Analysing Keratinocytic Skin Tumours Biology Essay

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The skin is a remarkable organ being the largest in human body accounting for 15% of the total body weight in adult humans and having 6 million cells, 5000 sensory points and 150 glands in each square centimeter. It has a complex structure, arranged in three layers derived from ectodermal and mesodermal origin. The layers include from top to bottom, the epidermis (and its appendages), the dermis and the hypodermis. The epidermis undergoes constant wear and tear and estimated 2-3 billion cells are shed daily. These are replaced by keratinocytes originating from mitotic divisions of stem cells of the basal layer of epidermis. This dynamicity makes this layer a 'fertile land' for neoplastic lesions. In fact, the tumours derived from epidermal keratinocytes i.e. keratinocytic tumours account for most of the neoplastic lesions of skin.

In its own, the burden of skin tumours is tremendous being numerous than those occurring in any other organ. According to American Cancer Society, no. of new cases of skin cancer diagnosed each year is more than the combined no. of cancers of the breast, prostate, lung and colon and the lifetime risk for the development of skin cancer in the USA is now 1 in 5. Melanoma and other skin cancers are ranked 12th most common in men and 15th most common in women by a 2004 WHO report (Global Burden of Disease) and were found in 706,000 persons out of the total population of 6,437 million. In a local study conducted at Ayub Medical College, skin cancers were found skin cancers to be just 1.04% of the total cancers reported over a fairly long period of nine years indicating low incidence in the region. Keratinocytic tumours dominate the above said picture by accounting for approximately 90% or more of all skin malignancies. Among keratinocytic tumours, basal cell carcinomas constitute the major bulk constituting 70% of all keratinocytic tumours and 50% of all skin malignancies according to different studies.

Keratinocytic tumours pose a significant public health problem and a financial burden. In US, the annual expenditure on treatment of non-melanoma skin cancers is estimated around 2 billion dollars. Fortunately these tumours have low mortality rate and are mostly curable on complete excision. These facts necessitate a better approach towards the early diagnosis and a deeper understanding of the pathogenesis of the lesions.

The main etiologic factor is solar radiations which causes DNA damage. Especially UVB (290-320 nm) is found to contribute in the formation of squamous and basal cell carcinomas. Other carcinogenic agents include tobacco use, human papilloma viruses, arsenic, industrial chemicals such as vinyl chloride, polycyclic aromatic hydrocarbons, and exposure to gasoline.

According to the WHO classification of skin tumours, keratinocytic tumours comprise a large spectrum of lesions ranging from benign proliferations i.e. acanthomas to malignant ones i.e. basal and squamous cell carcinomas.


Basal cell carcinoma 8090/3

Superficial basal cell carcinoma 8091/3

Nodular (solid) basal cell carcinoma 8097/3

Micronodular basal cell carcinoma 8090/3

Infiltrating basal cell carcinoma 8092/3

Fibroepithelial basal cell carcinoma 8093/3

Basal cell carcinoma with adnexal differentiation 8098/3

Basosquamous carcinoma 8094/3

Keratotic basal cell carcinoma 8090/3

Squamous cell carcinoma 8070/3

Acantholytic squamous cell carcinoma 8075/3

Spindle-cell squamous cell carcinoma 8074/3

Verrucous squamous cell carcinoma 8051/3

Pseudovascular squamous cell carcinoma 8075/3

Adenosquamous carcinoma 8560/3

Bowen disease

Bowenoid papulosis 8081/2

Actinic keratosis

Arsenical keratosis

PUVA keratosis


Verruca vulgaris

Verruca plantaris

Verruca plana


Epidermolytic acanthoma

Warty dyskeratoma

Acantholytic acanthoma

Solar lentigo

Seborrheic keratosis


Clear cell acanthoma

Large cell acanthoma

Keratoacanthoma 8071/1

Lichen planus-like keratosis


Morphology code of the International Classification of Diseases for Oncology (ICD-0) and the Systematized Nomenclature of Medicine (

Behaviour is coded /0 for benign tumors, /3 for malignant tumours, /2 for in situ carcinoma and /1 for borderline or uncertain behaviour.

