<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Piebaldism and can you explain it in depth? [/INST] Piebaldism refers to the absence of mature melanin-forming cells (melanocytes) in certain areas of the skin and hair. It is a rare autosomal dominant disorder of melanocyte development.: 867  Common characteristics include a congenital white forelock, scattered normal pigmented and hypopigmented macules and a triangular shaped depigmented patch on the forehead. There is nevertheless great variation in the degree and pattern of presentation, even within affected families. In some cases, piebaldism occurs together with severe developmental problems, as in Waardenburg syndrome and Hirschsprungs disease.
Piebaldism has been documented to occur in all races, and is found in nearly every species of mammal. The condition is very common in mice, rabbits, dogs, sheep, deer, cattle and horses—where selective breeding has increased the incidence of the mutation—but occurs among chimpanzees and other primates only as rarely as among humans. Piebaldism is unrelated to conditions such as vitiligo or poliosis.
Although piebaldism may visually appear to be partial albinism, it is a fundamentally different condition </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Traumatic alopecia and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Inflammatory linear verrucous epidermal nevus and can you explain it in depth? [/INST] Inflammatory Linear Verrucous Epidermal Nevus is a rare disease of the skin that presents as multiple, discrete, red papules that tend to coalesce into linear plaques that follow the Lines of Blaschko.  The plaques can be slightly warty (psoriaform) or scaly (eczema-like).  ILVEN is caused by somatic mutations that result in genetic mosaicism.  There is no cure, but different medical treatments can alleviate the symptoms.

Classification
ILVEN is a condition that normally only affects one side of the body (unilateral).  Usually the left side of patients is affected.  The condition is persistent and forms along characteristic lines.  It usually appears on an extremity in infancy or childhood.  Altman and Mehregan described six characteristic features of ILVEN: (1) early age of onset, (2) predominance in females (4:1 female-male ratio), (3) frequent involvement of the left leg, (4) pruritus, or "itchiness" (5) marked refractoriness to therapy, and (6) a distinctive psoriasiform and inflammatory histologic appearance.

Genetics
Most cases are sporadic, but a familial case, with the condition occurring in a mother and her daughter, has been described.It also has been proposed that activation of an autosomal dominant lethal mutation that survives by mosaicism may be the cause of the lesions. The mutated cells may survive in the due to proximity of normal cells. Another theory is that retrotransposable elements may be the cause of all skin conditions along the Lines of Blashko.  Some dogs have a coat variation based upon a similar mechanism.The classification of the disease has much to do with the appearance and location of the lesions (phenotype characteristics).  As this is a rare condition, it is possible that more than one genotype could cause a similar phenotype.  Different genes have been implicated, but the number of patients studied in each case is very low.
There is some evidence that interleukins 1 and 6, tumor necrosis factor α, and intercellular adhesion molecule-1 are upregulated in ILVEN, similar to psoriasis.

Histopathology
-The plaques are characterized histologically by hyperkeratosis which is a thickening of the outer layer of skin.  Hyperkeratosis is often associated with an abnormal amount of keratin production.  Also characteristic is moderate acanthosis a thickening of the stratum spinosum with elongation of rete ridges.- Characteristic histologic feature is regular alternation of slightly raised parakeratotic areas without a granular layer (hypogranulosis) and slightly depressed orthokeratotic areas with prominent granular layer (hypergranulosis). Orthokeratotic hyperkeratosis is characterised by hyperkeratosis with non-nucleated cells.  Parakeratotic hyperkeratosis is characterised by hyperkeratosis with nucleated cells.
- The orthokeratotic area shows a basket-weave-pattern.
- The dermis shows scattering of chronic inflammatory infiltrate (Munros microabscess) sometimes giving a spongiform appearance.
This is very similar to linear psoriasis, but it has been noted that the diseases are distinct entities by immunohistochemical analyses.

Immunohistochemistry
Patients with ILVEN with and without associated psoriasis, the number of Ki-67 positive nuclei, tended to be lower than is typically found in psoriasis.  Additionally, the number of keratin-10 positive cells and HLA-DR expression was higher as compared to psoriasis. In ILVEN without associated psoriasis all T-cell subsets and cells expressing NK receptors were reduced as compared to psoriasis, except for CD45RA+ cells.   In particular the density of CD8+, CD45RO+ and CD2+, CD94 and CD161 showed a marked difference between ILVEN without psoriasis and psoriasis itself. T cells relevant in the pathogenesis of psoriasis are markedly reduced in ILVEN without psoriasis as compared to psoriasis.

Treatment
Reported treatments include topical agents, dermabrasion, cryotherapy, laser therapy, and surgical excision. These therapies have a high failure rate because of incomplete relief of symptoms, scarring, or recurrence.
Though similar in appearance, ILVEN will not respond to therapies known to affect psoriasis </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Generalized essential telangiectasia and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Metatarsophalangeal joint sprain and can you explain it in depth? [/INST] A metatarsophalangeal joint sprain is an injury to the connective tissue between the foot and a toe (at a metatarsophalangeal joint, one of the joints in the ball of the foot). When the big toe is involved, it is known as "turf toe".

Causes
Turf toe is named from the injury being associated with playing sports on rigid surfaces such as artificial turf and is a fairly common injury among professional American football players.  Often, the injury occurs when someone or something falls on the back of the calf while that legs knee and tips of the toes are touching the ground.  The toe is hyperextended and thus the joint is injured.  Additionally, athletic shoes with very flexible soles combined with cleats that "grab" the turf will cause overextension of the big toe. This can occur on the lesser toes as well </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Sensenbrenner syndrome and can you explain it in depth? [/INST] Sensenbrenner syndrome (OMIM #218330) is a rare (less than 20 cases reported by 2010) multisystem disease first described by Judith A. Sensenbrenner in 1975. It is inherited in an autosomal recessive fashion, and a number of genes appear to be responsible. Three genes responsible have been identified: intraflagellar transport (IFT)122 (WDR10), IFT43—a subunit of the IFT complex A machinery of primary cilia, and WDR35 (IFT121: TULP4)It is also known as Sensenbrenner–Dorst–Owens syndrome, Levin syndrome I and cranioectodermal dysplasia (CED)

Presentation
These are pleomorphic and include
dolichocephaly (with or without sagittal suture synostosis)
microcephaly
pre- and postnatal growth retardation
brachydactyly
narrow thorax
rhizomelic dwarfism
epicanthal folds
hypodontia and/or microdontia
sparse, slow-growing, hyperpigmented, fine hair
nail dysplasia
hypohydrosis
chronic kidney failure
heart defects
liver fibrosis
visual deficits
photophobia
hypoplasia of the posterior corpus callosum
aberrant calcium homeostasisElectroretinography shows gross abnormalities.
Two fetuses of 19 and 23 weeks gestation have also been reported. They showed acromesomelic shortening, craniofacial characteristics with absence of craniosynostosis, small kidneys with tubular and glomerular microscopic cysts, persistent ductal plate with portal fibrosis in the liver, small adrenals, an enlarged cisterna magna and a posterior fossa cyst.

Cause
The gene IFT122 is located on the long arm of chromosome 3 (3q21-3q24). The gene lies on the Watson (plus) strand and is 80,047 bases in length. The encoded protein has 1241 amino acids and a predicted weight of 141.825 kiloDaltons (kDa). It is a member of the WD repeat protein family.WDR35 is also a member of the WD repeat protein family </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Reticular dysgenesis and can you explain it in depth? [/INST] Reticular dysgenesis (RD) is a rare, inherited autosomal recessive disease that results in immunodeficiency. Individuals with RD have mutations in both copies of the AK2 gene. Mutations in this gene lead to absence of AK2 protein. AK2 protein allows hematopoietic stem cells to differentiate and proliferate. Hematopoietic stem cells give rise to blood cells.Differentiation and proliferation of hematopoietic stem cells require a lot of energy and this energy is supplied by the mitochondria.  The energy metabolism of mitochondria is regulated by the AK2 protein. If there is a mutation in the protein, that means that the mitochondria metabolism most likely will be altered and will not be able to provide enough energy to the hematopoietic stem cells. As a result, hematopoietic stem cells will not be able to differentiate or proliferate.The immune system consists of specialized cells that work together to fight off bacteria, fungi and viruses. These cells include T lymphocytes (T cells), that primarily mediate the immune system, B lymphocytes (B cells) and Natural Killer cells. Patients with RD have a genetic defect that affects the T cells and at least one other type of immune cell. Since more than one type of immune cell is affected, this disease is classified as a severe combined immunodeficiency disease (SCID). A weakened immune system leaves patients susceptible to different kinds of infection. Commonly, patients who are diagnosed with RD also have bacterial sepsis and/or pneumonia. The annual incidence has been estimated at 1/3,000,000-1/5,000,000 and both females and males are affected.

Signs and symptoms
Risk factors
Condition follows an autosomal recessive patternThe mutated gene must be inherited from both the mother and father
Both males and females must have an equal frequency of inheritance

Diagnosis
Health professionals must look at a persons history, symptoms, physical exam and laboratory test in order to make a diagnosis. If the results show patients with low levels of lymphocytes, absence of granulocytes or absence of thymus then the patient may be suspected to have RD.

Treatment
RD can only be treated temporarily through hematopoietic stem cell transplantation (HSCT) and cytokine therapy.

