PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
The T-zone around the eyes, nose, and mouth demand a curative outcome that preserves cosmesis and function.
PERSPECTIVE AND PATTERNS OF SPREAD
Nonmelanoma skin cancer (NMSC) largely consists of basal cell cancers (BCCs) and cutaneous squamous cell cancers (SCCs). A new addition is Merkel cell cancers (MCC) among the many different malignances in the histopathologic classification (T1 histopathology skin cancers).
Patterns of spread tend to be bidirectional—horizontal or vertical—and provide the two major stage criteria: diameter measured in centimeters and depth measured in millimeters, respectively. With deeper penetration into dermis and hypodermis, invasion of underlying muscle and bone occur and prognosis becomes poor. Access to lymphatics in dermis increases risk for lymph node spread and possible perineural invasion, especially for the parotid gland region because of the widely distributed facial nerve (CNVII) and its numerous branches, which rapidly fan out in the face deep to the epidermis.
Cancers of the skin are the most common of all malignancies, with approximately 1 million new cancers annually in the Unites States. Worldwide, its overall incidence approaches that of all noncutaneous malignancies combined. Fortunately, these lesions are readily recognized and treatment is effective, resulting in high curability. The 1,000 deaths annually indicate that a fraction of 1% are dying (0.001%), often in reclusive or neglected patients. Skin cancer is largely due to actinic exposure, and the majority of neoplastic lesions arise in preexisting lesions. Premalignant lesions include solar keratosis, epithelial hyperplasia, leukoplakia, nevi, and burn scars. The face, eyelid, and ear are the most common sites for BCCs and SCCs (Fig. 50.1A).
Although the predominant cancers are basal cell or squamous cell, virtually every component cell or adnexal structure can give rise to a malignancy. The common etiology is mainly chronic exposure to ultraviolet, especially when coupled with a genetic predisposition (fair skin). Albinism, xeroderma pigmentosa, and basal cell nevus syndrome are hereditary, and individuals with these syndromes are vulnerable. Immunosuppressed patients are prone to squamous cell cancer. Papillomavirus—an oncovirus—has been implicated as a cause for keratoacan-thomas. Chronic irritation or inflammation, as with burn scars, can give rise to squamous cell cancer and contribute to its more aggressive behavior. Radiation induction of skin cancer is common, particularly in adolescents and young adults treated with moderate doses for acne. In blacks, mortality rates are disproportionately high and may be due to their more advanced stage at diagnosis. Facial cosmetic destruction is due to recurrent basal cell cancer, and death follows when this superficial cancer gains access to lymph nodes and then becomes metastatic, most often to lung.
Figure 50.1 | A. Incidence rate for basal cell carcinoma and squamous cell carcinoma.
Figure 50.1 | B. Patterns of spread. The spread pattern in skin is both horizontal and vertical and is color coded for stage: Tis, yellow; T1, green; T2, blue; T3, purple; and T4, red. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern (SIMLAP, Table 50.1).
Cancers of the skin are very superficial tumors by virtue of location. The patterns of spread initially may be horizontal or vertical (Fig. 50.1B, Table 50.1). Once deeper invasion occurs, the exact anatomic site provides many nuances to management because the head and neck are the prime sites. The T-zone around the eyes, nose, and mouth demand an outcome for deeper invasion of skin cancers that preserves cosmesis and function. If the underlying structures—muscle, bone, or cartilage—are involved, they play an important role in success or failure. Clinical detection is often by an annual systematic examination of the integumentary system by a dermatologist. Excisional biopsy or the Mohs technique of microscopic analysis of skin shavings is commonly used for diagnosis staging, as well as for treatment, to assure complete excision with clear margins. Careful palpation is essential in identifying the indurated cancer-infiltrated skin from normal skin and whether the lesion is fixed or freely mobile. Lymph node regions require careful clinical assessment with biopsy of suspicious nodes.
ORIENTATION OF HISTOGENESIS AND HISTOPATHOLOGY
Histogenesis
The integumentary system encompasses the entire skin surface, including its folds, openings, adnexae, derivatives, and appendages. In humans, it is the largest organ, and its derivatives include nails, hair, and sweat and sebaceous glands (Fig. 50.2A–C). The skin consists of two layers—the epidermis and the dermis. The superficial epidermis is nonvascular and consists of a stratified squamous epithelium with distinct cell types and layers referred to as stratums (Fig. 50.2A). The dermis is the vascular zone, and the epidermis is avascular. The majority of the dermis is a dense, irregular tangle of connective tissue, and below this is the hypodermis or subcutaneous tissue, which is mainly a mixture of fat and connective tissue that forms the fascial layers. The epidermis can be thick or thin in different regions of the body. Thick skin is largely keratinized and devoid of hair and glands, whereas thin skin contains hair and sweat and sebaceous glands and tends to be the site for malignancy.