Basal cell carcinoma (BCC) or basal cell epithelioma is the most common form of skin cancers with 1 million new cases diagnosed annually. In Australia, its prevalence is highest i.e. 2000 cases per 100,000 individuals. Its incidence is low in blacks, Asians and Hispanics. It has a male predilection with a 2:1 male-to-female ratio and typically occurs in adults. In Pakistan, BCC was found in 40% of diagnosed skin cancers according to a local study. BCCs develop predominantly in sun-damaged skin individuals who are fair skinned. It manifests as pearl papules or nodules with telangiectasia, sometimes with central ulcerations. It is not possible to evaluate some basal cell carcinomas from squamous cell carcinoma or even melanoma without skin biopsy. PTCH1 gene that functions as an inhibitor of the hedgehog signaling pathway is found to be abnormal in basal cell nevus syndrome (BCNS) patients and many sporadic cases as well. BCCs are locally invasive tumours and metastases occur in less than 1 in 10,000 tumours.

The microscopy of BCCs is diagnostic and depends on the sub-type. Nodular basal cell carcinomas make up 60-80% of all BCCs and occur most frequently on the head. The histological examination is characteristic showing large lobules of basaloid cells with peripheral palisading nuclei and retraction artefact. The second most common variant is superficial basal cell carcinoma making up of 10-30% of BCCs. It is characterized on histology by lobules of basaloid cells confined to papillary dermis only and occurs most frequently on trunk. Micronodular variant shows small nodules that permeate the dermis and are separated by normal collagen. A variant with slightly different morphology is infiltrative type in which strands or cords of basaloid cells are present rather than nests. In it, peripheral palisading and retraction artifact are not seen and perineural invasion is common. This variant has morphologic overlap with the tumour patterns in microcystic adnexal carcinoma and desmoplastic trichioepithelioma. Basosquamous carcinoma, another variant of BCC, is characterized by tumour cells having more abundant cytoplasm and more marked keratinization than typical basal cell carcinomas. This variant has a high proliferative activity, propensity for local destruction and potential for an early regional and distant metastasis. Some other variants pose a diagnostic problem and include keratotic basal cell carcinoma, pigmented basal cell carcinoma and basal cell carcinoma with areas of adnexal differentiation that can masquerade squamous cell carcinoma, melanoma and adnexal tumours respectively.

Squamous cell carcinoma (SCC) is the second most common form of skin cancers with 0.2 million new cases diagnosed annually. In Australia, its prevalence is highest i.e. 600 cases per 100,000 individuals. It is uncommon in Black people. In Pakistan, squamous cell carcinoma was found in 53.1% of diagnosed skin cancers according to a local study. Most cases arise on the sun-exposed skin of elderly people and ultraviolet radiation exposure especially UVB is the most important etiological factor. Other factors include burn scars, arsenic, HPV infection, long standing inflammatory and ulcerative lesions, coal tar and immunosuppression. SCCs grossly appear as shallow ulcers, often with a crust and indurated surrounding skin, or as plaques or nodules. In contrast to BCC, there are characteristic precursor lesions in case of SCC that include Bowen's disease, Marjolin ulcer, radiation scar or thermal burn. Histologically all the types show nests, sheets and strands of squamous epithelial cells with abundant eiosinophilic cytoplasm and vesicular nucleus extending into the dermis or even deeper. The other important features include prominent intercellular bridges, keratinization and horn pearl formation. Depending on the degree of differentiation, SCCs are subjectively categorized into 'well,' 'moderately' and 'poorly' differentiated types. In SCCs, neural, vascular or lymphatic invasion occurs but only in occasional cases.

Other than the above said types, there are some other characteristic variants. In acantholytic SCC, there is loosening of the intercellular bridges resulting in suprabasilar or intratumoural acantholysis and large intraepidermal spaces. This variant accounts for 2-4% of all cutaneous SCCs and common sites of involvement are the skin of the head and neck region, particularly on and around the ear. Verrucous SCC, also called Ackerman's tumour or Buschke-Löwenstein tumour, is characterized by a cauliflower-like appearance with exophytic and endophytic growth, and a papillomatous surface. On histology, it shows an asymmetric exophytic and endophytic growth pattern of atypical squamous epithelium with pushing rather than destructive or infiltrative margins. Tumour cells exhibit only minimal atypia and very low mitotic activity. An important diagnostic clue is the presence of neutrophils which sometimes may form small intraepidermal abscesses. Separating verrucous SCC from benign reactive processes and SCC of the more usual type is sometimes challenging for the histopathologist. Another variant causing significant diagnostic issues is spindle-cell SCC that is composed almost entirely of spindle cells with variable proportion of areas of typicality. It is difficult to distinguish this variant from other cutaneous spindle cell neoplasms like spindle cell melanoma, atypical fibroxanthoma and leiomyosarcoma. Still there are psuedovascular and adenosquamous variants with close differential to angiosarcoma and mucoepidermoid carcinoma respectively. Both these variants show more aggressive behaviour than other variants of SCC.

