Squamous Cell Carcinoma by lsy121925

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									Squamous Cell Carcinoma
Author: Debjani Sahni, MBBS, MRCP, Cutaneous Oncology Fellow, Brigham and Women's Hospital, Dana Farber Cancer Institute
Coauthor(s): Chrysalyne D Schmults, MD, Instructor in Dermatology, Harvard Medical School; Director, Mohs Micrographic Surgery Center,
Department of Dermatology, Brigham and Women's Hospital
Contributor Information and Disclosures
Updated: Mar 18, 2009

Introduction

Background
Cutaneous squamous cell carcinoma (SCC) is the second most common form of skin cancer and
accounts for 20% of cutaneous malignancies.1 Squamous cell carcinoma frequently arises on the
sun-exposed skin of middle-aged and elderly individuals. Most squamous cell carcinomas are
readily identified and removed in the physician's office as a minor surgical procedure. Larger and
more invasive lesions may require aggressive surgical management, radiation therapy, or both.
High-risk squamous cell carcinoma carries a significant risk of metastasis and, as such, requires
careful evaluation and treatment.

General risk factors associated with the development of squamous cell carcinoma are as
follows2,3,4,5,6,7,8 :

          Age older than 50 years
          Male sex
          Light skin; blonde or light brown hair; green, blue, or gray eyes
          Skin that sunburns easily (Fitzpatrick skin types I and II)
          Geography (closer to the equator)
          History of prior nonmelanoma skin cancer
          Exposure to UV light (high cumulative dose of sunshine, tanning beds, or medical UV
           treatments)
          Exposure to chemical carcinogens (eg, arsenic, tar)
          Exposure to ionizing radiation (medical treatments, occupational or accidental radiation
           exposure)
          Chronic immunosuppression
          Chronic scarring conditions
          Certain genodermatoses
          Human papillomavirus (HPV) infection (specific subtypes)

Pathophysiology
Squamous cell carcinoma is a malignant tumor of epidermal keratinocytes. Some cases of
squamous cell carcinoma occur de novo (ie, in the absence of a precursor lesion); however, some
squamous cell carcinomas arise from sun-induced precancerous lesions known as actinic
keratoses (AKs). Patients with multiple AKs are at increased risk for developing squamous cell
carcinoma.9 Squamous cell carcinoma is capable of locally infiltrative growth, spread to regional
lymph nodes, and distant metastasis, most often to the lungs.

Frequency
United States

Determining the true incidence of squamous cell carcinoma is difficult because health registries
exclude nonmelanoma skin cancer (including squamous cell carcinoma) from their databases
because of the high number of cases and limited resources to collect data and because the rate of
squamous cell carcinoma varies based on geographic locale. In 1994, the annual incidence in the
United States ranged from 81-136 cases per 100,000 population for men and 26-59 cases per
100,000 population for women.10

Studies also confirm a dramatic increase in the incidence of cutaneous squamous cell carcinoma
over the past several decades. For example, in Rochester, Minnesota, the annual age-adjusted
incidence rates of squamous cell carcinoma per 100,000 women rose from 47 cases from 1984-
1986 to 100 cases from 1990-1992. The corresponding rates for men increased from 126 cases to
191 cases per 100,000 population.11

One reason for the rising incidence of squamous cell carcinoma may be an increase in sun
exposure in the general population. Some postulate that ozone depletion may be intensifying UV
exposure. Other factors that may contribute to the increased incidence of squamous cell
carcinoma include the advancing age of the US population, earlier and more frequent diagnosis of
squamous cell carcinoma due to enhanced public awareness of skin cancer, and more frequent
skin examinations by physicians.

Additionally, the number of patients on immunosuppressive therapy, used in solid organ
transplantation and various rheumatologic and dermatologic conditions, is increasing. Squamous
cell carcinoma formation has been associated with immunosuppressive drug therapy in solid organ
transplantation patients, who have a markedly elevated risk of squamous cell carcinoma formation.
Metastasis also may be more common in this group.12
International

Prevalence rates of squamous cell carcinoma vary in different countries. The highest incidence
occurs in Australia, where the age-adjusted incidence has been calculated to be 1332 cases per
100,000 population for men and 755 cases per 100,000 population for women. Again, this is likely
due to large numbers of light-skinned people in this region who have had extensive sun
exposure.13

Mortality/Morbidity
Most squamous cell carcinomas are readily treated and produce few sequelae. A subset of high-
risk lesions causes most of the morbidity and the mortality associated with squamous cell
carcinoma. Such lesions may cause extensive destruction of tissue, and their removal may entail
substantial cosmetic deformity. The overall risk of metastasis for squamous cell carcinoma is in the
range of 2-6%; however, rates as high as 47% have been reported for cases with extensive
perineural invasion. Lymph node metastasis is associated with significant morbidity; however, 5-
year survival rates as high as 73% have been achieved with the combination of surgical
lymphadenectomy and radiation therapy.14 Once lung metastasis occurs, the disease is currently
incurable.
Race
Squamous cell carcinoma is the second leading cause of skin cancer in whites. 1 Persons of Irish or
Scottish ancestry have the highest prevalence in the United States. Squamous cell carcinoma is
relatively rare in people of African and Asian descent, although it is the most common form of skin
cancer in these groups. Squamous cell carcinoma in blacks carries a higher mortality rate, perhaps
due to delayed diagnosis because tumors are more likely to occur in sun-protected areas,
including the scalp and sites of previous injury and scarring.15
Sex
Squamous cell carcinoma occurs in men 2-3 times more frequently than it does in women, most
likely as a result of greater cumulative lifetime UV exposure.
Age
The typical age at presentation is approximately 70 years; however, this varies widely, and, in
certain high-risk groups (eg, organ transplant recipients [OTRs], patients with epidermolysis
bullosa), squamous cell carcinoma often manifests at a much younger age.
Clinical

History
A detailed patient history often reveals the presence of one or more risk factors for squamous cell
carcinoma (SCC) (see general risk factors in Background). Most squamous cell carcinomas are
discovered by patients and are brought to a physician's attention by the patient or a relative. The
typical squamous cell carcinoma manifests as a new or enlarging lesion that concerns the patient.
Squamous cell carcinoma is typically a slow-growing malignancy, but some lesions enlarge
rapidly. Although most squamous cell carcinoma patients are asymptomatic, symptoms such as
bleeding, weeping, pain, or tenderness may be noted, especially with larger tumors. Numbness,
tingling, or muscle weakness may reflect underlying perineural involvement, and this history finding
is important to elicit because it adversely impacts prognosis.16

          Actinically derived squamous cell carcinoma: The most common type of squamous cell
           carcinoma is the sun-induced type. As such, a history of long-term sun exposure dating
           back to childhood is frequently elicited. Many patients report having experienced multiple
           blistering sunburns during their lifetime, while others may have used indoor tanning beds
           or received UV light therapy (eg, psoralen plus UVA [PUVA] for psoriasis). Patients may
           have been treated in the past for sun-induced lesions such as AKs, basal cell carcinoma
           (BCC), melanoma, or squamous cell carcinoma.
          Immune suppression: Patients should always be questioned about possible sources of
           immunosuppression. A history of solid-organ transplantation, hematologic malignancy
           (particularly chronic lymphocytic leukemia [CLL]), HIV infection or AIDS, or long-term use
           of immunosuppressive medications (eg, as treatment for an autoimmune condition) may
           be elicited.
          Marjolin ulcer: This eponym refers to a squamous cell carcinoma that arises from
           chronically scarred or inflamed skin. Patients may report a change in the skin (eg,
           induration, elevation, ulceration, weeping) at the site of a preexisting scar or ulcer. The
           latency period is often 20-30 years; therefore, the diagnosis requires a high index of
           clinical suspicion.
          HPV-associated squamous cell carcinoma: Virally induced squamous cell carcinoma most
           commonly manifests as a new or enlarging warty growth on the penis, vulva, perianal
           area, or periungual region. Patients often present with a history of "warts" that have been
           refractory to various treatment modalities in the past. A history of previously documented
           genital HPV infection may be elicited.