This layer is loose connective tissue that has capillary loops, fibroblasts, and macrophages. The reticular layer is thicker and denser and has connective tissue without distinct boundaries. The hypodermis blends inferiorly and contains superficial fascia and fat tissues. This layer contains Pacinian corpuscles, whereas Meissner's corpuscles are at the dermal papillary level. Both provide the sensory receptors for skin. The skin appendages lie in the reticular layer, extend into the hypodermis, and include hair follicles, merocrine sweat glands, and apocrine sebaceous glands.
The layers that constitute the epidermis begin with germinal stem cells, stratum basale (Fig. 50.2B). The next layer is the stratum spinosum, which is four or five cells thick. The stratum granulosum is filled with granules of keratohyalin. When the cell loses its nucleus, it becomes the stratum lucidum. Finally, the piling of cells in the stratum corneum consists of flat, dead cells that provide the thickness to skin and account for its desquamation. There are numerous ancillary cells for different functions, such as sensory nerve endings into Merkel cells.
The dermis consists of a papillary and a reticular layer. The papillary layer is at the junction of epidermis and dermis and is irregular owing to raised projections of dermal papillae that interdigitate with epidermal ridges (Fig. 50.2C).
Figure 50.2 | Orientation of histogenesis. Integumentary overview. A. A cross section of the skin shows its cellular complexity and structures. There is the epidermis epithelial cover from which most skin cancers arise. This epidermal avascular layer rests on a base of subcutaneous tissue of fat and connective tissue, which is divided into a dermis of a papillary and areticular layer. B. Schematic diagram of keratinocytes in the epidermis consists of four layers of cells: basal cells, spinous cells, granular cells, and keratinized cells. rER, rough endoplasmic reticulum. C. Appendages such as eccrine gland and apocrine gland can give rise to adenocarcinomas.
Histopathology
The two most common cancers are basal cell cancer and squamous cell cancer, which are illustrated in Fig. 50.2D,E. However, because of the numerous cell types present in the dermis, a large variety of cancers, lymphomas, and melanomas can originate in the skin layer. The normal cell and the derivative malignancies are given in Table 50.2.
Figure 50.2 | D. Basal cell carcinoma, superficial type. Buds of atypical basaloid keratinocytes extend from the overlying epidermis into the papillary dermis. The peripheral keratinocytes mimic the stratum basalis by palisading. The separation artifact (arrow) is present because of poorly formed basement membrane components and the hyaluronic acid–rich stroma that contains collagenase. E. Squamous cell carcinoma. A microscopic view of the periphery of the lesion shows squamous cell carcinoma in situ. The entire epidermis is replaced by atypical keratinocytes. Mitoses and multinucleation of keratinocytes are apparent, as is apoptosis (straight arrows).
TNM STAGING CRITERIA
TNM STAGING CRITERIA
For the first six stages of the TNM staging system, the main criterion for skin cancer has been size: T1, 2 cm; T2, 5 cm; T3 >5 cm; and T4, invades deep underlying extradermal structures such as cartilage, bone, and skeletal muscle. The nodal categorization is simply N1 for nodal involvement. The reason for this rather simple staging system is that the vast majority of skin cancers fall into the T1N0 stage I. On the face or head and neck region, a 2-cm cancer is a relatively large area, particularly if negative margins are required. It is not only the margin around the cancer, but the depth of excision that matters. The major concern and reason for failure is the recurrent cancer that invades perineurally or into bone. These cancers can become very erosive and destructive. Distant metastases are rare and tend to be mainly pulmonary with squamous cell cancers. Basal cancers virtually never metastasize unless they are neglected and allowed to advance. The staging generally reflects the T stage progression.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
Skin, Cutaneous Squamous Cell Carcinoma, and Other Cutaneous Carcinomas
• Anatomic site of the eyelid is not included. It is staged by ophthalmic carcinoma of the Eyelid (see p. 48; Fig. 50.3).
• The T staging has eliminated the 5 cm size breakpoint and invasion of extradermal structures for T4. Two cm continues to differentiate T1 and 2; however, a list of clinical and histologic “high-risk features” has been created that can increase the prognosis of T staging, independent of tumor size.