Hematopoietic stem cell transplantation
Transplantation of stem cells are taken from the bone marrow, peripheral blood or umbilical cord of healthy, matched donors. Hematopoietic stem cell transplantation (HSCT) involves intravenous infusion of stem cells to those who have either a damaged bone marrow or defective immune system. Transplantation is a simple process. Bone marrow product is infused through a central vein over a period of several hours. The hematopoietic cells are able to go to the bone marrow through tracking mechanisms. Patients who suffer from RD will now have more stem cells that can differentiate into immune cells.

Cytokine Therapy
Recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) can be used as a temporary cure. GM-CSF stimulates production of white blood cells. This cure is commonly used in patients who are awaiting bone marrow transplantation. Response to this cure can vary. Those with a more severe combined immunodeficiency may have no response to this therapy.

Prognosis
The survival range is estimated to be 3 days to 17 weeks without treatment </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Buccal exostosis and can you explain it in depth? [/INST] A buccal exostosis is an exostosis (bone prominence) on the buccal surface (cheek side) of the alveolar ridge of the maxilla or mandible. More commonly seen in the maxilla than the mandible, buccal exostoses are considered to be site specific. Existing as asymptomatic bony nodules, buccal exostoses don’t usually present until adult life, and some consider buccal exostoses to be a variation of normal anatomy rather than disease. Bone is thought to become hyperplastic, consisting of mature cortical and trabecular bone with a smooth outer surface.  They are less common when compared with mandibular tori.

Signs and symptoms
Buccal exostoses are bony hamartomas, which are non- malignant, exophytic nodular outgrowths of dense cortical bone that are relatively avascular.’Symptoms:
Buccal exostoses generally tend to be asymptomatic and are usually painless.
However, they may increase patient concern about poor aesthetics, inability to perform oral hygiene procedures due to difficulty in cleaning around the area with a toothbrush, and compromised periodontal health by causing food lodgement, which could lead to patients reporting increased bleeding when tooth brushing.
Signs:

They tend to appear in early adolescence and may very slowly increase in size with time.
Buccal exostoses generally occur bilaterally.
Found usually in the premolar and molar region.
These benign growths affect both the jaws. The maxilla is shown to display a higher prevalence rate of 5.1:1 in comparison to mandible.  Males also are afflicted more than females with a prevalence rate of 1.66:1, in all intraoral locations.The overlying mucosa appears to be stretched but intact and normal in colour.

Causes
Why buccal exostoses form is unclear, but it may involve bruxism (tooth clenching and grinding), and genetic factors. Typically they first appear in early adulthood.

Diagnosis
The presence of buccal exostosis can be diagnosed by both clinical examination and radiological interpretation of the oral cavity.
Clinically, buccal exostoses appear as single, broad-based masses, usually situated bilaterally in the premolar and molar region on the facial surface of the maxillary alveolar bone. The mass is generally smooth although in some cases a sharp, bony prominence may be present resulting in tenderness beneath the mucosa. Initial presentation usually occurs in early adolescence and the lesions may slowly enlarge up to 3–4 cm in diameter with time, however there is no malignant potential. Despite buccal exostoses being generally painless and self-limiting, they may cause patient concern regarding poor aesthetics, food lodgement and compromised oral hygiene. Their tendency to grow in size may also contribute to periodontal disease as a result of food build up in the area of the lesion.Radiographically, buccal exostoses can be identified as round, well-defined structures which superimpose the roots of the teeth, normally in the premolar and molar region. Dental panoramic tomography and cone beam tomography can be used to confirm diagnosis.An additional biopsy for diagnosis of buccal exostosis is not usually recommended, however it is important to rule out the possibility of early osseosarcomas and chondrosarcomas </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Pili torti and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Aponeurotic fibroma and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Staphylococcal scalded skin syndrome and can you explain it in depth? [/INST] Staphylococcal scalded skin syndrome (SSSS) is a dermatological condition caused by Staphylococcus aureus.

Signs and symptoms
The disease presents with the widespread formation of fluid-filled blisters that are thin walled and easily ruptured, and the patient can be positive for Nikolskys sign. Ritters disease of the newborn is the most severe form of SSSS, with similar signs and symptoms. SSSS often includes a widespread painful erythroderma, often involving the face, diaper, and other intertriginous areas. Extensive areas of desquamation might be present. Perioral crusting and fissuring are seen early in the course. Unlike toxic epidermal necrolysis, SSSS spares the mucous membranes. It is most common in children under 6 years, but can be seen in adults who are immunosuppressed or have kidney failure.

Pathophysiology
The syndrome is induced by epidermolytic exotoxins (exfoliatin) A and B, which are released by S. aureus and cause detachment within the epidermal layer, by breaking down the desmosomes.  One of the exotoxins is encoded on the bacterial chromosome, while the other is encoded on a plasmid. These exotoxins are proteases that cleave desmoglein-1, which normally holds the granulosum and spinosum layers together, similar to the pathophysiology of the autoimmune skin disease, pemphigus vulgaris.

Diagnosis
SSSS is a clinical diagnosis. This is sometimes confirmed by isolation of S. aureus from blood, mucous membranes, or skin biopsy; however, these are often negative. Skin biopsy may show separation of the superficial layer of the epidermis (intraepidermal separation), differentiating SSSS from TEN, wherein the separation occurs at the dermo-epidermal junction (subepidermal separation). SSSS may be difficult to distinguish from toxic epidermal necrolysis and pustular psoriasis.

Treatment
The mainstay of treatment for SSSS is supportive care along with eradication of the primary infection </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Melanoma and can you explain it in depth? [/INST] Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In women, they most commonly occur on the legs, while in men, they most commonly occur on the back. About 25% of melanomas develop from moles. Changes in a mole that can indicate melanoma include an increase in size, irregular edges, change in color, itchiness, or skin breakdown.The primary cause of melanoma is ultraviolet light (UV) exposure in those with low levels of the skin pigment melanin. The UV light may be from the sun or other sources, such as tanning devices. Those with many moles, a history of affected family members, and poor immune function are at greater risk. A number of rare genetic conditions, such as xeroderma pigmentosum, also increase the risk. Diagnosis is by biopsy and analysis of any skin lesion that has signs of being potentially cancerous.Using sunscreen and avoiding UV light may prevent melanoma. Treatment is typically removal by surgery. In those with slightly larger cancers, nearby lymph nodes may be tested for spread (metastasis). Most people are cured if spread has not occurred. For those in whom melanoma has spread, immunotherapy, biologic therapy, radiation therapy, or chemotherapy may improve survival. With treatment, the five-year survival rates in the United States are 99% among those with localized disease, 65% when the disease has spread to lymph nodes, and 25% among those with distant spread. The likelihood that melanoma will reoccur or spread depends on its thickness, how fast the cells are dividing, and whether or not the overlying skin has broken down.Melanoma is the most dangerous type of skin cancer. Globally, in 2012, it newly occurred in 232,000 people. In 2015,  3.1 million people had active disease, which resulted in 59,800 deaths. Australia and New Zealand have the highest rates of melanoma in the world. High rates also occur in Northern Europe and North America, while it is less common in Asia, Africa, and Latin America. In the United States, melanoma occurs about 1.6 times more often in men than women. Melanoma has become more common since the 1960s in areas mostly populated by people of European descent.

Signs and symptoms
Early signs of melanoma are changes to the shape or color of existing moles or, in the case of nodular melanoma, the appearance of a new lump anywhere on the skin. At later stages, the mole may itch, ulcerate, or bleed. Early signs of melanoma are summarized by the mnemonic "ABCDEF":
Asymmetry
Borders (irregular with edges and corners)
Colour (variegated)
Diameter (greater than 6 mm (0.24 in), about the size of a pencil eraser)
Evolving over timeThis classification does not apply to nodular melanoma, which has its own classifications:
Elevated above the skin surface
Firm to the touch
GrowingMetastatic melanoma may cause nonspecific paraneoplastic symptoms, including loss of appetite, nausea, vomiting, and fatigue. Metastasis (spread) of early melanoma is possible, but relatively rare; less than a fifth of melanomas diagnosed early become metastatic. Brain metastases are particularly common in patients with metastatic melanoma. It can also spread to the liver, bones, abdomen, or distant lymph nodes.

Cause
Melanomas are usually caused by DNA damage resulting from exposure to UV light from the sun. Genetics also play a role. Melanoma can also occur in skin areas with little sun exposure (i.e. mouth, soles of feet, palms of hands, genital areas). People with dysplastic nevus syndrome, also known as familial atypical multiple mole melanoma, are at increased risk for the development of melanoma.Having more than 50 moles indicates an increased risk melanoma might arise. A weakened immune system makes cancer development easier due to the bodys weakened ability to fight cancer cells.