Physical
Squamous cell carcinoma (SCC) may manifest as a variety of primary morphologies with or
without associated symptoms.

          Squamous cell carcinoma in situ (SCCis): Squamous cell carcinoma in situ is defined
           histologically by atypia involving the full thickness of the epidermis but without invasion
           into the dermis. Clinically, lesions of squamous cell carcinoma in situ range from a scaly
           pink patch to a thin keratotic papule or plaque similar to an AK. Bowen disease is a
           subtype of squamous cell carcinoma in situ characterized by a sharply demarcated pink
           plaque arising on non–sun-exposed skin. Erythroplasia of Queyrat refers to Bowen
           disease of the glans penis, which manifests as one or more velvety red plaques.




            Squamous cell carcinoma in situ, Bowen disease. Courtesy of Hon Pak, MD.




            Squamous cell carcinoma. Courtesy of Hon Pak, MD.
   Typical squamous cell carcinoma: The characteristic invasive squamous cell carcinoma is
    a raised, firm, pink-to-flesh–colored keratotic papule or plaque arising on sun-exposed
    skin. Approximately 70% of all squamous cell carcinomas occur on the head and neck,
    with an additional 15% found on the upper extremities. Surface changes may include
    scaling, ulceration, crusting, or the presence of a cutaneous horn. Less commonly,
    squamous cell carcinoma may manifest as a pink cutaneous nodule without overlying
    surface changes. The absence of surface changes should raise suspicion of a metastatic
    focus from another skin or nonskin primary site or a different and potentially more lethal
    tumor such as Merkel cell carcinoma. A background of severely sun-damaged skin,
    including solar elastosis, mottled dyspigmentation, telangiectasia, and multiple AKs, is
    often noted.




      Large sun-induced squamous cell carcinoma on the forehead/temple.




      Squamous cell carcinoma. Courtesy of Hon Pak, MD.


   Periungual squamous cell carcinoma: Periungual squamous cell carcinoma typically
    mimics a verruca and is frequently misdiagnosed for years as a wart prior to biopsy. Less
    commonly, lesions may resemble chronic paronychia with swelling, erythema, and
    tenderness of the nail fold; onychodystrophy also may be noted.
   Marjolin ulcer: This subtype of squamous cell carcinoma appears as a new area of
    induration, elevation, or ulceration at the site of a preexisting scar or ulcer. Patients with
    this form of squamous cell carcinoma can have a poor prognosis. The diagnosis of
    Marjolin ulcer should be considered in any ulcer that fails to heal with standard therapy.
   Perioral squamous cell carcinoma: Squamous cell carcinoma of the lip usually arises on
    the vermillion border of the lower lip. It is sometimes predated by a precursor lesion,
    actinic cheilitis, which manifests as xerosis, fissuring, atrophy, and dyspigmentation.
    Actinic cheilitis is analogous to AK of the skin. Squamous cell carcinoma on the lip
    manifests as a new papule, erosion, or focus of erythema/induration. Intraoral squamous
    cell carcinoma typically manifests as a white plaque (leukoplakia) with or without reddish
    reticulation (erythroplakia). Common locations include the anterior floor of the mouth, the
    lateral tongue, and the buccal vestibule.
   Anogenital squamous cell carcinoma: Squamous cell carcinoma in the anogenital region
    may manifest as a moist, red plaque on the glans penis; indurated or ulcerated lesions
    may be seen on the vulva, external anus, or scrotum. Associated symptoms include pain,
    pruritus, and intermittent bleeding.
        Verrucous carcinoma: Verrucous carcinoma is a subtype of squamous cell carcinoma that
         can be locally destructive but rarely metastasizes. Lesions appear as exophytic, fungating,
         verrucous nodules or plaques, which may be described as "cauliflowerlike." Verrucous
         carcinoma is further subdivided based on its location in the anogenital region (Buschke-
         Löwenstein tumor), the oral cavity (oral florid papillomatosis), and the plantar foot
         (epithelioma cuniculatum).
        Lymphadenopathy: With any invasive (not in situ) squamous cell carcinoma, regional
         lymph nodes should be examined. Lymph node enlargement must be further evaluated by
         fine-needle aspiration (FNA) or nodal biopsy.

Causes
The primary cause of most squamous cell carcinoma (SCC) is cumulative lifetime sun exposure.
The frequency of squamous cell carcinoma is increased at lower latitudes, correlating with an
increased intensity of ambient light. Other causes of squamous cell carcinoma are discussed
below.

