Keratinocyte Carcinomas and Other Non-Melanocytic Tumors.

Question 1

Risk factors and epidemiology of skin cancers?

Answer 1

Predisposing factors : UV exposure, viruses like HPV and genetic predisposition.

Question 2

What is actinic keratosis?

Answer 2

Also called solar keratosis. It is not considered a real cancer but a precancerous lesion. Caused by atypical proliferation of cells occurring in the basal layer of the epidermis. Common lesion in 60-70 year olds especially in cases of chronic sun exposure. It presents as a macule/papule which is scaly and is localized in sun exposed sites. Not cured can lead to invasive SCC. There are three grades :
1. Palpable but barely visible.
2. Palpable and visible.
3. Hypertrophic.

Question 3

What is carcinoma in situ (Bowens disease)?

Answer 3

It occurs when the clonal proliferation involves the epidermis only. It is characterized by a red desquamative patch, asymptomatic with sharp irregular borders, usually solitary and slowly expanding. It has a predilection for the trunk and the extremities (not for the face like actinic). A biopsy is needed to distinguish it from eczema/psoriasis.
Main features are hyperkeratosis, acanthosis which is thickening of the epidermis, hypercellularity, loss of polarity and multinucleated cells.

Question 4

What is the difference between carcinoma in situ and actinic keratosis?

Answer 4

In Bowen’s disease, the malignant proliferation involves all the layers of the epidermis while in actinic keratosis only the basal layer is involved in the malignant proliferation. Both are lesions characterized by a complete resolution, but the difference is evident from a histological and clinical point of view: Bowen’s disease carries a higher risk of developing invasive squamous cell carcinoma.

Question 5

What is erythoplasia of Queryat?

Answer 5

Type of squamous cell carcinoma in situ involving only the
epidermis and occurring in the male genitalia as a red shiny area usually on the glans and the foreskin. The risk of metastasis is higher compared to Bowen’s disease because the site of involvement is a semi-mucosa characterized by the presence of more vessels.

Question 6

Epidemiology of SCC? Clinical presentation?

Answer 6

It is the second most common malignant cutaneous lesion after basal cell carcinoma with an increase in percentage reaching 200% in the last 30 years. The annual incidence shows 10/100.000 cases in Italy per year.

Clinical presentation of squamous cell carcinoma: crusted or keratotic area with red borders that is not easy to differentiate from actinic keratosis; the lesions are usually thicker and more keratotic. It can also have a nodular, verrucous warty, and chronic ulceration appearance. Sometimes SCC can present as a cutaneous horn with underlining SCC, as a warty verrucous plaque, or as a non-healing ulcerated plaque (in typically sun-exposed areas).

Question 7

What are some special sites of SCC involvement?

Answer 7

a) SCC of the lip: considered as less prone to metastasize compared to other types of SCC;commonly associated with smoking in men.
b) SCC of the tongue: more frequent in males with an ulcerated appearance and a higher risk of metastasis.
c) SCC of the penis: area at high risk of metastasis; important role of oncogenic HPV (16-18).
d) SCC of the scrotum: it has been associated with chimney sweeps in the past but is now very rare, it may occur in patients with psoriasis undergoing UV rays’ therapy.
e) SCC of the vulva: lesion sometimes called lichen sclera-atrophic. It is a white fibrotic transformation of the vulva affecting 50-70 years old women.
f) SCC of the nails: not easily differentiated from periungual warts (very common lesionsespecially in young people). Commonly associated with human oncogenic HPV.

Question 8

What are some subtypes of SCC?

Answer 8

Verrucous carcinoma: a term used to indicate a type of SCC very well differentiated from the classical one from a histopathological point of view and usually less aggressive. Well-differentiated growing lesion that can be of three types: oral mucosa, anogenital region and plantar area.

Marjolins ulcer : very aggressive SCC arising on a chronic scarring process, high risk of metastasis.

Question 9

How is SCC diagnosed?

Answer 9

Clinical examination involving the exploration of the local regional lymph nodes. The gold standard is the histopathological examination also useful to differentiate between the different subtypes.
One of the dermatoscopic clues for defining SCC is the presence of whitish keratotic areas (crusts and ulcers can be present too).
Histopathology is characterized by nests of malignant squamous epithelial cells arising from the epidermis with mitotic figures, atypical nuclei, and a variable type of keratinization. Lesions in which we see keratin pearls (eosinophilic lesions) are well differentiated and this is a sign of a better prognosis.

Important to note diameter of lesion, involve the of lips, ear and genitalia. H area of the face.