UV radiation
The UV radiation from tanning beds increases the risk of melanoma. The International Agency for Research on Cancer finds that tanning beds are "carcinogenic to humans" and that people who begin using tanning devices before the age of thirty years are 75% more likely to develop melanoma.Those who work in airplanes also appear to have an increased risk, believed to be due to greater exposure to UV.UVB light (wavelengths between 315 and 280 nm) from the sun is absorbed by skin cell DNA and results in a type of direct DNA damage called cyclobutane pyrimidine dimers. Thymine, cytosine, or cytosine-thymine dimers are formed by the joining of two adjacent pyrimidine bases within a DNA strand. Somewhat similarly to UVB, UVA light (longer wavelengths between 400 and 315 nm) from the sun or from tanning beds can also be directly absorbed by skin DNA (at about 1/100 to 1/1000 of the efficiency of UVB).Exposure to radiation (UVA and UVB) is one of the major contributors to the development of melanoma. Occasional extreme sun exposure (resulting in "sunburn") is causally related to melanoma. Melanoma is most common on the back in men and on legs in women (areas of intermittent sun exposure). The risk appears to be strongly influenced by socioeconomic conditions rather than indoor versus outdoor occupations; it is more common in professional and administrative workers than unskilled workers. Other factors are mutations in or total loss of tumor suppressor genes. Use of sunbeds (with deeply penetrating UVA rays) has been linked to the development of skin cancers, including melanoma.Possible significant elements in determining risk include the intensity and duration of sun exposure, the age at which sun exposure occurs, and the degree of skin pigmentation. Melanoma rates tend to be highest in countries settled by migrants from Northern Europe which have a large amount of direct, intense sunlight to which the skin of the settlers is not adapted, most notably Australia. Exposure during childhood is a more important risk factor than exposure in adulthood. This is seen in migration studies in Australia.Having multiple severe sunburns increases the likelihood that future sunburns develop into melanoma due to cumulative damage. The sun and tanning beds are the main sources of UV radiation that increase the risk for melanoma and living close to the equator increases exposure to UV radiation.

Genetics
A number of rare mutations, which often run in families, greatly increase melanoma susceptibility. Several genes increase risks. Some rare genes have a relatively high risk of causing melanoma; some more common genes, such as a gene called MC1R that causes red hair, have a relatively lower elevated risk. Genetic testing can be used to search for the mutations.One class of mutations affects the gene CDKN2A. An alternative reading frame mutation in this gene leads to the destabilization of p53, a transcription factor involved in apoptosis and in 50% of human cancers. Another mutation in the same gene results in a nonfunctional inhibitor of CDK4, a cyclin-dependent kinase that promotes cell division. Mutations that cause the skin condition xeroderma pigmentosum  (XP) also increase melanoma susceptibility. Scattered throughout the genome, these mutations reduce a cells ability to repair DNA. Both CDKN2A and XP mutations are highly penetrant (the chances of a carrier to express the phenotype is high).Familial melanoma  is genetically heterogeneous, and loci for familial melanoma appear on the chromosome arms 1p, 9p and 12q. Multiple genetic events have been related to melanomas pathogenesis (disease development). The multiple tumor suppressor 1 (CDKN2A/MTS1) gene encodes p16INK4a – a low-molecular weight protein inhibitor of cyclin-dependent protein kinases (CDKs) – which has been localised to the p21 region of human chromosome 9. FAMMM is typically characterized by having 50 or more combined moles in addition to a family history of melanoma. It is transmitted autosomal dominantly and mostly associated with the CDKN2A mutations. People who have CDKN2A mutation associated FAMMM have a 38 fold increased risk of pancreatic cancer.Other mutations confer lower risk, but are more common in the population. People with mutations in the MC1R gene are two to four times more likely to develop melanoma than those with two wild-type (typical unaffected type) copies. MC1R mutations are very common, and all red-haired people have a mutated copy. Mutation of the MDM2 SNP309 gene is associated with increased risks for younger women.Fair- and red-haired people, persons with multiple atypical nevi or dysplastic nevi and persons born with giant congenital melanocytic nevi are at increased risk.A family history of melanoma greatly increases a persons risk, because mutations in several genes have been found in melanoma-prone families. People with a history of one melanoma are at increased risk of developing a second primary tumor.Fair skin is the result of having less melanin in the skin, which means less protection from UV radiation exists. A family history could indicate a genetic predisposition to melanoma.

Pathophysiology
The earliest stage of melanoma starts when melanocytes begin out-of-control growth. Melanocytes are found between the outer layer of the skin (the epidermis) and the next layer (the dermis). This early stage of the disease is called the radial growth phase, when the tumor is less than 1 mm thick, and spreads at the level of the basal epidermis. Because the cancer cells have not yet reached the blood vessels deeper in the skin, it is very unlikely that this early-stage melanoma will spread to other parts of the body. If the melanoma is detected at this stage, then it can usually be completely removed with surgery.When the tumor cells start to move in a different direction – vertically up into the epidermis and into the papillary dermis – cell behaviour changes dramatically.The next step in the evolution is the invasive radial growth phase, in which individual cells start to acquire invasive potential. From this point on, melanoma is capable of spreading. The Breslows depth of the lesion is usually less than 1 mm (0.04 in), while the Clark level is usually 2.
The vertical growth phase (VGP) following is invasive melanoma. The tumor becomes able to grow into the surrounding tissue and can spread around the body through blood or lymph vessels. The tumor thickness is usually more than 1 mm (0.04 in), and the tumor involves the deeper parts of the dermis.
The host elicits an immunological reaction against the tumor during the VGP, which is judged by the presence and activity of the tumor infiltrating lymphocytes (TILs). These cells sometimes completely destroy the primary tumor; this is called regression, which is the latest stage of development. In certain cases, the primary tumor is completely destroyed and only the metastatic tumor is discovered. About 40% of human melanomas contain activating mutations affecting the structure of the B-Raf protein, resulting in constitutive signaling through the Raf to MAP kinase pathway.An insult common to most cancers is damage to DNA.  UVA light mainly causes thymine dimers. UVA also produces reactive oxygen species and these inflict other DNA damage, primarily single-strand breaks, oxidized pyrimidines and the oxidized purine 8-oxoguanine (a mutagenic DNA change) at 1/10, 1/10, and 1/3rd the frequencies of UVA-induced thymine dimers, respectively.
If unrepaired, CPD photoproducts can lead to mutations by inaccurate translesion synthesis during DNA replication or repair. The most frequent mutations due to inaccurate synthesis past CPDs are cytosine to thymine (C>T) or CC>TT transition mutations. These are commonly referred to as UV fingerprint mutations, as they are the most specific mutation caused by UV, being frequently found in sun-exposed skin, but rarely found in internal organs. Errors in DNA repair of UV photoproducts, or inaccurate synthesis past these photoproducts, can also lead to deletions, insertions, and chromosomal translocations.
The entire genomes of 25 melanomas were sequenced. On average, about 80,000 mutated bases (mostly C>T transitions) and about 100 structural rearrangements were found per melanoma genome. This is much higher than the roughly 70 mutations across generations (parent to child). Among the 25 melanomas, about 6,000 protein-coding genes had missense, nonsense, or splice site mutations. The transcriptomes of over 100 melanomas has also been sequenced and analyzed. Almost 70% of all human protein-coding genes are expressed in melanoma. Most of these genes are also expressed in other normal and cancer tissues, with some 200 genes showing a more specific expression pattern in melanoma compared to other forms of cancer. Examples of melanoma specific genes are tyrosinase, MLANA, and PMEL.UV radiation causes damage to the DNA of cells, typically thymine dimerization, which when unrepaired can create mutations in the cells genes. This strong mutagenic factor makes cutaneous melanoma the tumor type with the highest number of mutations. When the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in protooncogenes or tumor suppressor genes, the rate of mitosis in the mutation-bearing cells can become uncontrolled, leading to the formation of a tumor. Data from patients suggest that aberrant levels of activating transcription factor in the nucleus of melanoma cells are associated with increased metastatic activity of melanoma cells; studies from mice on skin cancer tend to confirm a role for activating transcription factor-2 in cancer progression.Cancer stem cells may also be involved.

Gene mutations
Large-scale studies, such as The Cancer Genome Atlas, have characterized recurrent somatic alterations likely driving initiation and development of cutaneous melanoma. The Cancer Genome Atlas study has established four subtypes : BRAF mutant, RAS mutant, NF1 mutant, and triple wild-type.The most frequent mutation occurs in the 600th codon of BRAF (50% of cases). BRAF is normally involved in cell growth, and this specific mutation renders the protein constitutively active and independent of normal physiological regulation, thus fostering tumor growth. RAS genes (NRAS, HRAS and KRAS) are also recurrently mutated (30% of TCGA cases) and mutations in the 61st or 12th codons trigger oncogenic activity. Loss-of-function mutations often affect tumor suppressor genes such as NF1, TP53 and CDKN2A. Other oncogenic alterations include fusions involving various kinases such as BRAF, RAF1, ALK, RET, ROS1, NTRK1., NTRK3 and MET BRAF, RAS, and NF1 mutations and kinase fusions are remarkably mutually exclusive, as they occur in different subsets of patients. Assessment of mutation status can, therefore, improve patient stratification and inform targeted therapy with specific inhibitors.In some cases (3-7%) mutated versions of BRAF and NRAS undergo copy-number amplification.

Metastasis
The research done by Sarnas team proved that heavily pigmented melanoma cells have Youngs modulus about 4.93, when in non-pigmented ones it was only 0.98. In another experiment they found that elasticity of melanoma cells is important for its metastasis and growth: non-pigmented tumors were bigger than pigmented and it was much easier for them to spread. They shown that there are both pigmented and non-pigmented cells in melanoma tumors, so that they can both be drug-resistant and metastatic.