• Grade has been included as one of the “high-risk features” within T category and now contributes toward the final stage grouping. Other “high-risk features” include primary anatomic site ear or hair-bearing lip, >2mm depth, Clark level ≥ IV, or perineural invasion.
• Advanced T stage is reserved for bony extension or involvement (e.g., maxilla, mandible, orbit, temporal bone, or perineural invasion of skull base or axial skeleton for T3 and T4, respectively).
• Nodal (N) staging has been completely revised to reflect published evidence-based data demonstrating that survival decreases with increasing nodal size and number of nodes involved.
• Because the majority of cSCC tumors occur on the head and neck integument, the seventh edition staging system for cSCC and other cutaneous carcinomas was made congruent with the general principles of AJCC Head and Neck staging system.
• In the seventh edition of the TNM Staging Manual, dramatic changes have occurred. “Cutaneous Basal and Squamous Cell Carcinoma and Other Cutaneous Carcinomas” is an entirely new staging system that, for the first time, reflects a multidisciplinary effort to provide a mechanism for staging nonmelanoma skin cancers according to evidence-based medicine. In total, seven board-certified disciplines collaborated to develop this chapter: Dermatology, Otolaryngology-Head and Neck Surgery, Surgical Oncology, Dermatopathology, Oncology, Plastic Surgery, and Oral and Maxillofacial Surgery. The basis of the data is focused on squamous cell carcinoma. All other nonmelanoma skin carcinomas (except Merkel cell carcinoma) will be staged according to the cSCC staging system.
• The Merkel Cell carcinoma staging system has also been newly designed and added.
The TNM staging matrix is color coded for identification of stage group once T and N stages are determined (Table 50.3).
BASAL CELL AND SQUAMOUS CELL CANCER
Figure 50.3 | TNM staging diagram arranged vertically with TN definitions on the left and stage groupings on the right. Skin cancers are the most common curable cancers when detected early (T1, T2) and even when advanced (T3), but resectability decreases with T4 cancers due to deep invasion of cartilage, muscle, and bone (purple lane). Color bars are coded for stage: stage T0, yellow; I, green; II, blue; III, purple; IV, red; and metastatic disease to viscera and nodes, black.
MERKEL CELL CARCINOMA
Perspective and Patterns of Spread
Merkel cell carcinomas (MCCs) are aggressive primary cutaneous neuroendocrine cancers resembling small-cell cancers of lung in their clinical behavior. Typically the lesion presents as a nodular, firm, red-to-violaceous papule on the exposed areas of the face, neck, and hand. Hosts tend to be fair skinned, favor sunbathing, and tend to be older (>50 years) and male. A specific virus has been identified in MCC and is termed MC polyoma virus. Other predisposing factors are immunosuppression and organ transplantation. The first sign could be a metastasis in nodes or lung in 10% to 15% of presentations.
The predominant spread pattern is to regional lymph nodes. Clinically negative lymph nodes are positive pathologically in one third of patients. Sentinel lymph node biopsies are advised and necessary to stage patients. The status of lymph node involvement affects survival.
Histopathology Classification
MCC consists of large, solid nests of undifferentiated cells that microscopically suggest small-cell lung cancers with active mitosis and nuclear fragments (Fig. 50.4A, B). Immunostaining is specific with cytokeratin 20, resulting in a “perinuclear dot” pattern, and neuroendocrine markers such as chromogranin and synaptophysin can also be positive.
TNM Staging Criteria
MCCs are staged for first time in the seventh edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual. According to p. 315, patients with primary Merkel cell carcinoma with no evidence of regional or distant metastases (either clinically or pathologically) are divided into two stages: stage I for primary tumors ≤2 cm in size and stage II for primary tumors >2 cm in size. Stages I and II are further divided into A and B substages based on method of nodal evaluation. Patients who have pathologically proven node-negative disease (by microscopic evaluation of their draining lymph nodes) have improved survival (substaged as A) compared with those who are only evaluated clinically (substaged as B). Stage II has an additional substage (IIC) for tumors with extracutaneous invasion (T4) and negative node status regardless of whether the negative node status was established microscopically or clinically. Stage III is also divided into A and B categories, for patients with microscopically positive and clinically occult nodes (IIIA) and macroscopic nodes (IIIB). There are no subgroups of stage IV Merkel cell carcinoma (Table 50.3B).