        UV sunlight exposure
              o The component of sunlight believed to be most important in cutaneous
                  carcinogenesis is UVB (290-320 nm), which is both an initiator and a promoter of
                  carcinogenesis. In animal models, UV-induced photocarcinogenesis appears to
                  involve the UVB and UVA-2 spectral ranges.17
              o UVB-induced photocarcinogenesis appears to work by suppressing the immune
                  system in several ways. The UVB spectrum inhibits antigen presentation, induces
                  the release of immunosuppressive cytokines, and elicits DNA damage,
                  specifically the generation of pyrimidine dimers in keratinocyte DNA that is a
                  molecular trigger of UV-mediated immunosuppression.18
              o Inactivation of the tumor suppressor gene TP53 occurs in up to 90% of all
                  cutaneous squamous cell carcinoma lesions.19 Other tumor suppressor genes
                  found to be mutated in squamous cell carcinoma include P16 (INK4a) and P14
                  (ARF).20
        Therapeutic UV exposure: UV light treatments used for psoriasis (and other recalcitrant
         dermatoses) also predispose to the development of squamous cell carcinoma. PUVA is
         particularly phototoxic and mutations in both TP53 and the oncogene Ha-Ras are present
         in a large proportion of PUVA-associated squamous cell carcinoma.21 In addition to being
         mutagenic, UVA in conjunction with UVB is a potent suppressor of the cutaneous immune
         system, which likely contributes to its role in cutaneous carcinogenesis.
        Fair complexion: Individuals with skin types I and II account for most of the patients who
         develop squamous cell carcinoma; patients with oculocutaneous albinism are also at risk,
         and squamous cell carcinomas account for the most common type of cutaneous
         malignancy in this group. Such individuals lack natural protection from UV-induced
         carcinogenesis, owing to reduced levels of the photoprotective pigment, melanin. 22
        Ionizing radiation: Therapeutic ionizing radiation is typically associated with the later
         development of BCCs, but the risk of developing squamous cell carcinomas is also
         increased.23 Most patients with radiation-induced tumors have a remote history of x-ray
         therapy for acne vulgaris, although patients developing squamous cell carcinoma in
         radiation ports for Hodgkin disease or thyroid cancer treatment is not uncommon.
        Chemical carcinogens: Exposure to arsenic is a well-established cause of cutaneous
         squamous cell carcinoma and internal cancers.4 Today, the main source of arsenic is
         contaminated well water, although arsenic may also be found in traditional Chinese
         medicines. Other carcinogens associated with squamous cell carcinoma include polycyclic
         aromatic hydrocarbons such as tar, soot, and pitch.
        DNA repair failure: Healthy human skin is constantly repairing UV-induced damage
         through DNA repair mechanisms. Patients with xeroderma pigmentosum have a
         deficiency in an enzyme essential for normal DNA repair and are thus prone to the
         development of innumerable squamous cell carcinomas, and, less commonly, other
         cutaneous tumors.24
        Iatrogenic immunosuppression: The use of immunosuppressive medications to prevent
         rejection in OTRs is associated with a 65- to 250-fold increased risk of developing
         squamous cell carcinoma compared with the general population.25
              o The primary risk factor in these patients is cumulative lifetime UV exposure in
                  combination with having skin type I or II. This risk also increases with the number
              of years posttransplantation, presumably because of the cumulative effects of
              prolonged immunosuppressive therapy.
         o The greatest risk occurs in heart transplant patients, with diminishing risk seen in
              recipients of kidney and liver transplants, which correlates with the degree of
              immunosuppression (ie, number and/or dosage of medications) typically required
              to prevent rejection in these patient populations.
         o Pretransplantation end-organ disease may also impact the development of
              posttransplant squamous cell carcinoma. For example, among renal transplant
              recipients, the highest prevalence of skin cancer was observed in patients with
              polycystic kidney disease, while the lowest incidence was seen in those with
              diabetic nephropathy. Similarly, cholestatic liver disease was associated with a
              greater posttransplantation risk of skin cancer compared with other causes of
              liver failure.
   Noniatrogenic immunosuppression: In addition to iatrogenic immunosuppression, defects
    in cell-mediated immunity related to lymphoproliferative disorders (eg, CLL) predispose to
    the development of aggressive squamous cell carcinoma. The specific mechanisms by
    which immunosuppression leads to squamous cell carcinoma development are poorly
    understood, but diminished immunosurveillance is thought to be critical. CD8 + T cells
    specific for the tumor suppressor gene TP53 have been observed in patients with
    squamous cell carcinoma, suggesting that a functional immune system may target
    keratinocytes expressing mutated TP53.26 Suppression of the immune system would
    presumably abrogate this response and might be expected to facilitate the development of
    squamous cell carcinoma.
   HPV: Infection with specific subtypes of HPV is believed to play a role in the development
    of anogenital and periungual squamous cell carcinoma. HPV types 6 and 11 are
    associated with Buschke-Löwenstein tumors, whereas HPV type 16 has been frequently
    identified in both genital and periungual squamous cell carcinoma, suggesting the
    possibility of genital-digital spread.27,28 HPV types 5 and 8 are associated with cutaneous
    squamous cell carcinoma in transplantation patients.29
   Chronic inflammation
         o Chronic inflammation, irrespective of the underlying etiology, may lead to the
              development of squamous cell carcinoma. Both noninfectious inflammatory
              diseases and chronic infections have been associated with squamous cell
              carcinoma.
         o Likewise, the Marjolin ulcer variant of squamous cell carcinoma may develop in
              patients with a chronic scarring condition such as dystrophic epidermolysis
              bullosa. In fact, the leading cause of death in patients with dystrophic
              epidermolysis bullosa is metastatic cutaneous squamous cell carcinoma.8 More
              recently, evidence suggests that patients with junctional epidermolysis bullosa
              may also be at increased risk for developing squamous cell carcinoma.30 The
              underlying pathogenesis of such lesions is not understood, but mutations in the
              TP53 and P16 tumor suppressor genes have been described in dystrophic
              epidermolysis bullosa–associated squamous cell carcinoma.31
   Some of the conditions that predispose to the development of squamous cell carcinoma
    are highlighted as follows:
         o Chronic inflammatory and scarring conditions
                    Burn scar or thermal injury
                    Venous ulcer
                    Lymphedema
                    Discoid lupus erythematosus
                    Erosive oral lichen planus
                    Lichen sclerosis et atrophicus
                    Mutilating keratoderma
                    Necrobiotic lipoidica
         o Chronic infections
                    Osteomyelitis
                    Acne conglobata
                    Hidradenitis suppurativa
                    Dissecting cellulitis of scalp
                    Lupus vulgaris
                    Lymphogranuloma venereum
                    Granuloma inguinale
                    Chronic deep fungal infection
                o      Genetic syndromes and dermatoses
                           Dystrophic epidermolysis bullosa
                           Epidermodysplasia verruciformis
                           Xeroderma pigmentosum
                           Oculocutaneous albinism
                           Dyskeratosis congenita
                           Porokeratosis (Mibelli type, disseminated superficial actinic type, linear
                               type)
                           Nevus sebaceous
                           KID (keratitis, ichthyosis, deafness) syndrome

Differential Diagnoses
   Actinic Keratosis      Warts, Genital
Atypical Fibroxanthoma   Warts, Nongenital
 Basal Cell Carcinoma
  Keratoacanthoma
Pyoderma Gangrenosum
Workup

Imaging Studies
Imaging is not routinely indicated for diagnosing cutaneous squamous cell carcinoma (SCC).
However, radiologic imaging should be obtained in patients with regional lymphadenopathy and/or
neurologic symptoms suggestive of perineural involvement. CT scanning, MRI, ultrasonography, or
positron-emission tomography (PET) scanning may be used depending on the specific question
being addressed, although the selection of one modality over another is often based on clinician
and institutional preference. Currently, no formal guidelines regarding the use of radiologic imaging
in cutaneous squamous cell carcinoma have been developed.
Disease staging workup in high-risk squamous cell carcinoma

         Physical examination of lymph nodes: In all squamous cell carcinoma patients, the
          draining nodal basins should be palpated. If nodes are palpable, a biopsy should be
          performed using FNA or excision. If lymph nodes are clinically negative but the tumor
          meets high-risk criteria, little data are available to guide what should be done next.
          Subsequently, management currently varies with regard to further staging.32,33 See "High-
          risk squamous cell carcinoma" in Prognosis.
         Radiologic staging
               o Only a few studies have reported on the utility of radiologic imaging in cutaneous
                   squamous cell carcinoma. One study of MRI and CT scanning in patients with
                   histologically proven perineurally invasive squamous cell carcinoma showed only
                   20% of asymptomatic patients to have positive findings discovered from imaging
                   studies. Thus, CT scanning and MRI appear to be poor in detecting
                   asymptomatic nerve involvement. However, positive imaging findings did
                   correlate with worse outcomes. The 5-year survival rate was 50% if CT scanning
                   or MRI findings were positive, versus 86% if they were negative.34
               o Two studies reported on radiologic imaging for detecting subclinical nodal
                   metastasis.35 The first, a study of vulvar squamous cell carcinoma, indicated that
                   ultrasonography followed by FNA for suspicious nodes was superior to CT
                   scanning in staging subclinical nodal metastasis, with ultrasound-guided FNA
                   demonstrating 80% sensitivity and 100% specificity. The second is a small study
                   of PET scanning in 9 patients with high-risk squamous cell carcinoma. PET
                   scanning detected subclinical nodal metastasis in 3 of 9 patients. 36 Thus, PET
                   scanning and ultrasound-guided FNA may be capable of detecting many cases of
                   subclinical nodal metastasis.
         Sentinel lymph node biopsy (SLNB): A review of the 85 reported cases of SLNB in high-
          risk, nonanogenital cutaneous squamous cell carcinoma showed that 21% of cases were
          positive based on SLNB findings. This indicates that SLNB likely can detect many cases
          of subclinical nodal metastasis. How the sensitivity of SLNB compares with that of PET
          scanning or ultrasound-guided FNA and whether detection of subclinical nodal metastasis
          impacts survival are unknown. However, because the 5-year survival rate of patients with
          nodal metastasis is as high as 73% with aggressive treatment,14 early detection of nodal
          metastasis may prove more beneficial in squamous cell carcinoma than in melanoma.
       Summary: Little data are available to guide decisions about staging of nodal basins in
        high-risk squamous cell carcinoma. However, PET scanning, ultrasound-guided FNA, and
        SLNB all appear to offer a good chance of detecting subclinical nodal metastasis with low
        morbidity. Thus, nodal staging may be considered in patients with high-risk squamous cell
        carcinoma. Development of prognostic models that better predict the risk of nodal
        metastasis will allow for more rational decisions about which patients should undergo
        nodal staging.