Bowen disease (BD) is an intraepidermal carcinoma found commonly in fair complexion Caucasian men. It is also known as squamous cell carcinoma in situ. Male-to-female ratio is 4:1. In 1991, a study from Minnesota reported the annual average rate of Bowen disease as 14 cases per 100,000 whites. In 1994, a study from Hawaii reported a rate 10 times higher i.e. 142 cases per 100,000 whites. It commonly occurs in the age range of 60-80 years. The possible etiologies include chronic sun damage, human papilloma virus (HPV) infection, trauma, chronic irritation, tobacco and immunity. It occurs predominantly on sun-exposed areas of skin and clinically presents as single or multiple erythematous, rounded to irregular, scaly, keratotic, eroded patches or plaques devoid of hair. The surrounding skin is unaffected. The clinical entity of erythroplasia of Queyrat (EPQ) is regarded as BD of the glans penis. The microscopic features of BD are loss of polarity of epidermis with atypical keratinocytes, abnormal mitoses, dyskeratosis, pale-staining to vacuolated cells and occasional multinucleated cells. All these changes are confined to epidermis and the dermo-epidermal basement membrane remains intact. A chronic inflammatory infiltrate is usual in the upper dermis. The abnormal keratinizing cells are reactive for glucose-6-phosphate dehydrogenase and often show aneuploidy and/or p53 mutations.

Bowenoid papulosis, another keratinocytic lesion, is differentiated from BD clinically by its appearance as popular to coalescing lesions in anogenital region and microscopically by its salt and pepper distribution of abnormal keratinocytes and mitoses and frequent HPV positivity in the affected epidermis.

Actinic keratosis (AK) or solar keratosis is a common intraepidermal neoplasm observed in sun-damaged skin. In Australia, the country with the highest skin cancer rate in the world, the prevalence of actinic keratosis among adults older than 40 years has been reported to range from 40-60%. The prevalence of actinic keratosis is much higher in individuals with fair skin and blue eyes and is lower in individuals with darker skin types. The patients commonly present with multiple persistent, asymptomatic erythematous lesions. There are six types of AK sharing a common feature i.e. keratinocytes atypia in epidermis, but not involving the whole thickness as seen in BD. The atypical features include nuclear enlargement, hyperchromasia, pleomorphism, nucleolar prominence, mitotic activity, dyskeratosis and cytoplasmic pallor. Solar elastosis and chronic inflammation is routinely seen in dermis. The variants are described on the presence of specific features i.e. hypertrophic variant has acanthosis and papillomatosis in hypertrophic AK, intraepidermal clefting in AK, increased melanin in atypical keratinocytes in pigmented AK, flattening of rete ridges in atrophic AK, keratinocytic apoptosis and band-like infiltrate in lichenoid AK and bowen-like full thickness involvement in bowenoid AK. The bowenoid AK is differentiated from BD by less defined edge, follicular sparing and acrosyringeal involvement. Immunohistochemically AK shows similar pattern of keratin and involcurin staining as seen in normal epidermis, but CD95 (Fas) is lost in two thirds of AK and retinoid receptors are reduced. There are p53 mutations seen in 50% cases. Untreated AK has been reported to develop into invasive SCC in 8-20% of patients.

PUVA keratosis occurs in PUVA-treated skin and resembles AK. The third member of the group i.e. arsenical keratosis is a clinicopathoogic diagnosis occurring in patients exposed to arsenic and commonly occurs on thenar eminences, lateral borders of palms, base or lateral surfaces of fingers, soles, heels and toes. Clinically it begins as yellowish verrucous papules and on histology, a spectrum of changes can be present like vacuolated cells in the Malpighian layer, compact hyperkeratosis, acanthosis, papillomatosis and patterns resembling hypertrophic AK or seborrhoeic keratosis.

Verrucas are common epithelial tumours caused by human papilloma viruses (HPV) and occur with equal frequency in both sexes. The prevalence of cutaneous warts is upto 10% in 2-12 years children, regressing spontaneously in 1-2 years. HPVs are epitheliotropic and particularly HPV types 16 and 18 have been found to promote proliferation of suprabasal epidermal cells. The infected keratinocytes are not lysed, but shed with desquamating cornified layer.