Diagnosis
Looking at the area in question is the most common method of suspecting a melanoma. Moles that are irregular in color or shape are typically treated as candidates. To detect melanomas (and increase survival rates), it is recommended to learn to recognize them (see "ABCDE" mnemonic), to regularly examine moles for changes (shape, size, color, itching or bleeding) and to consult a qualified physician when a candidate appears.However, many melanomas present as lesions smaller than 6 mm in diameter, and all melanomas are malignant when they first appear as a small dot. Physicians typically examine all moles, including those less than 6 mm in diameter. Seborrheic keratosis may meet some or all of the ABCD criteria, and can lead to false alarms. Doctors can generally distinguish seborrheic keratosis from melanoma upon examination or with dermatoscopy.Some advocate replacing "enlarging" with "evolving": moles that change and evolve are a concern. Alternatively, some practitioners prefer "elevation". Elevation can help identify a melanoma, but lack of elevation does not mean that the lesion is not a melanoma. Most melanomas in the US are detected before they become elevated. By the time elevation is visible, they may have progressed to the more dangerous invasive stage.In-person inspection of suspicious skin lesions is more accurate than visual inspection of images of suspicious skin lesions. When used by trained specialists, dermoscopy is more helpful to identify malignant lesions than use of the naked eye alone. Reflectance confocal microscopy may have better sensitivity and specificity than dermoscopy in diagnosing cutaneous melanoma but more studies are needed to confirm this result.

Ugly duckling
One method is the "ugly duckling sign". Correlation of common lesion characteristics is made. Lesions that deviate from the common characteristics are labeled an "ugly duckling", and a further professional exam is required. The "Little Red Riding Hood" sign suggests that individuals with fair skin and light-colored hair might have difficult-to-diagnose amelanotic melanomas. Extra care is required when examining such individuals, as they might have multiple melanomas and severely dysplastic nevi. A dermatoscope must be used to detect "ugly ducklings", as many melanomas in these individuals resemble nonmelanomas or are considered to be "wolves in sheeps clothing". These fair-skinned individuals often have lightly pigmented or amelanotic melanomas that do not present easy-to-observe color changes and variations. Their borders are often indistinct, complicating visual identification without a dermatoscope.
Amelanotic melanomas and melanomas arising in fair-skinned individuals are very difficult to detect, as they fail to show many of the characteristics in the ABCD rule, break the "ugly duckling" sign, and are hard to distinguish from acne scarring, insect bites, dermatofibromas, or lentigines.

Biopsy
Following a visual examination and a dermatoscopic exam, or in vivo diagnostic tools such as a confocal microscope, the doctor may biopsy the suspicious mole. A skin biopsy performed under local anesthesia is often required to assist in making or confirming the diagnosis and in defining severity. Elliptical excisional biopsies may remove the tumor, followed by histological analysis and Breslow scoring. Incisional biopsies such as punch biopsies are usually contraindicated in suspected melanomas, because of the possibility of sampling error or local implantation causing misestimation of tumour thickness. However, fears that such biopsies may increase the risk of metastatic disease seem unfounded.Total body photography, which involves photographic documentation of as much body surface as possible, is often used during follow-up for high-risk patients. The technique has been reported to enable early detection and provides a cost-effective approach (with any digital camera), but its efficacy has been questioned due to its inability to detect macroscopic changes. The diagnosis method should be used in conjunction with (and not as a replacement for) dermoscopic imaging, with a combination of both methods appearing to give extremely high rates of detection.

Histopathologic types
Melanoma is a type of neuroectodermal neoplasm. There are four main types of melanoma:
Other histopathologic types are:

Mucosal melanoma; When melanoma occurs on mucous membranes.
Desmoplastic melanoma
Melanoma with small nevus-like cells
Melanoma with features of a Spitz nevus
Uveal melanoma
Vaginal melanoma
Polypoid melanoma, a subclass of nodular melanoma.

In situ or invasive
A melanoma in situ has not invaded beyond the basement membrane, whereas an invasive melanoma has spread beyond it.
Some histopathological types of melanoma are inherently invasive, including nodular melanoma and lentigo maligna melanoma, where the in situ counterpart to lentigo maligna melanoma is lentigo maligna. Lentigo maligna is sometimes classified as a very early melanoma, and sometimes a precursor to melanoma.Superficial spreading melanomas and acral lentiginous melanomas can be either in situ or invasive, but acral lentiginous melanomas are almost always invasive.

Staging
Further context on cancer staging is available at TNM.

Metastatic melanomas can be detected by X-rays, CT scans, MRIs, PET and PET/CTs, ultrasound, LDH testing and photoacoustic detection. However, there is lack of evidence in the accuracy of staging of people with melanoma with various imaging methods.Melanoma stages according to AJCC, 8th edition:
TX: Primary tumor thickness cannot be assessed (such as a diagnosis by curettage)
T0: No evidence of primary tumor (such as unknown primary or completely regressed melanoma)Stage 1 and 2 require an N (lymph node) class of:

N0 – No regional metastases.Stage 1, 2 and 3 require an M (metastasis status) of:

M0: No evidence of distant metastasisOlder systems include "Clark level" and "Breslows depth", quantifying microscopic depth of tumor invasion.

Laboratory
Lactate dehydrogenase (LDH) tests are often used to screen for metastases, although many patients with metastases (even end-stage) have a normal LDH; extraordinarily high LDH often indicates the metastatic spread of the disease to the liver.
It is common for patients diagnosed with melanoma to have chest X-rays and an LDH test, and in some cases CT, MRI, PET, and/or PET/CT scans. Although controversial, sentinel lymph node biopsies and examination of the lymph nodes are also performed in patients to assess spread to the lymph nodes. A diagnosis of melanoma is supported by the presence of the S-100 protein marker.
HMB-45 is a monoclonal antibody that reacts against an antigen present in melanocytic tumors such as melanomas. It is used in anatomic pathology as a marker for such tumors. The antibody was generated to an extract of melanoma. It reacts positively against melanocytic tumors but not other tumors, thus demonstrating specificity and sensitivity. The antibody also reacts positively against junctional nevus cells but not intradermal nevi, and against fetal melanocytes but not normal adult melanocytes.
HMB-45 is nonreactive with almost all non-melanoma human malignancies, with the exception of rare tumors showing evidence of melanogenesis (e.g., pigmented schwannoma, clear cell sarcoma) or tumors associated with tuberous sclerosis complex (angiomyolipoma and lymphangiomyoma).

Prevention
There is no evidence to support or refute adult population screening for malignant melanoma.

Ultraviolet radiation
Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds), following sun protection measures and wearing sun protective clothing (long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection.
Using artificial light for tanning was once believed to help prevent skin cancers, but it can actually lead to an increased incidence of melanomas.UV nail lamps, which are used in nail salons to dry nail polish, are another common and widespread source of UV radiation that could be avoided. Although the risk of developing skin cancer through UV nail lamp use is low, it is still recommended to wear fingerless gloves and/or apply SPF 30 or greater sunscreen to the hands before using a UV nail lamp.The body uses UV light to generate vitamin D so there is a need to balance getting enough sunlight to maintain healthy vitamin D levels and reducing the risk of melanoma; it takes around a half-hour of sunlight for the body to generate its vitamin D for the day and this is about the same amount of time it takes for fair-skinned people to get a sunburn. Exposure to sunlight can be intermittent instead of all at one time.

Sunscreen
Sunscreen appears to be effective in preventing melanoma. In the past, use of sunscreens with a sun protection factor (SPF) rating of 50 or higher on exposed areas were recommended; as older sunscreens more effectively blocked UVA with higher SPF. Currently, newer sunscreen ingredients (avobenzone, zinc oxide, and titanium dioxide) effectively block both UVA and UVB even at lower SPFs. Sunscreen also protects against squamous cell carcinoma, another skin cancer.Concerns have been raised that sunscreen might create a false sense of security against sun damage.

Medications
A 2005 review found tentative evidence that statin and fibrate medication may decrease the risk of melanoma. A 2006 review however did not support any benefit.

Treatment
Confirmation of the clinical diagnosis is done with a skin biopsy. This is usually followed up with a wider excision of the scar or tumor. Depending on the stage, a sentinel lymph node biopsy may be performed. Controversy exists around trial evidence for sentinel lymph node biopsy; with unclear evidence of benefit as of 2015. Treatment of advanced malignant melanoma is performed from a multidisciplinary approach.