Procedures
Skin biopsy

Although the diagnosis of squamous cell carcinoma is often strongly suspected based on clinical
findings, a skin biopsy is required for definitive diagnosis. A shave biopsy, punch biopsy, incisional
biopsy, or excisional biopsy may be used. The biopsy is routinely performed in the physician's
office after the patient is given a local anesthetic.

All skin biopsy samples obtained to diagnose squamous cell carcinoma must reach at least the
depth of the mid dermis to allow for a determination of the presence or absence of invasive
disease. For high-risk lesions, a larger sample may be helpful to assess for perineural invasion
and other histologic features that confer a greater risk of metastasis. Given recent information
about depth being an important prognostic factor (analogous to melanoma), a large punch biopsy
through the center of the lesion or excisional biopsy may be best, particularly in high-risk lesions or
immunosuppressed patients.37

Pathologic analyses may be completed by a dermatologist or a general pathologist, but they are
preferably completed by a dermatopathologist with extensive experience in squamous cell
carcinoma.

Patients with regional lymphadenopathy identified by clinical examination or imaging studies
should undergo a lymph node biopsy or FNA for histologic evaluation. SLNB has been used to
identify micrometastasis in patients with high-risk squamous cell carcinoma and clinically negative
nodes, with 21% positivity.38 While SLNB appears to be able to detect most subclinical metastasis,
whether early detection of lymph node metastasis leads to enhanced survival in squamous cell
carcinoma is unknown, because controlled studies have not been conducted. Complete
lymphadenectomy of the draining nodal basin has also been suggested for high-risk tumors with
an estimated metastatic risk of 20% or greater. However, because prognostic models do not exist,
knowing precisely which patients fall into this category is difficult. Thus, when it is feasible, SLNB
offers a low-morbidity approach to accurately staging high-risk squamous cell carcinoma.
Histologic Findings
The biopsy report for squamous cell carcinoma often carries prognostic implications. Recognizing
the implications of the various histologic subtypes of squamous cell carcinoma is important, and
the astute clinician uses his or her understanding of histopathology to advantage in planning the
appropriate therapeutic intervention.

Squamous cell carcinoma in situ is characterized by an intraepidermal proliferation of atypical
keratinocytes. Hyperkeratosis, acanthosis, and confluent parakeratosis are seen within the
epidermis, and the keratinocytes lie in complete disorder, resulting in the classic "windblown"
appearance. Cellular atypia, including pleomorphism, hyperchromatic nuclei, and mitoses, is
prominent. Atypical keratinocytes may be found in the basal layer and often extend deeply down
hair follicles, but they do not invade the dermis.

The main feature that distinguishes invasive squamous cell carcinoma from squamous cell
carcinoma in situ is invasion of malignant keratinocytes through the basement membrane and into
the dermis. Keratinization results in the production of squamous eddies or keratin pearls. The
neoplastic cells may demonstrate varying degrees of squamous differentiation and atypia. If the
tumor is poorly differentiated, this fact is typically reported by the dermatopathologist because the
degree of differentiation has prognostic implications (ie, poorly differentiated tumors have been
associated with a higher risk of metastasis).

Several variants of squamous cell carcinoma can be distinguished by clinical and/or histologic
criteria. In some cases, these tumors may be difficult to distinguish from other malignancies based
on routine histology findings alone. Therefore, immunohistochemical staining with antibodies to
cytokeratins and epithelial membrane antigen is often used to confirm the epithelial (ie,
keratinocyte) origin of the tumor. The salient features of keratoacanthoma, spindle cell squamous
cell carcinoma, acantholytic (adenoid) squamous cell carcinoma, and verrucous carcinoma are
highlighted in the following table.

Histologic and Clinical Features of Squamous Cell Carcinoma Variants

Open table in new window

Tumor                        Histologic Characteristics                       Clinical Characteristics

Keratoacanthoma              Keratin-filled crater                            Solitary nodule
                             Well-differentiated (mild atypia)                Central craterlike depression
                             Neutrophil microabscesses                        Rapid growth
                             Eosinophils in dermal infiltrate                 May spontaneously involute

Spindle cell SCC             Atypical spindle cells                           Resembles typical SCC
                             Foci of squamous differentiation                 May be clinically aggressive
                             May resemble other spindle cell tumors (eg,
                             atypical fibroxanthoma)

Acantholytic (adenoid) SCC   Glandlike differentiation                        Arises on sun-damaged skin
                             Acantholysis                                     Elderly patients
                             May resemble adenocarcinoma or sweat gland       Resembles typical SCC
                             carcinoma                                        Clinically aggressive

Verrucous carcinoma          Well-differentiated (minimal atypia)             Oral, genital, or plantar foot
                             Resembles verruca                                Indolent growth
                             Bulbous downward proliferation                   Locally destructive
                             "Bulldozing" invasion                            Rarely metastasizes

Sarcomatoid SCC              Poorly differentiated cells resembling sarcoma   Clinical appearance may be that of typical SCC
                                                                              or may have more nodular appearance with
                                                                              less surface change
                                                                              Elevated risk of local recurrence and
                                                                              metastasis

Tumor                        Histologic Characteristics                       Clinical Characteristics

Keratoacanthoma              Keratin-filled crater                            Solitary nodule
                             Well-differentiated (mild atypia)                Central craterlike depression
                             Neutrophil microabscesses                        Rapid growth
                             Eosinophils in dermal infiltrate                 May spontaneously involute

Spindle cell SCC             Atypical spindle cells                           Resembles typical SCC
                             Foci of squamous differentiation                 May be clinically aggressive
                             May resemble other spindle cell tumors (eg,
                             atypical fibroxanthoma)

Acantholytic (adenoid) SCC   Glandlike differentiation                        Arises on sun-damaged skin
                             Acantholysis                                     Elderly patients
                             May resemble adenocarcinoma or sweat gland       Resembles typical SCC
                             carcinoma                                        Clinically aggressive

Verrucous carcinoma          Well-differentiated (minimal atypia)             Oral, genital, or plantar foot
                             Resembles verruca                                Indolent growth
                             Bulbous downward proliferation                   Locally destructive
                             "Bulldozing" invasion                            Rarely metastasizes

Sarcomatoid SCC              Poorly differentiated cells resembling sarcoma   Clinical appearance may be that of typical SCC
                                                                              or may have more nodular appearance with
                                                                              less surface change
                                                                              Elevated risk of local recurrence and
                                                                              metastasis

Staging
Squamous cell carcinoma is staged according to American Joint Committee on Cancer guidelines,
which use the TNM classification system. Most cutaneous squamous cell carcinomas are not
metastatic at the time of presentation; therefore, the tumor stage in such cases is based solely on
the characteristics of the primary lesion. Staging of metastatic disease takes into account the
presence or absence of regional lymph node and distant metastasis. The staging system is
currently being updated to incorporate more information about tumor factors that impact prognosis.
The new staging system will be available in 2010. Meanwhile, current classification of the primary
tumor is described below.