Question 10

SCC causes and triggers?

Answer 10

Sun, chemicals, genetic factors, light skin phototypes, immunosuppression, transplantation especially heart recipients.

Question 11

How can we prevent and treat SCC?

Answer 11

Photoprotection especially in the pediatric age, treatment of actinic keratosis, treatment of chronic star inflammations such as ulcers or burns and treatments of dermatosis such as lichen planus.

1st line therapy is surgical excision depending on type, location and age.
Cryotherapy and radiotherapy in larger lesions.

Follow up every 6 moths for the first two years and then once a year for 5 years. If it has not returned after 5 years the risk is almost 0.

Question 12

What sign should we look for in progression form actinic keratosis to SCC?

Answer 12

Rapid extension of the patch, erosion, ulceration that bleeds easily.
Deep infiltration and inflammation.

Question 13

Basal cell carcinoma epidemiology?

Answer 13

Most frequent cancer in the world. It occurs mostly in sun- exposed areas such as the face. Males are more prone to develop basal cell carcinoma. Maximum incidence in countries with high sun exposure such as Australia but in these areas also genetic background plays a major role because most of the population is of Celtic origin.

In squamous cell carcinoma the trigger is chronic sun exposure, in basal cell carcinoma it is the acute intermittent ent exposure to UV rays.

It is associated to mutations in the PTCH gene which controls the growth of various tissues, patients born with basal cell naevus syndrome are born with a mutation of one allele of PTCH1 gene and may develop hundreds of BCCs.

Question 14

What are some Basal cell carcinoma clinical presentations?

Answer 14

It may be present as a slow-growing lesion. The clue to differentiate BCC from SCC is the slightly raised pearly irregular translucent edge in BCC.Squamous cell carcinoma has a faster way of growing in comparison to BCC.

• Nodulocystic BCC: nodule with pearly border; sometimes ulcerated. The nodular presentation is the most frequent and it is a more benign variant since the borders of the tumor are the
ones under our eyes. This variant is prevalent in the face.

• Pigmented BCC is tricky because it mimics a melanoma (DDX), and the raised pearly borders are a way of differentiating BCC from a melanoma.

• Ulcer BCC that does not kill; it presents the pearly translucent border.

• Sclerodermiform BCC variant has a highly dangerous behavior since it is difficult to delineate the borders (not well demarcated). The lesion could be a fibrotic sclerodermiform plaque and
in this case, it could be difficult to remove it since it is locally aggressive.
• Superficial-type BCC is prevalent in the trunk.

Question 15

Prognosis and treatment of BCC?

Answer 15

BCC unlike SCC has only local invasive growth and never metastasizes, there are some very rare exceptions. It is less dangerous than SCC. Looking at the lesion there is an increase in chance of relapse if it is over 2 cm in diameter, involves the H area of the face, histologically characterized by infiltrative growth.

Treatment is complete surgical excision if possible. Laser, radio and cryotherapy.

Question 16

What is Kaposi Sarcoma?

Answer 16

Vascular neoplasms requiring the involvement of Herpes viral infection (HHV8) for its development. Proliferating cells are endothelial cells of vessels. One of the most common clinical manifestations associated with AIDS is Kaposi sarcoma.
4 variants of Kaposi sarcoma:

• Classic sporadic (Mediterranean variant; most common): differently from AIDS-associated KS is
a chronic disorder occurring mainly in the Mediterranean area.
Differently from AIDS-associated KS, the classic type is characterized by red violaceous nodules/papules on legs and feet only with slow indolent growth. Legs and feet are typical sites involved in classic KS. The involvement of the GI system or lungs is extremely rare but may occur. It may develop in patients 70 years old.

• AIDS-associated: it spreads to every internal organ (especially the GI tract and lungs). Red/violaceous lesions/nodules on the conjuncAva, and oral mucosa (gums).
• Endemic (African).
• Transplant associated (iatrogenic).

Question 17

What are lymphomas?

Answer 17

These neoplasms are proliferations of monoclonal lymphoid cells of primary cutaneous onset. Lymphomas are divided into Hodgkin and non-Hodgkin; primary cutaneous lymphomas are non-Hodgkin lymphomas. The typical organs involved in lymphomas are the lymph nodes and bone marrow but in primary cutaneous lymphoma, only the skin is involved (the origin of the lymphoma is in the skin), and sometimes the monoclonal proliferation remains in the skin and the patient may remain for many years only with it before involving the lymph nodes.

Question 18

What are T cell lymphomas?