Surgery
Excisional biopsies may remove the tumor, but further surgery is often necessary to reduce the risk of recurrence. Complete surgical excision with adequate surgical margins and assessment for the presence of detectable metastatic disease along with short- and long-term followup is standard. Often this is done by a wide local excision (WLE) with 1–2 cm (0.4–0.8 in) margins. Melanoma-in-situ and lentigo malignas are treated with narrower surgical margins, usually 0.2–0.5 cm (0.1–0.2 in). Many surgeons consider 0.5 cm (0.2 in) the standard of care for standard excision of melanoma-in-situ, but 0.2 cm (0.1 in) margin might be acceptable for margin controlled surgery (Mohs surgery, or the double-bladed technique with margin control). The wide excision aims to reduce the rate of tumor recurrence at the site of the original lesion. This is a common pattern of treatment failure in melanoma. Considerable research has aimed to elucidate appropriate margins for excision with a general trend toward less aggressive treatment during the last decades. A 2009 meta-analysis of randomized controlled trials found a small difference in survival rates favoring wide excision of primary cutaneous melanomas, but these results were not statistically significant.Mohs surgery has been reported with cure rate as low as 77% and as high as 98.0% for melanoma-in-situ. CCPDMA and the "double scalpel" peripheral margin controlled surgery is equivalent to Mohs surgery in effectiveness on this "intra-epithelial" type of melanoma.
Melanomas that spread usually do so to the lymph nodes in the area of the tumor before spreading elsewhere. Attempts to improve survival by removing lymph nodes surgically (lymphadenectomy) were associated with many complications, but no overall survival benefit. Recently, the technique of sentinel lymph node biopsy has been developed to reduce the complications of lymph node surgery while allowing assessment of the involvement of nodes with tumor.Biopsy of sentinel lymph nodes is a widely used procedure when treating cutaneous melanoma.Neither sentinel lymph node biopsy nor other diagnostic tests should be performed to evaluate early, thin melanoma, including melanoma in situ, T1a melanoma or T1b melanoma ≤ 0.5mm. People with these conditions are unlikely to have the cancer spread to their lymph nodes or anywhere else and have a 5-year survival rate of 97%. Because of these considerations, sentinel lymph node biopsy is considered unnecessary health care for them. Furthermore, baseline blood tests and radiographic studies should not be performed only based on identifying this kind of melanoma, as there are more accurate tests for detecting cancer and these tests have high false-positive rates. To potentially correct false positives, gene expression profiling may be used as auxiliary testing for ambiguous and small lesions.Sentinel lymph node biopsy is often performed, especially for T1b/T2+ tumors, mucosal tumors, ocular melanoma and tumors of the limbs. A process called lymphoscintigraphy is performed in which a radioactive tracer is injected at the tumor site to localize the sentinel node(s). Further precision is provided using a blue tracer dye, and surgery is performed to biopsy the node(s). Routine hematoxylin and eosin (H&E) and immunoperoxidase staining will be adequate to rule out node involvement. Polymerase chain reaction (PCR) tests on nodes, usually performed to test for entry into clinical trials, now demonstrate that many patients with a negative sentinel lymph node actually had a small number of positive cells in their nodes. Alternatively, a fine-needle aspiration biopsy may be performed and is often used to test masses.
If a lymph node is positive, depending on the extent of lymph node spread, a radical lymph node dissection will often be performed. If the disease is completely resected, the patient will be considered for adjuvant therapy.
Excisional skin biopsy is the management of choice. Here, the suspect lesion is totally removed with an adequate (but minimal, usually 1 or 2 mm) ellipse of surrounding skin and tissue. To avoid disruption of the local lymphatic drainage, the preferred surgical margin for the initial biopsy should be narrow (1 mm). The biopsy should include the epidermal, dermal, and subcutaneous layers of the skin. This enables the histopathologist to determine the thickness of the melanoma by microscopic examination. This is described by Breslows thickness (measured in millimeters). However, for large lesions, such as suspected lentigo maligna, or for lesions in surgically difficult areas (face, toes, fingers, eyelids), a small punch biopsy in representative areas will give adequate information and will not disrupt the final staging or depth determination. In no circumstances should the initial biopsy include the final surgical margin (0.5 cm, 1.0 cm, or 2 cm), as a misdiagnosis can result in excessive scarring and morbidity from the procedure. A large initial excision will disrupt the local lymphatic drainage and can affect further lymphangiogram-directed lymphnode dissection. A small punch biopsy can be used at any time where for logistical and personal reasons a patient refuses more invasive excisional biopsy. Small punch biopsies are minimally invasive and heal quickly, usually without noticeable scarring.

Add on treatment
High-risk melanomas may require adjuvant treatment, although attitudes to this vary in different countries. In the United States, most patients in otherwise good health will begin up to a year of high-dose interferon treatment, which has severe side effects, but may improve the patients prognosis slightly. However, the British Association of Dermatologists guidelines on melanoma state that interferon is not recommended as a standard adjuvant treatment for melanoma. A 2013 meta-analysis suggested that the addition of interferon alpha increased disease-free and overall survival for people with AJCC TNM stage II-III cutaneous melanoma. A 2011 meta-analysis showed that interferon could lengthen the time before a melanoma comes back but increased survival by only 3% at 5 years. The unpleasant side effects also greatly decrease quality of life.In the European Union, interferon is usually not used outside the scope of clinical trials.

Chemotherapy
Chemotherapy drugs such as Dacarbazine have been the backbone of metastatic melanoma treatment since FDA approval in 1975; however, its efficacy in terms of survival has never been proven in an RCT.In people with locally advanced cutaneous malignancies and sarcoma, isolated limb infusion (ILI) has been found to be a minimally invasive and well-tolerated procedure for delivering regional chemotherapy.

Targeted therapy
Melanoma cells have mutations that allow them to survive and grow indefinitely in the body. Small-molecule targeted therapies work by blocking the genes involved in pathways for tumor proliferation and survival. The main treatments are BRAF, C-Kit and NRAS inhibitors. These inhibitors work to inhibit the downstream pathways involved in cell proliferation and tumour development due to specific gene mutations. People can be treated with small-molecule targeted inhibitors if they are positive for the specific mutation. BRAF inhibitors, such as vemurafenib and dabrafenib and a MEK inhibitor trametinib are the most effective, approved treatments for BRAF positive melanoma. Melanoma tumors can develop resistance during therapy which can make therapy no longer effective, but combining the use of BRAF and MEK inhibitors may create a fast and lasting melanoma therapy response.A number of treatments improve survival over traditional chemotherapy. Biochemotherapy (chemotherapy with cytokines IL-2 and IFN-α) combined with BRAF inhibitors improved survival for people with BRAF positive melanoma. Biochemotherapy alone did not improve overall survival and had higher toxicity than chemotherapy. Combining multiple chemotherapy agents (polychemotherapy) did not improve survival over monochemotherapy. Targeted therapies result in relatively short progression-free survival (PFS) times. The therapy combination of dabrafenib and trametinib has a 3-year PFS of 23%, and 5-year PFS of 13%.

Immunotherapy
Immunotherapy is aimed at stimulating the persons immune system against the tumor, by enhancing the bodys own ability to recognize and kill cancer cells.  The current approach to treating melanoma with immunotherapy includes three broad categories of treatments including cytokines, immune check point inhibitors, and adoptive cell transfer. These treatment options are most often used in people with metastatic melanoma and significantly improves overall survival. However, these treatments are often costly. For example, one immune check point inhibitor treatment, pembrolizumab, costs $10,000 to US$12,000 for a single dose administered every 3 weeks.Cytokine therapies used for melanoma include IFN-a and IL-2. IL-2 (Proleukin) was the first new therapy approved (1990 EU, 1992 US) for the treatment of metastatic melanoma in 20 years. IL-2 may offer the possibility of a complete and long-lasting remission in this disease in a small percentage of people with melanoma. Intralesional IL-2 for in-transit metastases has a high complete response rate ranging from 40 to 100%. Similarly, IFN-a has shown only modest survival benefits and high toxicity, limiting its use as a stand-alone therapy.Immune check point inhibitors include anti-CTLA-4 monoclonal antibodies (ipilimumab and tremelimumab), toll-like receptor (TLR) agonists, CD40 agonists, anti-PD-1 (pembrolizumab, pidilizumab, and nivolumab) and PD-L1 antibodies. Evidence suggests that anti-PD-1 antibodies are more effective than anti-CTLA4 antibodies with less systemic toxicity. The five-year progression-free survival for immunotherapy with pembrolizumab is 21%. A therapeutic approach that includes the combination of different therapies improves overall survival and progression-free survival compared to treatment with the separate immunotherapy drugs alone.Ongoing research is looking at treatment by adoptive cell transfer. Adoptive cell transfer refers to the application of pre-stimulated, modified T cells or dendritic cells and is presently used to minimize complications from graft-versus-host disease.The combination nivolumab/relatlimab (Opdualag) was approved for medical use in the United States in March 2022.

Lentigo maligna
Standard excision is still being done by most surgeons. Unfortunately, the recurrence rate is exceedingly high (up to 50%). This is due to the ill-defined visible surgical margin, and the facial location of the lesions (often forcing the surgeon to use a narrow surgical margin). The narrow surgical margin used, combined with the limitation of the standard "bread-loafing" technique of fixed tissue histology – result in a high "false negative" error rate, and frequent recurrences. Margin control (peripheral margins) is necessary to eliminate the false negative errors. If bread loafing is used, distances from sections should approach 0.1 mm to assure that the method approaches complete margin control. A meta-analysis of the literature in 2014 found no randomized controlled trials of surgical interventions to treat lentigo maligna or melanoma in-situ, even though surgery is the most widely used treatment.Mohs surgery has been done with cure rate reported to be as low as 77%, and as high as 95% by another author. The "double scalpel" peripheral margin controlled excision method approximates the Mohs method in margin control, but requires a pathologist intimately familiar with the complexity of managing the vertical margin on the thin peripheral sections and staining methods.Some melanocytic nevi, and melanoma-in-situ (lentigo maligna) have resolved with an experimental treatment, imiquimod (Aldara) topical cream, an immune enhancing agent. Some dermasurgeons are combining the 2 methods: surgically excising the cancer and then treating the area with Aldara cream postoperatively for three months. While some studies have suggested the adjuvant use of topical tazarotene, the current evidence is insufficient to recommend it and suggests that it increases topical inflammation, leading to lower patient compliance.

Radiation
Radiation therapy is often used after surgical resection for patients with locally or regionally advanced melanoma or for patients with unresectable distant metastases. Kilovoltage x-ray beams are often used for these treatments and have the property of the maximum radiation dose occurring close to the skin surface. It may reduce the rate of local recurrence but does not prolong survival. Radioimmunotherapy of metastatic melanoma is currently under investigation.
Radiotherapy has a role in the palliation of metastatic melanoma.