In skin, there are three main types; vulgaris, plantaris and plana. Veruuca vulgaris or common wart is usually associated with HPV-2 and found commonly on exposed parts like fingers and dorsum of hands. It presents clinically as hard, rough-surfaced papules. Common histologic features include epidermis shows hyperkeratosis, acanthosis, papillamatosis with overlying columns of parakeratosis and koilocytoses in upper layers. Rarely, Bowen disease or squamous cell carcinoma can develop in a common wart, usually in immunocompromised patients. Verruca plantaris or myrmecia occurs on the sole of foot and over pressure points. It is characterized by endophytic proliferation of rete ridges and prominent eiosinophilic inclusions. Verruca plana or flat warts appear as flat-topped, smooth papules and are associated with HPV-3 and HPV-10. Most lesions are located on the back of the hands and fingers, distal forearm, lower leg and face. Histologically these warts show loose hyperkeratosis with basket-weave pattern and epidermal hyperplasia. There is no papillomatosis in contrast to other two types of warts. Flat warts are known to commonly persist for several years and resolve spontaneously.

Acanthomas include benign tumors of epidermal keratinocytes with some unifying characters that include benign behavior, epidermal hyperplasia, and lack of dysplasia. In addition to acanthosis, each one of the acanthomas has its own unique pattern of aberrant keratinization as epidermoid keratinization in seborrheic keratosis, absence of keratinization in clear cell acanthoma, epidermolytic hyperkeratosis in epidermolytic acanthoma, dyskeratosis in warty dyskeratoma, etc.

Epidermal acanthomas present as asymptomatic, keratotic papules and can occur at any site on skin. These are characterized histologically by perinuclear vacuolatization in keratinocytes wxcept that of basal layer, hypergranulosis with large basophilic granules and intracytoplasmic amorphous eosinophilic bodies.

Warty dyskeratoma or follicular dyskeratoma commonly involves the head and neck region. It is a papulonodular lesion with usually a central keratin plug and, on histology, shows a well-demarcated endophytic lesion characterized by prominent acantholytic dyskeratosis. This results in suprabasal clefting with formation of villi which protrude into a lacuna, a feature also seen in Darier's disease. The stroma often shows a characteristic appearance with dense collagen or fibroblasts and focal intrastromal clefts.

Acantholytic acanthoma is characterized by microscopic features of acantholysis putting it in close differential with pemphigus vulgaris, pemphigus vegetans, superficial pemphigus, Grover's disease or Hailey-Hailey disease. Truncal skin, i.e., back, chest, or flank, is most commonly involved. These present grossly as scaly, flesh-colored papules, and are usually seen after sixth decade.

Solar lentigo or lentigo simplex is characterized by a clinically flat epidermis with microscopic acanthosis and highly localized well-circumscribed pigment on sun exposed skin. To make a diagnosis of lentigo, the requisite features include localized epidermal hyperplasia, marked epidermal hypermelanosis, and the lack of nevomelanocytic nests. Peutz-Jeghers syndrome is associated with the presence of numerous lentigines associated with multiple hamartomatous gastrointestinal polyps.

Seborrheic keratoses or seborrheic warts are the most common benign tumor in older individuals. In 2000, Memon et al found in a British population younger than 40 years that 8.3% of the males and 16.7% of the females had at least one seborrheic keratosis. In an Australian population, 23.5% of individuals aged 15-30 years were found to have at least one seborrheic keratosis, with no significant differences between the sexes. It is more common in elderly Caucasian patients. These appear clinically as slightly raised, tan to brown or black papules, often have a "stuck on" appearance and can be easily removed. Leser-Trélat syndrome is characterized by presence of multiple pruritic seborrhoeic keratoses associated with malignancy. On basis of histology, it has seven distinct types. Acanthotic or common type has broad columns or sheets of basaloid or squamoid cells with intervening horn cysts. Reticulated type shows a net like or retiform pattern of acanthosis. Pigmented type demonstrates pronounced epidermal melanin pigment. Clonal type is an unusual form characterized by whorled collections or nests of keratinocytes within the thickened epidermis. It has similar appearance to SCC but lacks the usual cell atypia. Irritated type has a heavy lichenoid inflammatory cell infiltrate in the upper dermis and numerous apoptotic bodies. Hyperkeratotic type shows varying degrees of hyperkeratosis, papillomatosis and acanthosis and may resemble verruca vulgaris. Flat type reveals mild hyperkeratosis, often mild basal pigmentation ('dirty feet') and only minimal acanthosis. There are no horn cysts in this type.

