimulator of the immune system in advanced forms of the disease (St. III, IV). Unlike interferon therapy, it does not have as many side effects. The effectiveness of the vaccines given alone has not been proven, but the combination of a peptide vaccine (gp100:209-217(210M)) with high-dose IL - 2 therapy is promising, so far, with good results.

The third avenue of research is the so-called BRAF-inhibitors (Vemurafenib), i.e. inhibitors of certain mutated forms of serine-threonine kinases. Vemurafenib therapy significantly reduces the risk of disease progression and prolongs survival. However, further studies must complement this pathway.

Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4), can be used for metastatic or unresectable melanoma. By blocking CTLA-4, the activity and proliferation of T-lymphocytes is strengthened. The actual anti-tumor mechanism of action is non -specific, mediated by the activity of T-lymphocytes.

As can be seen from the previous text, the diagnosis and therapy of malignant melanoma is dependent on interdisciplinary cooperation. It involves a dermatologist, pathologist, surgeon, nuclear medicine specialist, oncologist, or radiation oncologist.

Patients who have been diagnosed with malignant melanoma should be screened for the risk of relapse. Metastases most often appear 1-3 years after treatment of the primary tumor. 4-8% of patients with a history of malignant melanoma will develop a new primary melanoma within 3-5 years.

Kaposi's sarcoma
Kaposi's sarcoma is a mesenchymal malignant vascular tumor.

Etiology
An association with HHV-8 has been demonstrated. Occurs in immunosuppressed patients.

We recognize 4 variants of Kaposi's sarcoma :


 * 1) classic form (lower limbs of elderly people);
 * 2) iatrogenic form in immunosuppressed patients after cytostatic treatment, e.g. after transplants;
 * 3) endemic form (Africa);
 * 4) epidemic form in patients with AIDS.

Classic form
Hard, livid, slowly growing bumps, deep red in color, later even brown. Location around the ankles and lower legs. There is a risk of exulceration and bleeding. Diffuse swelling is typically associated.

Disseminated form
It occurs anywhere on the trunk and mucous membranes. Most often in connection with AIDS. In addition to the skin, it also affects internal organs. Skin manifestations are very varied. He behaves very aggressively and progresses quickly.

Diagnosis
Histopathologically. Image of atypical capillaries in corium. In the slit-like spaces are spindle-shaped cells filled with erythrocytes.

Diff. diagnosis

 * Pseudo-Kaposi's sarcoma - occurs in chronic venous insufficiency.
 * Hemangioma
 * Hemangiosarcoma

Therapy
For the classic form, especially surgical. For systemic involvement, mainly AIDS treatment, then interferon- α, chemotherapy.

Prognosis
Good in classic form. It tends to be fatal in the case of total disability.

Verrucous carcinoma
Verrucous carcinoma (Carcinoma verrucosum) is a highly differentiated variant of squamous cell carcinoma of the skin, characterized by slow growth and a warty surface.

It belongs to Malignant|invasive carcinoma but has a very low tendency to metastasize.

Epidemiology
It occurs mainly in elderly patients in areas with scars, chronic wounds, and chronic venous insufficiency. In some cases, an association with HPV 6 and 11 has been demonstrated.

Clinical picture
Four forms are distinguished, mainly according to localization.

Diagnosis
Histological. It is an asymmetrically proliferating formation in the epidermis. It contains horn-filled crypts.

Therapy
Surgical treatment is necessary. It is supplemented with radiotherapy, chemotherapy, laser tumor destruction, or general treatment with retinoids, and interferons.

Reference

 * 1) SWETTER, Susan M.  Cutaneous melanoma [online]. Last revision 2011, [cit. 2012-02-23]. < https://emedicine.medscape.com/article/1100753-overview >.
 * 2) KRUŽICOVA, Zuzana. Malignant melanoma [online]. ©2010. [feeling. 2012-03-09]. < https://zdravi.euro.cz/clanek/postgradualni-medicina/maligni-melanom-450829 >.
 * 3) SWETTER, Susan M.  Cutaneous melanoma [online]. Last revision 2011, [cit. 2012-02-23]. < https://emedicine.medscape.com/article/1100753-overview >.
 * 4) SWETTER, Susan M.  Cutaneous melanoma [online]. Last revision 2011, [cit. 2012-02-23]. < https://emedicine.medscape.com/article/1100753-clinical >.
 * 5) SWETTER, Susan M.  Cutaneous melanoma [online]. Last revision 2011, [cit. 2012-02-23]. < https://emedicine.medscape.com/article/1100753-clinical >.
 * 6) SWETTER, Susan M.  Cutaneous melanoma [online]. Last revision 2011, [cit. 2012-02-23]. < https://emedicine.medscape.com/article/1100753-clinical >.
 * 7) SWETTER, Susan M.  Cutaneous melanoma [online]. Last revision 2011, [cit. 2012-02-23]. < https://emedicine.medscape.com/article/1100753-workup >.
 * 8) SWETTER, Susan M.  Cutaneous melanoma [online]. Last revision 2011, [cit. 2012-02-23]. < https://emedicine.medscape.com/article/1100753-workup >.
 * 9) SWETTER, Susan M.  Cutaneous melanoma [online]. Last revision 2011, [cit. 2012-02-23]. < https://emedicine.medscape.com/article/1100753-workup >.
 * 10) SWETTER, Susan M.  Cutaneous melanoma [online]. Last revision 2011, [cit. 2012-02-23]. < https://emedicine.medscape.com/article/1100753-workup >.
 * 11) SWETTER, Susan M.  Cutaneous melanoma [online]. Last revision 2011, [cit. 2012-02-23]. < https://emedicine.medscape.com/article/1100753-treatment >.
 * 12) Rogerio I. Neves. Increased Post–Operative Complications With Methylene Blue Versus Lymphazurin In Sentinel Lymph Node Biopsies For Skin Cancers [online]. ©2011. [feeling. 2012-03-09]. < http://200.40.135.66:90/toc/7574/2011/7574-20110401-5-10.pdf >.
 * 13) SWETTER, Susan M.  Cutaneous melanoma [online]. Last revision 2011, [cit. 2012-02-23]. < https://emedicine.medscape.com/article/1100753-treatment >.
 * 14) SWETTER, Susan M.  Cutaneous melanoma [online]. Last revision 2011, [cit. 2012-02-23]. < https://emedicine.medscape.com/article/1100753-medication >.
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