         TX - Primary tumor cannot be assessed
        T0 - No evidence of primary tumor
        Tis - Carcinoma in situ
        T1 - Tumor less than 2 cm in greatest diameter
        T2 - Tumor 2-5 cm in greatest diameter
        T3 - Tumor greater than 5 cm in greatest diameter
        T4 - Tumor with deep invasion into cartilage, muscle, or bone

Treatment

Medical Care
Nonsurgical options for the treatment of cutaneous squamous cell carcinoma (SCC) include topical
chemotherapy, topical immune response modifiers, photodynamic therapy (PDT), radiotherapy,
and systemic chemotherapy. The use of topical therapy and PDT is generally limited to
premalignant (ie, actinic keratoses [AKs]) and in situ lesions. Radiation therapy is a primary
treatment option for patients in whom surgery is not feasible and is an adjuvant therapy for those
with metastatic or high-risk cutaneous squamous cell carcinoma. In current practice, systemic
chemotherapy is used exclusively for patients with metastatic disease. However, newer more
targeted drugs, such as epidermal growth factor receptor (EGFR) antagonists (eg, cetuximab),
have favorable adverse effect profiles and await trails to determine if they are beneficial in high-risk
squamous cell carcinoma.

Topical chemotherapy

Topical formulations of 5-fluorouracil (5-FU) are available for the treatment of AKs and superficial
basal cell carcinomas (BCCs). Successful treatment of in situ squamous cell carcinoma has also
been reported.39 Invasive squamous cell carcinoma should not be treated with topical
chemotherapy. An oral form of 5-FU (capecitabine), which is approved by the US Food and Drug
Administration (FDA) for other forms of cancer, may be considered in patients with diffuse in situ
squamous cell carcinoma over large skin areas, on which topical 5-FU is difficult to apply.
However, studies of efficacy have not yet been performed.

Topical immune response modifiers

Imiquimod is an imidazoquinoline that enhances cell-mediated immune responses via the
induction of proinflammatory cytokines. It is approved by the FDA for the treatment of genital warts
(ie, condylomata acuminata), AKs, and superficial BCC. Imiquimod cream has also shown
effectiveness in the treatment of Bowen disease as monotherapy and in combination with topical
5-FU. However, systemic flulike symptoms and other adverse effects can occur when applied to
large surface areas; therefore, using this agent in patients with diffuse in situ squamous cell
carcinoma is difficult.40,41

Photodynamic therapy

Treatment with PDT involves the application of a photosensitizer (given topically or systemically)
followed by exposure to a light source. The resulting photochemical reaction causes inflammation
and destruction of the targeted lesion(s). PDT is used primarily to treat large numbers of AKs in a
single session. Squamous cell carcinoma in situ is also amenable to PDT, although a wide range
of recurrence rates (0-52%) have been reported. At this time, PDT is not recommended for
treatment of invasive squamous cell carcinoma.42

Radiation therapy

Radiation therapy offers the potential advantage of avoiding the deformity and trauma of a surgical
procedure. Cure rates for T1 lesions range from 85-95%. However, a number of disadvantages are
associated with radiation therapy. For example, radiation therapy is expensive and requires a
significant time commitment because treatments are usually given 3-5 times per week for 4-8
weeks. Most patients experience significant irritation at the radiation site, and they frequently
develop erythema, erosions, alopecia, and pain, which may require narcotic-level analgesia.
Although the initial cosmetic result following radiation is usually good, the long-term outcome is
often poor, owing to the development of cutaneous atrophy, dyspigmentation, and telangiectasia in
the radiation field. Patients treated with radiation also have a slightly increased risk of developing
cutaneous carcinoma (most commonly squamous cell carcinoma) or sarcoma later in life.
Radiation therapy does not involve histologic margin control and has a lower cure rate compared
with surgery. For these reasons, as well as those discussed in the preceding paragraph, primary
radiation therapy for squamous cell carcinoma is generally restricted to older patients who cannot
tolerate or who refuse surgery.

In contrast, radiation is routinely used as an adjunct to surgical treatment in cases of nodal
metastasis, and the reported 5-year cure rate is 73% for combined surgical and radiation therapy
to involved nodal basins.14
The use of adjuvant radiotherapy in high-risk cutaneous squamous cell carcinoma in the absence
of known metastasis is more controversial because studies have not been conducted to verify its
benefit. In the setting of high-risk squamous cell carcinoma, every attempt should be made to
obtain clear surgical margins. Administration of adjuvant radiotherapy, which may include both the
primary site and the draining nodal basins, is usually reserved for cases in which surgical margins
are in doubt or when the patient has substantial nerve involvement.43
Systemic chemotherapy

A variety of different chemotherapeutic agents have been used to treat metastatic cutaneous
squamous cell carcinoma. Many of the current protocols have been adapted from those used to
treat metastatic head and neck squamous cell carcinoma. Capecitabine (Xeloda), an oral
formation of 5-FU, either alone or in combination with interferon alfa, has shown some efficacy in
the treatment of advanced cutaneous squamous cell carcinoma.44

Reduction in immunosuppression

In OTRs, a reduction in the magnitude of immunosuppression may be an effective adjuvant
therapeutic strategy in the treatment of aggressive squamous cell carcinoma. Because a decrease
in immunosuppression may increase the risk for rejection of the transplanted organ, this strategy
should only be considered in selected high-risk patients and under the careful management of the
transplantation physician, who must closely monitor the patient for signs and symptoms of organ
rejection.45
Surgical Care
Most squamous cell carcinomas (SCCs) are readily treated in the physician's office by surgical or
destructive methods, with a high expectation of cure. The treatment of squamous cell carcinoma
must take into account multiple patient- and lesion-specific factors. The standard modalities
available for the treatment of localized (primary) invasive squamous cell carcinoma are described
below. Because squamous cell carcinoma is a lesion that can recur, metastasize, and cause
death, and because recurrent squamous cell carcinoma carries a worse prognosis, every
opportunity should be taken to effect complete tumor extirpation at first presentation.
Cryotherapy

Cryotherapy with liquid nitrogen is a safe and low-cost procedure for the ablation of selected in situ
squamous cell carcinomas. The 5-year cure rate for squamous cell carcinoma can be 95% or
greater with proper tumor selection and technique. In the United States, cryosurgery is routinely
used for in situ disease and AKs. It is not often used for invasive squamous cell carcinoma
because deeper portions of the tumor may not be eradicated by this technique and because the
development of scar tissue at the site of cryotherapy might obscure a recurrence. The risks
associated with cryotherapy include transient pain, edema, and blistering. Hypopigmentation and
alopecia are also common and may be permanent, so treatment of hair-bearing areas and in
darkly pigmented individuals is generally not recommended.46
Electrodesiccation and curettage

Electrodesiccation and curettage (ED&C) is a simple technique that can be used to treat low-risk
squamous cell carcinoma on the trunk and extremities. The tumor indications are similar to those
of cryotherapy. In addition, ED&C can be used to treat superficially invasive squamous cell
carcinomas without high-risk characteristics. However, the thick scars that often occur after ED&C
can delay the diagnosis of cancer recurrence. Subsequently, ED&C should be used with caution in
invasive squamous cell carcinoma. It is not appropriate for certain anatomic locations (ie, eyelids,
genitalia, lips, ears).
The technique is based on the delineation of tumor margins with a curette because tumor tissue is
generally more friable than the surrounding normal tissue. ED&C is known to be very technique-
dependent, and cure rates improve with a practitioner's experience. The main disadvantage of
ED&C is a lack of histologic margin control, and most dermatologic surgeons believe the actual
long-term cure rate for invasive squamous cell carcinoma is much lower than that quoted in the
literature. Tumor recurrence may result from failure of ED&C treatment to eradicate atypical cells
residing deep in the hair follicles or in the dermis. Nonetheless, the procedure is fast, minimally
invasive, well tolerated, and effective for properly selected lesions.
Excision with conventional margins

