Tx
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ
T1
Tumor 2 cm or less in greatest dimension
T2
Tumor more than 2 cm in greatest dimension
T3
Tumor invades to deeper extradermal structures like musculoskeletal, bone, cartilage, jaw, and orbit
T4
Tumor invades to skull bone or axial skeleton
Nx
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Regional lymph node metastases in one lymph node 3 cm or less in greatest dimension
N2
One lymph node metastases more than 3 cm, but no more than 6 cm, in greatest dimension or multiple lymph node metastases, but none more than 6 cm in the greatest dimension
N3
Metastases in regional lymph node more than 6 cm
M0
No distant metastasis
M1
Distant metastasis
Stage grouping | |||
|---|---|---|---|
0 | Tis | N0 | M0 |
I | T1 | N0 | M0 |
II | T2 | N0 | M0 |
III | T3 | N0 | M0 |
T1, T2, T3 | N1 | M0 | |
IV | T1, T2, T3 | N2, N3 | M0 |
T4 | Any N | M0 | |
Any T | Any N | M1 | |
7.2.3 Treatment
Several evaluations of BCC treatment have shown that the histologic subtype is an important risk factor for recurrence [3], which can affect the choice of treatment.
Although excision with negative margins has been the most effective approach to cure, at times radiation therapy is chosen as the first choice considering preservation of function, cosmesis, and patients’ preferences.
7.2.4 Follow-Up
Close follow-up after local disease is needed by examining the skin and regional lymph nodes every 3–6 months for the first 2 years after diagnosis, then 6–12 months for the next 3 years, and then annually for life. If there was also regional lymph node involvement, then closer follow-up is needed as every 1–3 month for the first year, 2–4 month for the second year, 4–6 month for the third year, and 6–12 month annually for life [5]. Finally, routine sun-protection and self-examination is recommended.
7.3 Cutaneous Squamous Cell Carcinoma
Squamous cell carcinoma originates from the suprabasal epidermal keratinocytes [6]. SCC is the second most common skin cancer accounting for approximately 20 % of nonmelanoma skin cancers. Both BCC and SCC tend to spread mostly locally, but SCC in contrast to BCC has a higher rate of metastasis. Fair-skinned people are more susceptible compared to the general population and the incidence increases with advanced age. Actinic keratosis and Bowen’s disease (squamous cell carcinoma in situ) are believed to be the precursors of SCC. Cumulative UV exposure especially UVB is the most important risk factor and hence accounting for the higher incidence of this cancer in sun-exposed areas mostly including the head, neck, and arms. There are also other known extrinsic and intrinsic risk factors for SCC such as ionizing radiation exposure; exposure to environmental carcinogen, e.g., arsenic; scars; burns; chronic wounds; human papillomavirus infection especially HPV-16 and HPV-18 which are associated with squamous cell carcinoma of the genital region; and also extensive immunosuppression such as seen in solid organ transplant patients or leukemia [6–8].
7.3.1 Diagnosis
Squamous cell carcinoma is usually described as a firm, flesh-colored, or erythematous papule or plaque with crust or ulceration [6].
SCC has many clinicopathological variants such as verrucous carcinoma, spindle cell, keratoacanthoma, Bowen’s disease, and erythroplasia of Queyrat. The details of the histopathologic differences are out of the scope of this chapter, but it is important to recognize that these differences influence the prognosis. A common invasive SCC consists of invasion of epidermal cells of the spinous layer into the underlying dermis. Usually signs of keratinisation can occur as single cell dyskeratoses or concentric horn pearls [9].
7.3.2 Staging
To reflect a multidisciplinary effort to provide a mechanism for staging nonmelanoma skin cancers according to evidence-based medicine, the AJCC/UICC guidelines has come up with a new staging system in 2009 as shown in Table 7.1.
7.3.3 Treatment
Treatment options include topical imiquimod, topical 5-fluorouracil, photodynamic therapy, cryotherapy, curettage, and electrodessication, all of which can be especially considered for precursor lesions. For invasive squamous cell carcinoma, the treatment of choice remains excision with negative margins or MOHS micrographic surgery; the latter has been shown to have lower rate of reoccurrence [10].
Although radiation therapy sometimes is chosen as primary treatment when preservation of functionality and cosmesis is a priority, radiation therapy alone has a lower success rate when compared to surgery and a higher local reoccurrence rate [11]. Radiation therapy can be used as adjuvant to surgery especially when there is lymph node involvement or for perineural disease [5].
Chemotherapy usually with cisplatin or EGFR-targeted drugs, as a single agent or in combination with chemotherapeutic agents, should be reserved for more advanced stages of disease.
7.3.4 Follow-Up
The recommended guidelines for follow-up are the same as mentioned in the BCC follow-up. Additionally, during these follow-up visits, patient should be checked for development of new precursor lesions.
7.4 Melanoma
Melanoma accounts for the most lethal skin tumor, causing 90 % of skin cancer mortality.