The T stage is similar to that for other skin cancers, but stage groups are different due to N staging, which emphasizes pathologic staging (Fig. 50.4C).
Figure 50.4 | A. The Merkel cell, which differs from other immigrant cells, forms desmosomes with keratinocytes and is attached to a small nerve plate (nerve fiber terminal). The membrane-delimited, dense core granule is distinctive (inset). B. Merkel cell carcinoma. The tumor is composed of solid nests of undifferentiated cells that resemble small-cell carcinoma of the lung.
MERKEL CELL CARCINOMA
Figure 50.4 | C. TNM staging diagram arranged vertically with TN definitions on the left and stage groupings on the right. Color bars are coded for stage: stage T0, yellow; I, green; II, blue; III, purple; IV, red; and metastatic disease to viscera and nodes, black.
T-ONCOANATOMY
T-ONCOANATOMY
The skin can be divided into its surface sectors and the lymph node region that drains a sector.
The head and neck includes the face and scalp. The vast majority of cancers arise on the skin of the face. Therefore, it is the face and scalp that demand careful attention clinically because of the complex functions, cosmesis, and special senses. All need to be preserved when resecting the cancer. The lymph node drainage of the integumentary surface differs from the upper aerorespiratory and digestive passages.
• Anterior chest wall from the clavicles to the navel in males tends to be hirsute. Lesions on the skin of the anterior thoracic wall drain to the anterior axillary nodes.
• Posterior chest wall to the same level tends to be less hirsute, is exposed more often to the sun, and is subject to forming cancers. The regional nodes are along the posterior wall of the axilla, although all axillary nodes are at risk.
• The upper extremity is an infrequent sector involved with skin cancer, but it can be a site for burn and chronic inflammation. It is notorious for radiation-induced cancer in dentists who finger-held dental films during their practice. Serial resections occur, with loss of fingers, then the hand, and then the forearm. Involvement of epitrochlear node and then axillary nodes invariably leads to death from pulmonary metastases.
• Anterior abdominal wall drains into the femoral and inguinal nodes, but this sector of skin is rarely involved with skin cancers.
• Posterior abdominal wall or skin of the lower back is an infrequent site of malignancy and also drains to femoral and inguinal nodes anteriorly.
• The lower extremity is not a common site for skin cancers. Burns or chronic inflammation may cause lesions to evolve from hyperplasia to dysplasia and on to neoplasia. Popliteal nodes drain the foot and leg and ultimately drain into superficial femoral lymph nodes, which also drain the thigh.
Skin cancers are predominantly located on and in the face. To fully appreciate the anatomy, it is important to be aware of the surrounding structures and especially the underlying muscles and nerves. As the cancer advances and invades, the reconstruction is more than cosmesis. A particularly troublesome area is over the parotid gland because perineural invasion of the widely branching facial nerve is a major concern (Fig. 50.5A, B).
Figure 50.5 | Cutaneous branches of trigeminal nerve, muscles of facial expression, and arteries of the face. A. Anterior view dissection of facial skin to reveal underlying muscles, nerves, and bones. B. Lateral view. Note the wide web distribution of facial nerve branches.
N-ONCOANATOMY
N-ONCOANATOMY
N-oncoanatomy of the skin surfaces emphasizes the anterior location for most if not all lymph node stations.
• The face and scalp drain into the superficial ring of high neck nodes at the junction of the mandible and neck: submental, submandibular, preauricular, mastoid, and occipital nodes. Once involved, the rest of the deep lymph nodes in the neck along the carotid sheath and internal jugular vein are at risk (Fig. 50.6A).
• The axillary nodes are the recipients of lymphatics of the upper extremity and upper half of the body, both anterior and posterior skin surfaces (Fig. 50.6A).
• The femoral and inguinal nodes drain the lower extremity and the lower half of the body, both the anterior and posterior skin surfaces (Fig. 50.6A).
The skin lymphatics of the face are different from head and neck cancers, since they drain to a ring of nodes that hang like a necklace from the occiput to below the ear and the parotid and anteriorly to the submaxillary and submandibular regions (Fig. 50.6B).
Once the cancer invades and advances, involving deeper underlying structures, the deeper cervical nodes can become at risk for involvement (Fig. 50.6C).
Figure 50.6 | A. Overview of the structures constituting the lymphatic system. Because lymphatic tissue is the main component of some organs, they are regarded as organs of the lymphatic system (spleen, thymus, and lymph nodes). Ultimately, the lymphatic vessels empty into the bloodstream by joining the large veins at the base of the neck. The thoracic duct is the largest lymphatic vessel. BALT, bronchus-associated lymphoid tissue; GALT, gut-associated lymphoid tissue.