Standard excision with conventional permanent (ie, fixed) tissue sections is an excellent, highly
effective, and well-tolerated therapy for many primary squamous cell carcinomas. Cure rates
following simple excision of well-defined T1 lesions may be as high as 95-99%. The generally
accepted 5-year cure rate for primary squamous cell carcinoma treated with standard excision is
92%; this rate drops to 77% for recurrent squamous cell carcinoma.
A 4-mm margin of normal tissue is recommended for lower-risk lesions (<2 cm, well-differentiated,
without subcutaneous fat invasion) on the trunk and extremities. For lesions larger than 2 cm,
invasive to fat, and in high-risk locations (ie, central face, ears, scalp, genitalia, hands, feet), a 6-
mm margin of normal tissue is recommended. Given the cosmetic and functional impact of these
wider margins, tumors in this latter category are often removed via Mohs surgery (see below) to
achieve high cure rates while sparing normal tissue. The depth of an excision should always
include a portion of the subcutaneous fat.
One pitfall of standard excision is that histologic margins can be reported to be negative when they
are, in fact, positive (false negative) because the traditional "bread-loaf" method of tissue
sectioning typically results in evaluation of less than 1% of the specimen’s margins. More
commonly, a greater amount of healthy tissue is removed than is necessary for complete tumor
extirpation. Therefore, simple excision is most valuable in the treatment of small primary
squamous cell carcinomas on the trunk, extremities, or neck, where tissue sparing is less
essential.47
Mohs micrographic surgery

Mohs micrographic surgery (MMS) is a specialized technique for removing many forms of skin
cancer, including squamous cell carcinoma. Because of its many advantages, MMS is the
procedure of choice for squamous cell carcinoma in which tissue preservation is needed, for ill-
defined squamous cell carcinoma, and for high-risk squamous cell carcinoma. The main
advantage of MMS over simple excision is the ability to histologically examine nearly 100% of the
surgical margins and to carefully map residual foci of invasive carcinoma. This residual tumor is
removed in a step-wise fashion until clear margins are obtained.
MMS provides the best available cure rates (94-99%) for squamous cell carcinoma and has been
of particular value in curing squamous cell carcinoma associated with perineural invasion. In a
comprehensive historical review, Rowe et al48 noted that local recurrences are less frequent when
squamous cell carcinoma is treated with MMS compared with all non-Mohs modalities. This local
recurrence rate differential in favor of MMS was observed in primary squamous cell carcinoma of
the skin and lip (3.1% vs 10.9%), for locally recurrent squamous cell carcinoma (10% vs 23.3%),
for poorly differentiated squamous cell carcinoma (32.6% vs 53.6%), and for squamous cell
carcinoma with perineural involvement (0% vs 47%). MMS offers the added benefit of preserving
healthy tissue, thus facilitating reconstruction and optimizing cosmetic and functional outcomes.
MMS is routinely performed in an outpatient setting with local anesthesia and, therefore, is safe
and cost effective. As a result of the fellowship training programs in Mohs surgery overseen by the
American College of Mohs Surgery and the new Accreditation Council for Graduate Medical
Education (ACGME)–accredited Procedural Dermatology Fellowship programs, MMS has become
widely available throughout the United States.49,50
Care of patients with diffuse actinic keratosis and in situ squamous cell carcinoma

Many patients with a history of extensive sun exposure and light skin develop epidermal atypia in
the form of AK and in situ squamous cell carcinoma over large areas of their skin. Most of these
patients also develop multiple invasive squamous cell carcinomas. The management of such
patients is highly labor intensive and involves the following steps:
       Surgically remove all tumors that clinically appear to have to have an invasive (dermal)
        component and confirm clearance of histologic margins.
       Evaluate for underlying immunosuppression, such as from CLL or an overly impaired
        immune system from immunosuppressive or immunomodulatory therapy. If this is
        suspected, discuss with the patient’s other doctors whether the immunosuppression can
        be safely remedied or lessened.
       Perform field treatment of the areas of epidermal atypia. Treatment options include topical
        chemotherapy with 5-FU or PDT. Imiquimod has limited utility in diffuse disease because
        adverse effects increase when applied to large surface areas. If 5-FU therapy is planned,
        remove any hyperkeratotic lesions with a curette just prior to beginning therapy to
        enhance penetration of the medication to the basal layer. A full course of 5-FU therapy is
        twice-daily administration for 4 weeks. Patients who cannot tolerate this duration may try
        shorter courses and then resume treatment after a healing phase. Subsequent treatments
        become more tolerable as the epidermal damage is corrected.
       Follow the patient closely for recurrence of actinic keratosis/squamous cell carcinoma in
        situ and for new invasive squamous cell carcinomas. Field treatment may need to be
        repeated every 6-12 months to keep precursor actinic keratosis and squamous cell
        carcinoma in situ lesions to a minimum.
       Oral retinoids in the form of low-dose acitretin can decrease new cancer formation,
        although they do not generally alter the course of existing tumors.51 Although most patients
        do not require retinoids if the above measures are taken, patients who are still developing
        multiple cancers 6-12 months after beginning an intensive program to clear disease may
        benefit from retinoid therapy. Once the desired effect is achieved, considering a dose
        reduction of long-term maintenance therapy rather than discontinuing therapy is better
        because the latter typically leads to a rebound of multiple squamous cell carcinoma
        formation.

Treatment of patients with high-risk tumors

Management of primary tumors
See "High-risk squamous cell carcinoma" in Prognosis. The use of ED&C in the treatment of high-
risk squamous cell carcinoma, particularly in immunocompromised individuals, is best avoided,
because histologic margin status cannot be evaluated. Clear margins must be obtained for optimal
outcomes.

Ensuring clear surgical margins wherever possible is highly recommended. A systematic review of
available data for high-risk squamous cell carcinoma compared cases with clear surgical margins
(n = 943) versus those in which margins were not specified (n = 1506) and demonstrated
statistically better outcomes in cases in which clear margins were documented, with risks of local
recurrence, regional metastasis, distant metastasis, and disease-specific death of 5%, 5%, 1%,
and 1%, respectively, in clear-margin cases versus 8%, 14%, 7%, and 7% in cases with
undocumented margins.43

A prospective study identified several risk factors for incomplete excision of squamous cell
carcinomas, namely, ear lesions, invasive lesions, and previously incompletely excised lesions
referred for reexcision. The study also recommended more care with tumor markings, taking
margins of at least 5 mm, deeper margins, and referring such lesions to centers with personnel
who have more experience.52

No controlled comparative studies of Mohs versus excision in high-risk squamous cell carcinoma
have been performed, but case series data suggest that Mohs is superior to excision for high-risk
squamous cell carcinoma patients.49