The incidence rates in the white population have increased three- to fivefolds. This increase ranges from 10 to 60 cases per 100,000 inhabitants and year depending of the region, but the highest reported rates are from Australia and the southern states of the United States [12]. The expectations are that this rising trend will continue at least for the next two decades. The main risk factors include sun exposure, atypical nevi, positive family history for melanoma, and fair skin type.
This heterogenous disease presents mainly as four different subtypes, including superficially spreading (SSM), nodular (NMM), lentigo maligna (LMM), and acrolentiginous melanoma (ALM). Eyes, meninges, and mucosal tissue affectation exists as well but is rare.
Arising from melanocytic cells, the majority of melanoma types show clear pigmentation except for the rare amelanotic melanoma type.
Metastases can involve any organ, but there is a preference for skin, lungs, liver, brain, and lymph nodes.
7.4.1 Diagnosis and Staging
The latest European consensus-based interdisciplinary guidelines for melanoma are reviewed and published by Garbe et al. in 2010 [13].
According to the AJCC (American Joint Committee on Cancer) system, in 2001 a new TNM classification was defined for cutaneous melanoma (Table 7.2) [13–15].
Classification | Thickness (mm) | Ulceration status |
|---|---|---|
Tis | NA | NA |
T1 | <1.00 | (a) Without ulceration and mitosis < 1/mm2 |
(b) With ulceration or mitosis > 1/mm2 | ||
T2 | 1.01–2.00 | (a) Without ulceration |
(b) With ulceration | ||
T3 | 2.01–4.00 | (a) Without ulceration |
(b) With ulceration | ||
T4 | >4.00 | (a) Without ulceration |
(b) With ulceration | ||
N | No. of metastatic nodes | Nodal metastatic burden |
N0 | 0 | NA |
N1 | 1 | (a) Micrometastasisa |
(b) Macrometastasisb | ||
N2 | 2–3 | (a) Micrometastasisa |
(b) Macrometastasisb | ||
(c) In-transit metastases/satellites without metastatic nodes | ||
N3 | +4 metastatic nodes, or matted nodes, or in-transit metastases/satellites with metastatic nodes | |
M | Site | Serum LDH |
M0 | No distant metastases | NA |
M1a | Distant skin, subcutaneous, or nodal metastases | Normal |
M1b | Lung metastases | Normal |
M1c | All other visceral | Normal |
Metastases | Elevated | |
Any distant metastasis |
Histopathologic analysis helps identify the clinicopathological subtype, tumor thickness in mm (also known as Breslow depth), the ulceration status, the level of invasion (Clark I–V), presence of potential microsatellites, and lateral and deep excision margins [13].
7.4.2 General Staging Recommendations
Chest X-ray and regional lymph node and abdominal (including pelvis and retroperitoneum) ultrasound are recommended as staging procedures at initial and follow-up examinations. Positron emission tomography- computed tomography (PET-CT) scans or magnet resonance imaging (MRI) is indicated in higher-risk patients. As a follow-up tool, LDH and serum S-100 levels are analyzed [16, 17] (refer to Table 7.3 for further details).
Stage | Primary tumor (pT) | Regional lymph node metastases (N) | Distant metastases (M) |
|---|---|---|---|
0 | In situ tumor | None | None |
IA | <1.0 mm, no ulceration | None | None |
IB | <1.0 mm with ulceration or Clark Level IV or V | None | None |
1.01–2.0 mm, no ulceration | |||
IIA | 1.01–2.0 mm with ulceration | None | None |
2.01–4.0 mm, no ulceration | |||
IIB | 2.01–4 mm with ulceration | None | None |
>4.0 mm, no ulceration | |||
IIC | >4.0 mm with ulceration | None | None |
IIIA | Any tumor thickness, no ulceration | Micrometastases | None |
IIIB | Any tumor thickness with ulceration | Up to 3 macrometastases | None |
Any tumor thickness, no ulceration | None but satellite and/or in-transit metastases | ||
Any tumor thickness, +/−ulceration | |||
IIIC | Any tumor thickness with ulceration | Up to three macrometastases | None |
Any tumor thickness, +/−ulceration | Four or more macrometastases or lymph node involvement extending beyond capsule, or satellite and/or in-transit metastases with lymph node involvement | ||
IV | Distant metastases |
7.4.3 Staging and Follow-Up in Melanoma Stage I (<1 mm: Low-Risk Scheme)
Recent changes of the AJCC guidelines include the mitotic rate (MR) as a relevant prognostic factor. Hence, if the primary lesion is equal or less than 1 mm in the presence of ulceration or at least 1 mitosis/mm2, SNLB is recommended (T1b–T4b). The 10-year survival is expected to be over 90 % [18, 19]. Please refer to Table 7.4 for further details.