Melanoacanthoma is commonly found on the head and trunk areas and manifests as pigmented papules, plaques or nodules. It is considered to be a variant of seborrhoeic keratosis. Histological picture of this lesion shows abundant dendritic melanocytes in all epidermal layers and keratinocytes rich in melanin granules.

Clear cell or Degos acanthoma was initially thought to be of follicular or sweat-gland origin but positivity for involucrin and epithelial membrane antigen indicated towards an epithelial origin. It is usually located on the lower extremities of middle-aged or elderly individuals and presents as a solitary, slowly growing, dome-shaped papule or plaque. It is characterized by glycogen rich, pale-staining keratinocytes within a background of epidermal psoriasiform hyperplasia. The clear cells show a strong Periodic acid- Schiff (PAS) reaction.

Large cell acanthoma usually affects actinically damaged skin and is characterized by hyperkeratosis, hypergranulosis and orthokeratosis. The large keratinocytes have nuclei roughly twice the size of adjacent epidermal or adnexal keratinocytes, and show minimal nuclear pleomorphism. Three variants have been described: a basic pattern with mild to moderate acanthosis, a verrucous pattern with papillomatosis and hyperkeratosis, and a flat-hyperkeratotic pattern.

Keratoacanthoma is a squamoproliferative tumours. It is most frequent in subtropical areas, has male preponderance and usually involves hair-bearing skin. Based on the Hawaiian data, the incidence of keratoacanthoma in ethnic Japanese, Filipino, and Hawaiian populations has been estimated to be 22, 7, and 6 per 100,000 respectively. The main etiologic factor is exposure to excessive sunlight. These acanthomas usually appear as solitary, flesh-coloured, dome-shaped nodules with a central keratin plug and tend to grow rapidly over 1-2 months with spontaneous involution after 3-6 months. Two clinical variants are important i.e. subungual variant which produces pressure erosion and usually fails to regress spontaneously and multiple variant which may be eruptive (Grzybowski type), self-healing (the Ferguson Smith type, autosomal dominant with an abnormality on chromosome 9q22), and a mixed eruptive and self-healing type (Witten and Zak type). Multiple lesions are also found to occur in immunosuppressed patients, in the Muir-Torre syndrome and at sites of trauma. On histology, a fully developed lesion show lipping of the edges of the lesion which overlap the central keratin-filled crater. There are blunt downgrowths of squamous epithelium into dermis forming an irregular lower border. The differential diagnosis from squamous cell carcinoma can be a difficult, and the features favouring keratoacanthoma include the flask-like configuration with a central keratin plug, the pattern of keratinization, the large central squamous cells, the lack of anaplasia and a sharp outline between tumour nests and the stroma. These acanthomas can recur in up to 8% of cases.

Lichen planus-like keratosis are heterogeneous epidermal or melanocytic lesions formed by involution of a solar lentigo, seborrhoeic keratosis, large cell acanthoma or other epidermal proliferative lesion. Most patients are middle-aged to elderly and females are affected more than males.

The above said WHO classification seems to be clear-cut not necessitating any further technology apart from routine hematoxylin and eosin (H & E) staining for diagnosis, nevertheless molecular technologies like immunohistochemistry (IHC) have resulted in a level of distinction between diagnoses which was not previously possible. IHC not only aids in establishing the differentiation between histologically resembling cases, but also provides comprehensive insights into the pathophysiology of the lesions. In case of tumours, the importance is further enhanced as the sub-typing and the understanding of molecular mechanisms based on IHC help in providing information which is essential in guiding therapy. The distinction between histologically similar tumors is often critical as therapeutic options often differ.

IHC is based on the demonstration of antigens (Ag) within tissue sections by means of specific antibodies (Abs). Once antigen-antibody (Ag-Ab) binding occurs, it is demonstrated with a coloured histochemical reaction visible by light microscopy or fluorochromes with ultraviolet light. Since its discovery by Coons in 1940s, IHC has undergone technical improvements, and thousands of Ags are now detectable in routinely fixed tissues. Abs can be polyclonal or monoclonal. Polyclonal antobodies are raised by injecting animals with peptide antigens, and when a secondary immune response is stimulated, antibodies are isolated from whole serum. Thus, polyclonal antibodies recognize several epitopes and are less specific as comapred to monoclonal ones. Another functional classification is dividing the antibodies into primary and secondary. Primary antibodies are raised against an antigen of interest and are typically unconjugated (unlabelled), while secondary antibodies are raised against primary antibodies. Hence, secondary antibodies recognize immunoglobulins of a particular species and are conjugated to either biotin or a reporter enzyme such as alkaline phosphatase or horse raddish peroxidase (HRP).