Adjuvant therapy
No comparative studies of surgery versus surgery plus adjuvant radiotherapy for high-risk
squamous cell carcinoma have been performed. With no clear evidence of benefit and the
potential of significant morbidity, clinical judgment is required in deciding which patients should
receive adjuvant radiation. One systematic review of available outcome data suggests that
adjuvant radiation be considered in patients with uncertain or positive surgical margins or
advanced nerve involvement (eg, involvement of named nerves, nerves 0.1 mm or greater in
diameter, or with clinical or radiologic evidence of nerve invasion).43 Adjuvant medication may also
be considered in select highest-risk cases. Options include oral 5-FU (Xeloda) and EGFR
inhibitors via oncology treatment centers. Although survival data are lacking, these medications
are generally well-tolerated with few adverse effects.
Consultations
Most cases of squamous cell carcinoma are easily and successfully treated by dermatologists or
Mohs surgeons. However, in certain cases, a multidisciplinary approach may be needed (see
"High-risk squamous cell carcinoma" in Prognosis). Such cases include the following:

        Large or deep tumors in which excision and reconstruction under local anesthesia is not
         feasible
        When clear surgical margins are not achieved or are in doubt
        Cases of nodal or distant metastasis

A multidisciplinary approach using MMS performed in conjunction with an otolaryngologist and/or a
plastic surgeon may aid in completely removing deeply invasive squamous cell carcinoma,
preserving a vital structure (eg, facial nerve), and facilitating the reconstruction of a large operative
defect. For example, Mohs surgery may be used in cases of squamous cell carcinoma of the scalp
involving bone to establish peripheral margins to the level of the galea. Mohs is then followed by
resection of the deep margin, including bone, with the patient under general anesthesia, performed
by a head and neck or plastic surgeon. Because the peripheral margins are established in
advance, the head and neck or plastic surgeon can then focus on the deep margin and
reconstruction. The patient is often spared hours of anesthesia time, lowering surgical morbidity.

Metastatic disease also requires aggressive management by a multidisciplinary team. Surgical
treatment of metastatic disease may require the expertise of an otolaryngologist, a general
surgeon, or a surgical oncologist. Adjuvant or palliative radiotherapy may be administered by a
radiation oncologist. A medical oncologist should be consulted if systemic chemotherapy is
considered for metastatic disease.




Follow-up

Further Outpatient Care
Low-risk tumors are usually cured with appropriate surgical therapy; however, patients who
develop one squamous cell carcinoma (SCC) have a 40% risk of developing additional squamous
cell carcinomas within the next 2 years. This risk is likely even greater as more time elapses. Thus,
patients with a history of squamous cell carcinoma should be evaluated with a complete skin
examination every 6-12 months.

Patients with high-risk tumors require skin and lymph node examinations at 3- to 6-month intervals
for at least 2 years after diagnosis. In very high-risk cases, surveillance with CT scanning or MRI
may be considered.
Deterrence/Prevention
General preventive measures

Prevention of squamous cell carcinoma is best accomplished by limiting exposure to UV radiation,
including both natural sunlight and artificial sources of UV light such as tanning beds. Wearing
protective clothing, limiting outdoor activities (especially between 10:00 am and 4:00 pm), and
applying a broad-spectrum sunscreen (ie, one that blocks UVA and UVB light) with a sun
protection factor of at least 15 every day all help reduce UV exposure.

Treatment of precancerous actinic keratoses (AKs) and in situ squamous cell carcinoma may
prevent the future development of invasive squamous cell carcinoma. Additionally, Patient
education regarding skin cancer warning signs and periodic self-directed and physician-directed
complete skin examinations are recommended.

Chemoprevention
Chemoprevention with systemic retinoids is effective for reducing the number of new squamous
cell carcinomas in both immunocompetent and immunosuppressed patients. Most recent studies
have focused on the prophylactic use of oral acitretin, which has a relatively long half-life
compared with isotretinoin. Low doses are often sufficient for prophylaxis. However, treatment
must be continued indefinitely because a relapse in tumor development occurs following
discontinuation of oral retinoids. Furthermore, systemic retinoids have not been shown to be
beneficial in treating existing squamous cell carcinoma or at reducing the risk of recurrence after
treatment.53

The mechanisms by which retinoids protect against the development of squamous cell carcinoma
have not been fully elucidated. Data suggest that retinoids induce the expression of proapoptotic
and antiproliferative genes, including TP53, caspases, and P73, in keratinocytes. The increase in
epidermal Langerhans cells noted in one study suggests that retinoids may also enhance
cutaneous immunosurveillance.54,55

Many patients are unable to tolerate the adverse effects associated with systemic retinoid therapy,
although lower doses are better tolerated than higher doses. Organ transplant recipients (OTRs)
appear to be more sensitive to the adverse effects of systemic retinoids compared with other
patients. Adverse effects of systemic retinoids include mucocutaneous xerosis, dyslipidemia, liver
function abnormalities, and teratogenicity.
Prognosis
Most squamous cell carcinomas are readily treated with an expectation of cure. Most large series
in the literature have reported the risk of nodal or distant metastasis for primary tumors to be 2-6%.
A subset of squamous cell carcinoma carries an elevated risk of local recurrence, nodal or distant
metastasis (usually to the lungs), and death. Tumors in this subset are termed high-risk squamous
cell carcinoma (see below). However, prognostic models do not exist for squamous cell carcinoma.
Because many of the risk factors below occur concurrently in single tumors and patients,
determining which risk factors have the greatest prognostic significance is difficult. In the absence
of prognostic models that take the presence of multiple risk factors into account, estimating risk for
individual patients is based on very limited data and gestalt. Due to the lack of data, evidence-
based decision making is often not possible. Subsequently, current management of high-risk
squamous cell carcinoma varies widely.32,33

In one case series, the 3-year disease-specific survival rate for squamous cell carcinoma was
estimated to be 85%. Survival rates approached 100% for lesions with no high-risk factors, but the
disease-specific death rate was 30% for patients with at least 1 risk factor.56 These estimates
derived from a case series may not be reflective of the risk for squamous cell carcinoma in general
and may overestimate risk. However, the data highlight that a subset of squamous cell carcinomas
do poorly (see below).
When squamous cell carcinoma does metastasize, it is usually occurs within 5 years from the time
of diagnosis and involves the primary (ie, first echelon) draining lymph nodes. In general,
metastasis from squamous cell carcinoma of the forehead, temples, eyelids, cheeks, and ears is to
the parotid nodes; metastasis from squamous cell carcinoma of the lips and perioral region is
primarily to the submental and submaxillary (upper cervical) nodes.

Once nodal metastasis of cutaneous squamous cell carcinoma has occurred, the overall 5-year
survival rate has historically been in the range of 25-35%. Prognosis is extremely poor for patients
with a compromised immune system, with metastasis to multiple lymph nodes, or with cervical
lymph nodes greater than 3 cm in diameter. Nevertheless, data published in 2005 show that the
combined use of surgery and adjuvant radiotherapy for patients with nodal metastasis increased
the 5-year disease-specific survival rate to 73%.14 Metastasis to distant organs remains incurable.
Thus, close surveillance and early detection of nodal metastasis can be life saving and is of
paramount importance.

High-risk squamous cell carcinoma

A subset of squamous cell carcinoma is considered high risk because it has been associated with
higher rates of recurrence, metastasis, and death in case series data. Squamous cell carcinoma
can be characterized as high-risk by virtue of tumor-related factors (intrinsic factors), patient-
related factors (extrinsic factors), or a combination of both.

Tumor-related factors in high-risk squamous cell carcinoma48
Tumor-related factors are (1) tumor location (ie, lips, ears, within a scar), (2) tumor size greater
than 2 cm (or 1.5 cm on ear or lip), (3), invasion to subcutaneous fat (or deeper), (4) poorly
differentiated tumor cells, (5) recurrent tumor, and (6) perineural involvement.