Stage (TNM) | Physical examination (months) | Physical examination (months) | Physical examination (months) | Locoregional lymph node ultrasound (months) | S-100 (months) | Abdominal ultrasound and chest X-ray (months) | CT, MRI, PET, or PET-CT (months) |
|---|---|---|---|---|---|---|---|
Years 1–3 | Years 4–5 | Years 6–10 | Years 1–5 | Years 1–5 | Years 1–5 | Years 1–5 | |
I (<T1N0) | 6 | 12 | 12 | – | – | – | – |
I (T2N0), IIA + B | 3 | 6 | 6–12 | 6–12 | 6–12 | Individual | – |
IIC, III | 3 | 3 | 6 | 6 | 6 | Individual | 6–12 |
IV | Individual | Individual | Individual | Individual | Individual | Individual | Individual |
7.4.4 Staging and Follow-Up in Melanoma Stage I + II (>1 mm: Intermediate-Risk Scheme)
According to Morton et al., the radical lymph node dissection of positive sentinel lymph nodes prolongs the disease-free survival, but not the overall survival [20].
SNLB is recommended for T1b–T4 with clinically or radiographically uninvolved lymph nodes [21].
According to the recent AJCC updates, T1b is referring to the degree of ulceration and the mitotic rate, but no longer the Clark level. The mitotic rate is the second most relevant factor determining prognosis after the tumor depth.
7.4.5 Staging and Follow-Up in Melanoma Stage III + IV (>4 mm + N + M: High-Risk Scheme)
Currently radical lymph node dissection is recommended following micrometastases in sentinel lymph nodes. Since the overall survival benefit of this procedure is very controversial, instead ultrasound follow-up of the lymph node basin can be considered [13].
The lactic dehydrogenase (LDH) level, being a relevant predictor of survival, has been recently included in the M category of the TNM staging system [15].
7.4.6 Therapy
Surgery is the first treatment choice of localized melanoma in any stage. But surgery is always not feasible for multiple reasons including the anatomical site. For example, lentigo maligna and lentigo maligna melanoma are mostly seen in the elderly population in the face area. If the lesion is small and the location is favorable, Mohs surgery with careful follow-up of the margins should be performed, but many times the anatomical site is not suitable, e.g., the eyelid, nose, or ear or the patient is high risk for surgery. In such cases, studies have shown that superficial radiotherapy with Grenz or soft X-rays is a reliable treatment option [22].
According to the melanoma subtype and stage, radiation therapy, adjuvant INF-alpha, and other immunotherapies and palliative chemotherapy serve as main therapeutic options [13]. The EORTC (European Organization for Research and Treatment of Cancer) 18991 phase II clinical trail showed pegylated interferon-alpha can be beneficial as adjuvant therapy for patients with stage II and III melanoma with microscopic nodal disease [23].
Small molecules targeting specific proteins are broadly investigated in pre- and clinical trials [24].
7.5 Merkel Cell Carcinoma
Merkel cell carcinoma (MCC) is a rare, aggressive malignancy of the skin, with tripling incidence during the past two decades. This neuroendocrine skin tumor has a high local, regional, and metastatic recurrence potential [26, 27].
Potential risk factors for developing Merkel cell carcinoma include advanced age, ultraviolet exposure, fair skin, and immune suppression. The mnemonic acronym “AEIOU” may increase awareness for Merkel cell carcinoma: asymptomatic/lack of tenderness, expanding rapidly (doubling in <3 months), immunosuppression, older than 50 years, and ultraviolet exposed skin site [28].
7.5.1 Diagnosis and Staging
Histologically, MCCs are small, round, blue cell tumors. The most difficult differentiation is often between primary MCC and metastatic small cell carcinoma of the lung. Until recently, different staging systems for MCC described in the literature were leading to significant confusion among patients, physicians, and researchers. In 2009, a new consensus staging system was adopted by the AJCC/UICC (Table 7.5). This new staging system is based on prognostic factor analysis of 5,823 MCC patients in the United States using information from the national cancer data base. Using this staging system, the extent of disease is highly predictive of survival with 5-year survival rates of 64 % for local, 39 % for regional nodal, and 18 % for distant metastatic disease [29].
Table 7.5
TNM criteria and stage groupings of new American Joint Committee on Cancer staging system for Merkel cell carcinoma [34]
T | |||
Tx, primary tumor cannot be assessed | |||
T0, no primary tumor | |||
Tis, in situ primary tumor | |||
T1, primary tumor <2 cm | |||
T2, primary tumor >2 but <5 cm | |||
T3, primary tumor >5 cm | |||
T4, primary tumor invades bone, muscle, fascia, or cartilage | |||
N | |||
Nx, regional nodes cannot be assessed | |||
N0, no regional node metastasisa | |||
cN0, nodes not clinically detectablea | |||
cN1, nodes clinically detectablea | |||
pN0, nodes negative by pathologic examination | |||
pNx, nodes not examined pathologically | |||
N1a, micrometastasisb | |||
N1b, macrometastasisc | |||
N2, in-transit metastasisd | |||
M | |||
Mx, distant metastasis cannot be assessed | |||
M0, no distant metastasis | |||
M1, distant metastasise | |||
M1a, distant skin, distant subcutaneous tissues, or distant lymph nodes |