Prognosis
Factors that affect prognosis include:

tumor thickness in millimeters (Breslows depth),
depth related to skin structures (Clark level),
type of melanoma,
presence of ulceration,
presence of lymphatic/perineural invasion,
presence of tumor-infiltrating lymphocytes (if present, prognosis is better),
location of lesion,
presence of satellite lesions, and
presence of regional or distant metastasis.Certain types of melanoma have worse prognoses but this is explained by their thickness. Less invasive melanomas even with lymph node metastases carry a better prognosis than deep melanomas without regional metastasis at time of staging. Local recurrences tend to behave similarly to a primary unless they are at the site of a wide local excision (as opposed to a staged excision or punch/shave excision) since these recurrences tend to indicate lymphatic invasion.
When melanomas have spread to the lymph nodes, one of the most important factors is the number of nodes with malignancy. Extent of malignancy within a node is also important; micrometastases in which malignancy is only microscopic have a more favorable prognosis than macrometastases. In some cases micrometastases may only be detected by special staining, and if malignancy is only detectable by a rarely employed test known as the polymerase chain reaction (PCR), the prognosis is better. Macrometastases in which malignancy is clinically apparent (in some cases cancer completely replaces a node) have a far worse prognosis, and if nodes are matted or if there is extracapsular extension, the prognosis is worse still. In addition to these variables, expression levels and copy number variations of a number of relevant genes may be used to support assessment of malignant melanoma prognosis.Stage IV melanoma, in which it has metastasized, is the most deadly skin malignancy: five-year survival is 22.5%. When there is distant metastasis, the cancer is generally considered incurable. The five-year survival rate is less than 10%. The median survival is 6–12 months. Treatment is palliative, focusing on life extension and quality of life. In some cases, patients may live many months or even years with metastatic melanoma (depending on the aggressiveness of the treatment). Metastases to skin and lungs have a better prognosis. Metastases to brain, bone and liver are associated with a worse prognosis. Survival is better with metastasis in which the location of the primary tumor is unknown.There is not enough definitive evidence to adequately stage, and thus give a prognosis for, ocular melanoma and melanoma of soft parts, or mucosal melanoma (e.g., rectal melanoma), although these tend to metastasize more easily. Even though regression may increase survival, when a melanoma has regressed, it is impossible to know its original size and thus the original tumor is often worse than a pathology report might indicate.
About 200 genes are prognostic in melanoma, with both unfavorable genes where high expression is correlated to poor survival and favorable genes where high expression is associated with longer survival times. Examples of unfavorable genes are MCM6 and TIMELESS; an example of a favorable gene is WIPI1.An increased neutorphil-to-lymphocyte ratio is associated with worse outcomes.

Epidemiology
Globally, in 2012, melanoma occurred in 232,000 people and resulted in 55,000 deaths. Australia and New Zealand have the highest rates of melanoma in the world. It has become more common in the last 20 years in areas that are mostly Caucasian.The rate of melanoma has increased in the recent years, but it is not clear to what extent changes in behavior, in the environment, or in early detection are involved.

Australia
Australia has a very high – and increasing – rate of melanoma. In 2012, deaths from melanoma occurred in 7.3–9.8 per 100,000 population. In Australia, melanoma is the third most common cancer in either sex; indeed, its incidence is higher than for lung cancer, although the latter accounts for more deaths. It is estimated that in 2012, more than 12,000 Australians were diagnosed with melanoma: given Australias modest population, this is better expressed as 59.6 new cases per 100,000 population per year; >1 in 10 of all new cancer cases were melanomas. Melanoma incidence in Australia is matter of significance, for the following reasons:

Australian melanoma incidence has increased by more than 30 per cent between 1991 and 2009.
Australian melanoma age-standardised incidence rates were, as of 2008, at least 12 times higher than the world average.
Australian melanoma incidence is, by some margin, the highest in the world.
Overall age-standardised cancer incidence in Australia is the highest in the world, and this is attributable to melanoma alone. Age-standardised overall cancer incidence is similar to New Zealand, but there is a statistically significant difference between Australia and all other parts of the developed world including North America, Western Europe, and the Mediterranean.

United States
In the United States about 9,000 people die from melanoma a year. In 2011 it affected 19.7 per 100,000, and resulted in death in 2.7 per 100,000.In 2013:

71,943 people in the United States were diagnosed with melanomas of the skin, including 42,430 men and 29,513 women.
9,394 people in the United States died from melanomas of the skin, including 6,239 men and 3,155 women.The American Cancer Societys estimates for melanoma incidence in the United States for 2017 are:

About 87,110 new melanomas will be diagnosed (about 52,170 in men and 34,940 in women).
About 9,730 people are expected to die of melanoma (about 6,380 men and 3,350 women).Melanoma is more than 20 times more common in whites than in African Americans. Overall, the lifetime risk of getting melanoma is about 2.5% (1 in 40) for whites, 0.1% (1 in 1,000) for African Americans, and 0.5% (1 in 200) for Hispanics.
The risk of melanoma increases as people age. The average age of people when the disease is diagnosed is 63.

History
Although melanoma is not a new disease, evidence for its occurrence in antiquity is rather scarce. However, one example lies in a 1960s examination of nine Peruvian mummies, radiocarbon dated to be approximately 2400 years old, which showed apparent signs of melanoma: melanotic masses in the skin and diffuse metastases to the bones.John Hunter is reported to be the first to operate on metastatic melanoma in 1787. Although not knowing precisely what it was, he described it as a "cancerous fungous excrescence". The excised tumor was preserved in the Hunterian Museum of the Royal College of Surgeons of England. It was not until 1968 that microscopic examination of the specimen revealed it to be an example of metastatic melanoma.The French physician René Laennec was the first to describe melanoma as a disease entity. His report was initially presented during a lecture for the Faculté de Médecine de Paris in 1804 and then published as a bulletin in 1806.The first English-language report of melanoma was presented by an English general practitioner from Stourbridge, William Norris in 1820. In his later work in 1857 he remarked that there is a familial predisposition for development of melanoma (Eight Cases of Melanosis with Pathological and Therapeutical Remarks on That Disease). Norris was also a pioneer in suggesting a link between nevi and melanoma and the possibility of a relationship between melanoma and environmental exposures, by observing that most of his patients had pale complexions. He also described that melanomas could be amelanotic and later showed the metastatic nature of melanoma by observing that they can disseminate to other visceral organs.
The first formal acknowledgment of advanced melanoma as untreatable came from Samuel Cooper in 1840. He stated that the only chance for a cure depends upon the early removal of the disease (i.e., early excision of the malignant mole) ...More than one and a half centuries later this situation remains largely unchanged.

Terminology
The word melanoma came to English from 19th-century New Latin and uses combining forms derived from ancient Greek roots: melano- (denoting melanin) + -oma (denoting a tissue mass and especially a neoplasm), in turn from Greek μέλας melas, "dark", and -ωμα oma, "process". The word melanoma has a long history of being used in a broader sense to refer to any melanocytic tumor, typically, but not always malignant, but today the narrower sense referring only to malignant types has become so dominant that benign tumors are usually not called melanomas anymore and the word melanoma is now usually taken to mean malignant melanoma unless otherwise specified. Terms such as "benign melanocytic tumor" unequivocally label the benign types, and modern histopathologic tumor classifications used in medicine do not use the word for benign tumors.

Research
Pharmacotherapy research for unresectable or metastatic malignant melanoma is ongoing.

Targeted therapies
In clinical research, adoptive cell therapy and gene therapy, are being tested.Two kinds of experimental treatments developed at the National Cancer Institute (NCI), have been used in metastatic melanoma with tentative success.The first treatment involves adoptive cell therapy (ACT) using TILs immune cells (tumor-infiltrating lymphocytes) isolated from a persons own melanoma tumor. These cells are grown in large numbers in a laboratory and returned to the patient after a treatment that temporarily reduces normal T cells in the patients body. TIL therapy following lymphodepletion can result in durable complete response in a variety of setups.The second treatment, adoptive transfer of genetically altered autologous lymphocytes, depends on delivering genes that encode so called T cell receptors (TCRs), into patients lymphocytes. After that manipulation lymphocytes recognize and bind to certain molecules found on the surface of melanoma cells and kill them.A cancer vaccine showed modest benefit in late-stage testing in 2009 against melanoma.

BRAF inhibitors
About 60% of melanomas contain a mutation in the B-Raf gene. Early clinical trials suggested that B-Raf inhibitors including Plexxicons vemurafenib could lead to substantial tumor regression in a majority of patients if their tumor contain the B-Raf mutation. In June 2011, a large clinical trial confirmed the positive findings from those earlier trials.In August 2011 Vemurafenib received FDA approval for the treatment of late-stage melanoma. In May 2013 the US FDA approved dabrafenib as a single agent treatment for patients with BRAF V600E mutation-positive advanced melanoma.Some researchers believe that combination therapies that simultaneously block multiple pathways may improve efficacy by making it more difficult for the tumor cells to mutate before being destroyed. In October 2012 a study reported that combining Dabrafenib with a MEK inhibitor trametinib led to even better outcomes. Compared to Dabrafenib alone, progression-free survival was increased to 41% from 9%, and the median progression-free survival increased to 9.4 months versus 5.8 months. Some side effects were, however, increased in the combined study.In January 2014, the FDA approved the combination of dabrafenib and trametinib for the treatment of people with BRAF V600E/K-mutant metastatic melanoma. In June 2018, the FDA approved the combination of a BRAF inhibitor encorafenib and a MEK inhibitor binimetinib for the treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.Eventual resistance to BRAF and MEK inhibitors may be due to a cell surface protein known as EphA2 which is now being investigated.