Answer 18

Most common type of primary cutaneous lymphoma. The most common type is mycosis fungoides. Occurring in males of 50 years old. Different stages can be distinguished:

• Initial early stage: patch stage characterized by itchy, erythematous, scaly, and desquamative lesions on flanks, gluteal area, abdomen, non-infiltrating. In this case, the DDX is with psoriasis, eczema. Sometimes a biopsy is needed for the differential diagnosis. Patients usually respond well to treatment; they rarely develop a systemic involvement.
• Second stage: plaque and nodule stage (Worse prognosis). Lesions are infiltrating. In this case, we consider the possibility of bone marrow biopsy, but this is not the rule.
• Last stage: the tumor stage (deep tissue infiltration ). In this case, bone marrow and lymph node exploration are performed. Patients may develop anaplastic large-cell lymphoma involving the internal organs. The 3rd stage is difficult to treat. Staging of lymph nodes and
  blood is done. proliferating cells in mycosis cells are CD4 helper lymphocytes.

Question 19

How is mycosis fungoides differentiated from eczema and psoriasis?

Answer 19

To differentiate mycosis fungoides from eczema and psoriasis inflammation: hyperchromatic lymphocyte proliferation in the epidermis. This is called epidermotropism (clonal expansion of
lymphocytes having a predilection for the epidermis).
Under electron microscopy: Histologically abnormally shaped nuclei> cerebriform cells.

Another variant of primary cutaneous T cell lymphoma is Baccaredda-Sezary syndrome: the leukemic variant of mycosis fungoides with a worse prognosis.
Patients are totally red and erythrodermic from head to feet; they may develop inguinal lymphadenopathy.

Question 20

What are B cell lymphomas?

Answer 20

B cell lymphomas (25% - 3 types all characterized by the development of red violaceous nodules and plaques).
They are low-grade lymphomas, but it is important to differentiate between primary and secondary involvement from an internal lymphoma (e.g., from a lymph node).
3 types :

1.B cell follicle center lymphoma: the most common type. The diagnosis is histological: there is a clinical suspicion, and a biopsy is done to diagnose it. It mostly occurs in women in the back of
the body.
2. Marginal zone B cell lymphoma: it is sometimes related to Borrelia infections; it is the less aggressive type. Both of them are not so aggressive; they are indolent lymphomas in fact at 5 years the prognosis is good (90-95 % of patients with primary cutaneous follicle or marginal type of lymphomas are alive so the prognosis is excellent). Therapy: radiotherapy or excision in case of a solitary lesion.
3. Diffuse large B cell lymphoma: is the most aggressive type since it can spread to internal organs, prognosis is worse (5-year survival: 50 %) than the other 2 types.

Question 21

What is seborrheic keratosis?

Answer 21

It is a benign lesion of keratinocytes. It is very frequent in middle age/old people but also in younger patients. It is very frequent on the trunk but also the on the face. There are different type of mutations, the most common being Fibroblasts Growth Factor Receptor 3 (FGFR3), and other are KRAS, EGFR, AKT, TERT. In this case these mutations lead to a benign lesions, but there are cases in which these mutations in other tissues of internal organs lead to malignant ones; the clinical evolution in seborrheic keratosis is very rare.

Usually, seborrheic keratosis is characterised by some slow-growing lesion, when there are multiple rapidly growing lesions this is called Lesér-Trelat; it is a paraneoplastic manifestation usually associated with some sort of internal malignancy (colorectal carcinoma, lung carcinoma).

Question 22

What is arsenic keratosis?

Answer 22

Is another form of keratosis typical of areas where there is arsenic pollution and water contamination. The lesions due to arsenic keratosis are called rain-drop lesions, they affect mainly the trunk but also the palmo-plantar skin.

Question 23

Tumors of the adnexa?

Answer 23

Pilomatricoma or pilomatrixcoma, considered to derive from the matrix of the hair, is a strange lesion. Sometimes it grow very rapidly, it could affect also children. Could occur everywhere in the body, but usually doesn’t affect the hair. Sometimes it has calcification inside, there could even be bone formation, it is characterised by the formation of a rim of highly proliferating epithelium. These tumors have mutation in exon 3 of gene encoding for beta-catenin.

Question 24

What is a dermatofibroma?

Answer 24

Also called a benign fibrous histiocytoma. It is found mainly at the level of the legs and arms. It is a papule covered by a thick pigmented epithelium. The lesion is composed of spindle cells in the dermis, intermingled with collagen. It is a benign lesion with no risk of progression, sometimes, possibly, it will regress.