M-ONCOANATOMY
M-ONCOANATOMY
There is a rich network of venous channels beneath all skin surfaces that allows for venous hematogenous spread once the dermal and hypodermal layers are penetrated by invading cancers. These venous collateral channels and plexus are rich and appear once obstruction occurs. The venous drainage of the face is shown in Fig. 50.6B, C.
Metastatic spread via superficial and deep jugular vein is to lung predominantly. With extensive recurrent and destructive basal cancers, which seldom metastasize early, aspiration into lung has been postulated but is an unlikely mechanism. Squamous cell cancers, as they invade lymph nodes, disseminate via focal veins. Merkel cell cancers are more virulent and are more prone to become metastatic.
MERKEL CELL CANCERS
These are similar to other cutaneous cancers and spread by jugular venous drainage with lung the major target organ, although remote cutaneous sites can be “in-transit” metastases distal to the primary site and between primary and regional nodes. Clinical detection of nodal disease may be via inspection, palpation, and/or imaging. Micrometastasis and macrometastasis are also possible:
• In-transit metastases: a tumor distinct from the primary lesion and located either (i) between the primary lesion and the draining regional lymph nodes or (ii) distal to the primary lesion.
• Micrometastases are diagnosed after sentinel or elective lymphadenectomy.
• Macrometastases are defined as clinically detectable nodal metastases and confirmed by therapeutic lymphadenectomy or needle biopsy.
Figure 50.6 | B. Superficial lymphatic and venous drainage of the head and neck. C. Deep drainage.
STAGING WORKUP
Rules of Classification and Staging
The clinical and pathologic classifications are identical; excisional biopsy is often performed. Clinical staging is based on physical examination, inspection and palpation of primary sites, and draining of regional nodes. Imaging with regular radiographs is adequate, and skull films may include facial bones and mandible for deeply invading or fixed cancers beyond T1 in size. Computed tomography may be desirable for deeper invasion and to detect subtle cortical erosions and sclerosis (Table 50.4).
Pathologic Staging
Complete resection of the entire site is most often performed and must provide adequate margins to determine whether there is any residuum. An immediate frozen section is essential to assure complete excision and negative margins. Mohs microsurgery provides free margins but is a time-consuming and meticulous surgical excision technique. The major advantage is being able to know that a clean, deep margin has been obtained. Cancer grading is advised, as well as determining histopathologic type.
Rules for Staging Merkel Cell Cancers
These include the same imaging workup (T) as for advanced squamous cell cancers. Pathologic staging is emphasized especially for nodes.
PROGNOSIS AND CANCER SURVIVAL
PROGNOSIS AND SURVIVAL
Cutaneous Basal and Squamous Cell Cancers
Early stage T1 cancers 2 cm in diameter and 2 mm in depth rarely recur or metastasize. Risk of local recurrence doubles with lesions >2 cm (15% vs. 7%).
Immunosuppressed (I) patients are very prone to develop SCC; organ transplant patients are 65 times more prone than age-matched controls and have an increased risk of local recurrence; these lesions can be large, >5 cm, and prove to be lethal. The limited number of prognostic factors are listed in Table 50.5.
Cancer Statistics and Survival
New cases of skin cancer are in the 1 million range annually and are highly curable when excised completely in their first, early stage, namely, precancerous keratosis or lesions 1 cm. Fortunately, heightened awareness by the medical profession and patients has resulted in high curability rates (95%). Once skin cancers recur in excisional scars or are neglected and invade deeply into muscle, cartilage, or bone, disfigurement and death can and do occur, with local control falling to 75%.
Merkel Cell Cancers
See Table 50.6.
Merkel Cell Survival Statistics
The seventh edition of the AJCC Cancer Staging Manual has the largest pool of patients (4,700, T = 3,297, N = 4,426) and provides detailed analysis based on stage T, N, M, T size, and N status.*
*Preceding passage from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York: Springer, 2010. p. 317–318.
Figure 50.7 | A. Generally, early localized skin cancers (BCC and SCC) are detected in the early localized stages and are highly curable. As the cancer progresses and the stage advances, survival decreases sharply. B. There are a larger number of prognostic factors for Merkel cell cancer (MCC) listed in the accompanying table. (Data from Edge SB, Byrd DR, and Compton CC, et al, AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010.)