Ipilimumab
At the American Society of Clinical Oncology Conference in June 2010, the Bristol-Myers Squibb pharmaceutical company reported the clinical findings of their drug ipilimumab. The study found an increase in median survival from 6.4 to 10 months in patients with advanced melanomas treated with the monoclonal ipilimumab, versus an experimental vaccine </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Allergic conjunctivitis and can you explain it in depth? [/INST] Allergic conjunctivitis (AC) is inflammation of the conjunctiva (the membrane covering the white part of the eye) due to allergy. Although allergens differ among patients, the most common cause is hay fever. Symptoms consist of redness (mainly due to vasodilation of the peripheral small blood vessels), edema (swelling) of the conjunctiva, itching, and increased lacrimation (production of tears). If this is combined with rhinitis, the condition is termed allergic rhinoconjunctivitis (ARC).
The symptoms are due to release of histamine and other active substances by mast cells, which stimulate dilation of blood vessels, irritate nerve endings, and increase secretion of tears.
Treatment of allergic conjunctivitis is by avoiding the allergen (e.g., avoiding grass in bloom during "hay fever season") and treatment with antihistamines, either topical (in the form of eye drops), or systemic (in the form of tablets). Antihistamines, medications that stabilize mast cells, and nonsteroidal anti-inflammatory drugs (NSAIDs) are generally safe and usually effective.

Signs and symptoms
The conjunctiva is a thin membrane that covers the eye. When an allergen irritates the conjunctiva, common symptoms that occur in the eye include: ocular itching, eyelid swelling, tearing, photophobia, watery discharge, and foreign body sensation (with pain).Itching is the most typical symptom of ocular allergy, and more than 75% of patients report this symptom when seeking treatment. Symptoms are usually worse for patients when the weather is warm and dry, whereas cooler weather with lower temperatures and rain tend to assuage symptoms. Signs in phlyctenular keratoconjunctivitis include small yellow nodules that develop over the cornea, which ulcerate after a few days.A study by Klein et al. showed that in addition to the physical discomfort allergic conjunctivitis causes, it also alters patients routines, with patients limiting certain activities such as going outdoors, reading, sleeping, and driving. Therefore, treating patients with allergic conjunctivitis may improve their everyday quality of life.

Causes
The cause of allergic conjunctivitis is an allergic reaction of the bodys immune system to an allergen. Allergic conjunctivitis is common in people who have other signs of allergic disease such as hay fever, asthma and eczema.Among the most common allergens that cause conjunctivitis are:
Pollen from trees, grass and ragweed
Animal skin and secretions such as saliva
Perfumes
Cosmetics
Skin medicines
Air pollution
Smoke
Dust mites
Balsam of Peru (used in food and drink for flavoring, in perfumes and toiletries for fragrance, and in medicine and pharmaceutical items for healing properties)
Eye drops (A reaction to preservatives in eye drops can cause toxic conjunctivitis)
Contact lens solution (some preservatives can irritate the eye over time resulting in conjunctivitis)
Contact lens (conjunctivitis is also caused by repeated mechanical irritation of the conjunctiva by contact lens wearers)Most cases of seasonal conjunctivitis are due to pollen and occur in the hay fever season, grass pollens in early summer and various other pollens and moulds may cause symptoms later in the summer.

Pathophysiology
The ocular allergic response is a cascade of events that is coordinated by mast cells. Beta chemokines such as eotaxin and MIP-1 alpha have been implicated in the priming and activation of mast cells in the ocular surface. When a particular allergen is present, sensitization takes place and prepares the system to launch an antigen specific response. TH2 differentiated T cells release cytokines, which promote the production of antigen specific immunoglobulin E (IgE). IgE then binds to IgE receptors on the surface of mast cells. Then, mast cells release histamine, which then leads to the release of cytokines, prostaglandins, and platelet-activating factor. Mast cell intermediaries cause an allergic inflammation and symptoms through the activation of inflammatory cells.When histamine is released from mast cells, it binds to H1 receptors on nerve endings and causes the ocular symptom of itching. Histamine also binds to H1 and H2 receptors of the conjunctival vasculature and causes vasodilatation. Mast cell-derived cytokines such as chemokine interleukin IL-8 are involved in recruitment of neutrophils. TH2 cytokines such as IL-5 recruit eosinophils and IL-4, IL-6, and IL-13, which promote increased sensitivity. Immediate symptoms are due to the molecular cascade. Encountering the allergen a patient is sensitive to leads to increased sensitization of the system and more powerful reactions. Advanced cases can progress to a state of chronic allergic inflammation.

Diagnosis
Classification
SAC and PAC
Both seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) are two acute allergic conjunctival disorders. SAC is the most common ocular allergy. Symptoms of the aforementioned ocular diseases include itching and pink to reddish eye(s). These two eye conditions are mediated by mast cells. Nonspecific measures to ameliorate symptoms include cold compresses, eyewashes with tear substitutes, and avoidance of allergens. Treatment consists of antihistamine, mast cell stabilizers, dual mechanism anti-allergen agents, or topical antihistamines. Corticosteroids are another option, but, considering the side-effects of cataracts and increased intraocular pressure, corticosteroids are reserved for more severe forms of allergic conjunctivitis such as vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC).

VKC and AKC
Both vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) are chronic allergic diseases wherein eosinophils, conjunctival fibroblasts, epithelial cells, mast cells, and TH2 lymphocytes aggravate the biochemistry and histology of the conjunctiva. VKC is a disease of childhood and is prevalent in males living in warm climates. AKC is frequently observed in males between the ages of 30 and 50. VKC and AKC can be treated by medications used to combat allergic conjunctivitis or the use of steroids. Maxwell-Lyons sign, shield ulcer, cobblestones papillae, gelatinous thickening at the limbus, and Horner-Trantas dots are specific features of vernal type.

Giant papillary conjunctivitis
Giant papillary conjunctivitis is not a true ocular allergic reaction and is caused by repeated mechanical irritation of the conjunctiva. Repeated contact with the conjunctival surface caused by the use of contact lenses is associated with GPC.

PKC
Phlyctenular keratoconjunctivitis (PKC) results from a delayed hypersensitivity/inflammatory reaction to antigens expressed by various pathogens. Common agents include Staph. aureus, Mycobacterium tuberculosis, Chlamydia and Candida.

Management
A detailed history allows doctors to determine whether the presenting symptoms are due to an allergen or another source. Diagnostic tests such as conjunctival scrapings to look for eosinophils are helpful in determining the cause of the allergic response. Antihistamines, mast cell stabilizers or dual activity drugs are safe and usually effective. Corticosteroids are reserved for more severe cases of inflammation, and their use should be monitored by an optometrist due to possible side-effects. When an allergen is identified, the person should avoid the allergen as much as possible.

Non-pharmacological methods
If the allergen is encountered and the symptoms are mild, a cold compress or artificial tears can be used to provide relief.

Mast cell stabilizers
Mast cell stabilizers can help people with allergic conjunctivitis. They tend to have delayed results, but they have fewer side-effects than the other treatments and last much longer than those of antihistamines. Some people are given an antihistamine at the same time so that there is some relief of symptoms before the mast cell stabilizers becomes effective. Doctors commonly prescribe lodoxamide and nedocromil as mast cell stabilizers, which come as eye drops.A mast cell stabilizer is a class of non-steroid controller medicine that reduces the release of inflammation-causing chemicals from mast cells. They block a calcium channel essential for mast cell degranulation, stabilizing the cell, thus preventing the release of histamine. Decongestants may also be prescribed. Another common mast cell stabilizer that is used for treating allergic conjunctivitis is sodium cromoglicate.

Antihistamines
Antihistamines such as diphenhydramine and chlorpheniramine are commonly used as treatment. People treated with H1 antihistamines exhibit reduced production of histamine and leukotrienes as well as downregulation of adhesion molecule expression on the vasculature which in turn attenuates allergic symptoms by 40–50%.

Dual Activity Agents
Dual-action medications are both mast cell stabilizers and antihistamines. They are the most common prescribed class of topical anti allergy agent. Olopatadine (Patanol, Pazeo) and ketotifen fumarate (Alaway or Zaditor) are both commonly prescribed. Ketotifen is available without a prescription in some countries.

Corticosteroids
Ester based "soft" steroids such as loteprednol (Alrex) are typically sufficient to calm inflammation due to allergies, and carry a much lower risk of adverse reactions than amide based steroids.
A systematic review of 30 trials, with 17 different treatment comparisons found that all topical antihistamines and mast cell stabilizers included for comparison were effective in reducing symptoms of seasonal allergic conjunctivitis </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Fibroadenoma and can you explain it in depth? [/INST] Fibroadenomas are benign breast tumours characterized by an admixture of stromal and epithelial tissue. Breasts are made of lobules (milk producing glands) and ducts (tubes that carry the milk to the nipple). These are surrounded by glandular, fibrous and fatty tissues. Fibroadenomas develop from the lobules. The glandular tissue and ducts grow over the lobule to form a solid lump.
Since both fibroadenomas, and breast lumps as a sign of breast cancer can appear similar, it is recommended to perform ultrasound analyses and possibly tissue sampling with subsequent histopathologic analysis in order to make a proper diagnosis. Unlike typical lumps from breast cancer, fibroadenomas are easy to move, with clearly defined edges.Fibroadenomas are sometimes called breast mice or a breast mouse owing to their high mobility in the breast.