There are two techniques used for the immunohistochemical detection of antigens in tissue, the direct method and the indirect method. The direct method involves reaction of a labeled antibody with the antigen in tissue section and is simple and fast. However, sensitivity is an issue because signal amplification is meager. On the other hand, in the indirect method, first an unlabeled primary antibody is made to react with tissue antigen and secondly a labeled secondary antibody directed against the primary antibody is involved. This method is more sensitive due to signal amplification through several secondary antibody reactions with different antigenic sites on the primary antibody. Routinely a biotinylated secondary antibody is coupled with streptavidin-horseradish peroxidase. This is reacted with 3,3HYPERLINK ",3'-Diaminobenzidine"'HYPERLINK ",3'-Diaminobenzidine"-Diaminobenzidine (DAB) to produce a brown staining wherever primary and secondary antibodies are attached in a process known as DAB staining.

The common problems with IHC include non-specific background staining because of non-immunological binding of the specific immune sera by hydrophobic and electrostatic forces to certain sites within tissue sections, false positive results due to inadequate or delayed fixation, and false staining if antibodies are contaminated. Another problem is endogenous peroxidase found in many tissues that can interfere with DAB staining. So the usual practice is to pretreat the tissue section with hydrogen peroxide solution prior to incubation of primary antibody, eliminating endogenous peroxidase activity. Special controls must be run in order to test the protocol and for the specificity of the antibody being used. Positive control is to test a protocol or procedure and make sure it works. Negative control is to test for the specificity of an antibody involved. First, no staining must be shown when omitting primary antibody or replacing a specific primary antibody with normal serum (must be the same species as primary antibody). Second, tissues with known negativity for an Ab can be used for comparison.


p63 gene is a member of the p53 family of transcription factors. It has been known by various names like KET, p40, p51, EEC3, OFC8, SHFM4, TP53L, TP73L, p51, TP63 etc. It codes for a protein p63 which is found in nucleus. 3q28


S100A6 gene is a member of the S100 family of transcription factors coding for various calcium binding proteins. Its other names include 2A9, PRA, 5B10, CABP and CACY. Its protein S100A6 is located in nucleus envelope, cytoplasm, cell membrane and peripheral membrane protein. The protein was characterized from Ehrlich ascites tumor (EAT) cells by Calabretta and his co-workers in 1986.

In humans, interestingly 16 out of 20 known members of S100 family including S100A6 have the genes clustered to chromosome 1q21, known as the epidermal differentiation complex. This region contains many genes that are expressed in epidermal keratinocytes including involcurin and filaggrin, indicating the importance of S100A6 in regulating epidermal cell cycle.

The S100 proteins belong to the Ca+2 binding EF-hand motif superfamily and have been implicated in a variety of cellular processes such as differentiation, regeneration, cell growth, and signal transduction in neoplastic cells. S100A6 protein has a low molecular weight and functions as a calcium sensor. Its monomer form binds two Ca2+ ions, with the first binding to the atypical EF-hand loop located in the N-terminal part of the molecule and the second one to the typical EF-hand loop located in the C-terminal part (Fig. ).

Fig. 1. Schematic structure of S100A6 showing its two EF-hand motifs each consisting of two helical regions and a loop.

S100A6 has been related to multiple cellular functions such as proliferation, differentiation, secretion, regeneration, and metastasis.

S100A6 gene is strongly expressed during the transition between G0 to S phase of the cell cycle. It had been proposed that p53 inhibits cell proliferation by suppressing the S100A6 promoter because mutant p53 has been shown to have no or weak suppression of the promoter resulting in increased S100A6 levels. In the same context, the use of antisense S100A6 had been shown to inhibit proliferation in fibroblasts. Another evidence implicating the definite role of S100A6 in cell cycle progression is that its expression is found to be elevated in response to growth factor-stimulated proliferation of quiescent fibroblasts

The up regulation of S100A6 in the renal collecting tubules in response to vasopressin indicates towards its role in transepithelial ion transport.