Signs and symptoms
Fibroadenomas are benign (not harmful in effect) tumours of the breast, most often present in women in their 20s and 30s. Clinically, fibroadenomas are usually solid breast lumps that are:
•	Painless•	Firm or rubbery•	Mobile•	Solitary-round with distinct, smooth borders
People who have a simple fibroadenoma have a slightly increased risk of developing malignant (harmful) breast cancer. Complex fibroadenomas may increase the risk of breast cancer.In the male breast, fibroepithelial tumors are very rare, and are mostly phyllodes tumors.  Exceptionally rare case reports exist of fibroadenomas in the male breast, however these cases may be associated with antiandrogen treatment.

Cause
The cause of fibroadenoma is unknown (idiopathic). A connection between fibroadenomas and reproductive hormones has been suggested which may explain why they present themselves during reproductive years, increase in size during pregnancy, and regress post-menopause.Higher intake of fruits and vegetables, higher number of live births, lower use of oral contraceptives and moderate exercise are associated with lower frequency of fibroadenomas.

Pathology
Cytology
The diagnostic findings on needle biopsy consist of abundant stromal cells, which appear as bare bipolar nuclei, throughout the aspirate; sheets of fairly uniform-size epithelial cells that are typically arranged in either an antler-like pattern or a honeycomb pattern.  These epithelial sheets tend to show typical metachromatic blue on Diff-Quik staining. Foam cells and apocrine cells may also be seen, although these are less diagnostic features. The gallery images below demonstrate these features.
Cellular fibroadenoma, also known as juvenile fibroadenoma, is a variant type of fibroadenoma with increased stromal cellularity.

Macroscopic
Approximately 90% of fibroadenomas are less than 3 cm in diameter.  However, these tumors have the potential to grow reaching a remarkable size, particularly in young individuals. The tumor is round or ovoid, elastic, and nodular, and has a smooth surface. The cut surface usually appears homogenous and firm, and is grey-white or tan in colour.
The pericanalicular type (hard) has a whorly appearance with a complete capsule, while the intracanalicular type (soft) has an incomplete capsule.

Microscopic
Fibroadenoma of the breast is a benign tumor composed of a biplastic proliferation of both stromal and epithelial components. This biplasia can be arranged in two growth patterns: pericanalicular (stromal proliferation around epithelial structures) and intracanalicular (stromal proliferation compressing the epithelial structures into clefts).
These tumors characteristically display hypovascular stroma compared to malignant neoplasms. Furthermore, the epithelial proliferation appears in a single terminal ductal unit and describes duct-like spaces surrounded by a fibroblastic stroma. The basement membrane is intact.

Molecular pathology
Up to 66% of fibroadenomas harbor mutations in the exon (exon 2) of the mediator complex subunit 12 (MED12) gene. In particular, these mutations are restricted to the stromal component.

Diagnosis
A fibroadenoma is usually diagnosed through clinical examination, ultrasound or mammography, and often a biopsy sample of the lump. Suspicious findings on imaging may result in a person needing a biopsy in order to gain a definitive diagnosis. There are three types of biopsies: Fine-needle aspiration, core-needle biopsy and surgical biopsy. The method of biopsy depends on the appearance, size and location of the breast mass.

Treatment
Fibroadenomas can be expected to shrink naturally and so, most are simply monitored. Monitoring fibroadenomas involves regular check-ups to make sure that the breast mass is not growing and is not potentially cancerous. Check-ups involve physical examinations performed every 3–6 months and optional diagnostic imaging performed every 6–12 months for 1–2 years. Generally, surgery is only recommended if the fibroadenoma gets larger or causes increased symptoms. They are removed with a small margin of normal breast tissue if the preoperative clinical investigations are suggestive of the necessity of this procedure.  A small amount of normal tissue must be removed in case the lesion turns out to be a phyllodes tumour on microscopic examination.Because needle biopsy is often a reliable diagnostic investigation, some doctors may decide not to operate to remove the lesion, and instead opt for clinical follow-up to observe the lesion over time using clinical examination and mammography to determine the rate of growth, if any, of the lesion.  A growth rate of less than sixteen percent per month in women under fifty years of age, and a growth rate of less than thirteen percent per month in women over fifty years of age have been published as safe growth rates for continued non-operative treatment and clinical observation.Some fibroadenomas respond to treatment with ormeloxifene.Fibroadenomas have not been shown to recur following complete excision or transform into phyllodes tumours following partial or incomplete excision.

Non-invasive Surgical Interventions
There are several non-invasive options for the treatment of fibroadenomas, including percutaneous radiofrequency ablation (RFA), cryoablation, and percutaneous microwave ablation. With the use of advanced medical imaging, these procedures do not require invasive surgery and have the potential for enhanced cosmetic results compared with conventional surgery.

Cryoablation
The FDA approved cryoablation of a fibroadenoma as a safe, effective, and minimally-invasive alternative to open surgical removal in 2001 </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Radioulnar synostosis and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Fungal keratitis and can you explain it in depth? [/INST] Fungal keratitis is a fungal infection of the cornea, which can lead to blindness. It generally presents with a red, painful eye and blurred vision. There is also increased sensitivity to light, and excessive tears or discharge.It is caused by fungal organisms such as Fusarium, Aspergillus or Candida.Fungal keratitis has a worldwide distribution, but is more common in the tropics. Around 1 million people become blind every year due to fungal keratitis. Theodor Leber first described a case of fungal keratitis caused by Aspergillus in 1879.

Signs and symptoms
The symptoms of fungal keratitis typically emerge over 5-10 days and present with a painful eye, blurred vision, and redness of eye. There is increased sensitivity to light, and excessive tears or discharge. The symptoms are markedly less as compared to a similar bacterial ulcer. Symptoms may be noted to persist after contact lenses are removed, or following antibiotic treatment.Signs: The eyelids and adnexa involved shows edema and redness, conjunctiva is chemosed. Ulcer may be present. It is a dry looking corneal ulcer with satellite lesions in the surrounding cornea. Usually associated with fungal ulcer is hypopyon, which is mostly white fluffy in appearance. Rarely, it may extend to the posterior segment to cause endophthalmitis in later stages, leading to the destruction of the eye. (Note: Fungal endophthalmitis is extremely rare)

Causes
Fungal keratitis has been reported to be caused by more than 70 different fungi, of which Fusarium, Aspergillus and Candida are responsible for 95% of cases.A. flavus and A. fumigatus are the most common types of Aspergillus to cause fungal keratitis. F. Solani is the most common type of Fusarium and others include Curvularia and Acremonium. C. albicans, C. guilliermondii and C. parapsilosis are the main types of Candida to cause fungal keratitis.

Pathophysiology
The precipitating event for fungal keratitis is trauma with a vegetable / organic matter. A thorn injury, or in agriculture workers, trauma with a wheat plant while cutting the harvest is typical. This implants the fungus directly in the cornea. The fungus grows slowly in the cornea and proliferates to involve the anterior and posterior stromal layers. The fungus can break through the descemets membrane and pass into the anterior chamber. The patient presents a few days or weeks later with fungal keratitis.

Diagnosis
The diagnosis is made by an ophthalmologist/optometrist correlating typical history, symptoms and signs. Many times it may be missed and misdiagnosed as bacterial ulcer. A definitive diagnosis is established only after a positive culture report (lactophenol cotton blue, calcoflour medium), typically taking a week, from the corneal scraping. Recent advances have been made in PCR ref 3./immunologic tests which can give a much quicker result.

Classification
Infectious keratitis can be bacterial, fungal, viral, or protozoal. Remarkable differences in presentation of the patient allows presumptive diagnosis by the eye care professional, helping in institution of appropriate anti-infective therapy.

Prevention
Prevention of trauma with vegetable / organic matter, particularly in agricultural workers while harvesting can reduce the incidence of fungal keratitis. Wearing of broad protective glasses with side shields is recommended for people at risk for such injuries.

Treatment
A presumptive diagnosis of fungal keratitis requires immediate empirical therapy. Natamycin ophthalmic suspension is the drug of choice for filamentous fungal infection. Fluconazole ophthalmic solution is recommended for Candida infection of the cornea. Amphotericin B eye drops may be required for non-responding cases, but can be quite toxic and requires expert pharmacist for preparation </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Candidal intertrigo and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Funisitis and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Ocular melanosis and can you explain it in depth? [/INST] Ocular melanosis (OM) is a blue-gray and/or brown lesion of the conjunctiva that can be separated into benign conjunctival epithelial melanosis (BCEM) and primary acquired melanosis (PAM), of which the latter is considered a risk factor for uveal melanoma. The disease is caused by an increase of melanocytes in the iris, choroid, and surrounding structures. Overproduction of pigment by these cells can block the trabecular meshwork through which fluid drains from the eye. The increased fluid in the eye leads to increased pressure, which can lead to glaucoma. In humans, this is sometimes known as pigment dispersion syndrome.

Benign Conjunctival Epithelial Melanosis
BCEM, also referred to as conjunctival hypermelanosis, complexion-associated melanosis, or racial melanosis, is a non-cancerous lesion of the conjunctiva that is more commonly found in dark-skinned individuals (over 90% of lesions are found in black persons and around 5% in white persons). It is due to excess production of melanin in the setting of a normal number of melanocytes in the conjunctiva. It appears very early in life and the pattern does not seem to change upon reaching adulthood. There can be asymmetrical involvement of the eyes, and lesions are usually described as flat, brown, and patchy areas of pigmentation.

Primary Acquired Melanosis
PAM is a potentially cancerous lesion of the conjunctiva, which has a higher risk of transforming into a malignant melanoma in white persons </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Mouth and genital ulcers with inflamed cartilage syndrome and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is GMS syndrome and can you explain it in depth? [/INST]  </s>