Additionally, a prospective study of 210 patients with a diverse range of squamous cell carcinomas
showed tumor-related factors were associated with adverse disease-specific survival using
univariate analyses.56 Specifically, these factors were (1) local recurrence at presentation (P = .05),
(2) invasion beyond subcutaneous tissue (P = .009), (3) depth in general (P = .05), (4) perineural
invasion (P = .002), and (5) size greater than or equal to 4 cm (P = .0003).
Detailed information on tumor-related factors is as follows:

        Location: The lips and the ears may have a higher rate of recurrent and metastatic
         disease than squamous cell carcinoma at other sites. The historical rates of metastases
         for squamous cell carcinoma of the external ear and the lip are approximately 11% and
         10-14%, respectively.48 Numerous studies have demonstrated that the Marjolin ulcer
         subtype of squamous cell carcinoma behaves aggressively, with metastatic rates of
         approximately 18-38%. These are tumors that arise from a preexisting chronic wound.
         Similarly, invasive squamous cell carcinoma of the anogenital region carries a greater risk
         of metastasis. The poor prognosis of both the Marjolin ulcer and anogenital subtypes is
         likely related to delayed diagnosis.
        Diameter: Lesions of invasive squamous cell carcinoma measuring less than 2 cm in
         diameter have been associated with a rate of metastasis of 9.1%, whereas those greater
         than 2 cm in diameter have a metastatic rate of up to 30.3%. A 2005 prospective study
         reported a 3-year disease-specific survival rate of 67% for lesions greater than 4 cm,
         compared with 93% for tumors smaller than 4 cm.56
        Depth: Increased depth of invasion of squamous cell carcinoma is strongly associated
         with local recurrence, metastasis, and death. Squamous cell carcinoma with a depth of
         less than 2 mm rarely metastasizes. Squamous cell carcinoma with a depth of invasion of
         2-4 mm has a historical recurrence rate of 5.3% and a metastasis rate of 6.7%. A 2008
         prospective cohort study found a rate of metastasis of 4% for tumors of 2-6 mm thick. For
         tumors thicker than 6 mm, the risk increased to 16%.57
        Cellular differentiation: More poorly differentiated tumors have a worse prognosis in
         cutaneous squamous cell carcinoma, with recurrence rates reported to be from 33-54%.48
         The actual value of histologic grading alone, however, is less clear because poorly
         differentiated tumors that metastasize or recur also usually have other primary risk factors
         (eg, large diameter, deep invasion). Nonetheless, poorly differentiated squamous cell
         carcinomas are generally accepted to behave more aggressively.
        Recurrent tumors: Local recurrence rates following extirpation of a recurrent squamous
         cell carcinoma range from 10-23%. Reported rates of metastasis are as high as 25-45%,
         but these figures may overestimate the risk in recurrences that are caught early.
        Perineural invasion: Perineural invasion has been estimated to occur in 2.4% of persons
         with cutaneous squamous cell carcinoma. The prognosis in such cases is worse, with
         historical rates of metastasis reported to be as high as 47%. Much lower rates of
         metastasis (8%) have been reported using MMS.48 The degree of nerve involvement likely
         has a large impact on prognosis. Involvement of major (ie, named) nerve branches carries
         a very high risk of recurrence, metastasis, and death. The risks are substantially
         decreased when tumor-free margins are painstakingly obtained by removal of the involved
         nerve. However, the prognosis is still guarded. One study showed the diameter of
         involved nerves to significantly impact outcomes, with no disease-specific deaths
         occurring in those with involvement of nerves less than 0.1 mm in diameter, compared to
         32% of patients dying from disease when nerves 0.1 mm or larger were involved.58

Patient-related factors in high-risk squamous cell carcinoma

General patient-related factors are (1) organ transplant recipient, (2) hematologic malignancy (eg,
CLL), (3) long-term immunosuppressive therapy, and (4) HIV infection or AIDS.

Detailed information on patient-related factors is as follows:

        Organ transplant recipients
            o A 65-fold increased risk of squamous cell carcinoma exists in OTRs. This
                 correlates with the intensity of immunosuppression, so that heart transplant
                 recipients have 3 times the risk of squamous cell carcinoma compared with
                 kidney transplant recipients.59 However, although the proportion of heart
                 transplant recipients developing new tumors is greater than in kidney transplant
                 recipients, the mean number of tumors per patient is higher in kidney transplant
                 recipients. This could be explained by a longer duration of immunosuppression in
                 patients who are younger at transplantation.
             o Additionally, OTRs have a high risk of developing further squamous cell
                 carcinomas, with 66% of OTRs developing a second squamous cell carcinoma
                 within 5 years of their first squamous cell carcinoma diagnosis. 60
             o In addition to squamous cell carcinomas being a more frequent occurrence in
                 OTRs, the tumors can be clinically very aggressive. In one study of cardiothoracic
                 transplant recipients (heart or heart-lung transplants), 4% of patients developed
                 aggressive cutaneous squamous cell carcinoma within 10 years of
                 transplantation. The majority (15 of 18) were poorly differentiated, and two thirds
                 of the patients with aggressive squamous cell carcinoma had distant-organ
                 metastases or died of their disease.61
       CLL: Squamous cell carcinoma arising in patients with CLL and small lymphocytic
        lymphoma (SLL) also carries a worse prognosis. For example, in patients with CLL, the
        recurrence rate of squamous cell carcinoma treated with MMS was 7-fold higher at 5
        years compared with patients without CLL.62 One study found that squamous cell
        carcinomas in CLL and SLL patients are often multiple (67%), high grade (56%), and with
        a high risk of recurrence and metastasis (25%) and death from disease (41%). 63
       HIV infection: HIV infection and AIDS are not definitively associated with high-risk
        squamous cell carcinoma. An increased incidence of anal and penile squamous cell
        carcinoma associated with human papillomavirus (HPV) has been reported in HIV
        patients. A high risk of recurrence has been reported after desiccation and curettage. 64 A
        small series reported cases of aggressive cutaneous squamous cell carcinoma in HIV
        patients, with a 50% mortality rate at 7 years.7

Other reported conditions associated with aggressive squamous cell carcinoma

       Bullous diseases: The risk of squamous cell carcinoma in patients with bullous disease is
        markedly elevated. The risk of death is particularly high in those with epidermolysis
        bullosa, with an 80% mortality rate 5 years after diagnosis of first primary squamous cell
        carcinoma.
       Arsenic exposure
       PUVA exposure

Patient Education
Patients should be counseled to avoid excessive UV radiation by limiting outdoor activity to early
morning and late afternoon, using protective clothing, and wearing a broad-brimmed hat to shade
the head and the neck area. Use of artificial tanning devices should be strongly discouraged
because this has been associated with a 2.5-fold increase in the risk of developing squamous cell
carcinoma. Daily application of a broad-spectrum sunscreen with a sun protection factor of at least
15 should also be encouraged. These measures are critically important for patients who are
immunosuppressed, and they should be an integral part of the educational program for patients
who have recently undergone organ transplantation.

Counseling patients regarding treatment of areas of chronic skin inflammation or trauma is
important in preventing the future development of squamous cell carcinoma at those sites.

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center.
Additionally, see eMedicine's patient education articles Skin Cancer and Skin Biopsy. For
information on cancer risk, prevention, and screening, see the AT-RISC Alliance and
the International Transplant Skin Cancer Collaborative. For more information about MMS, see
the American College of Mohs Surgery.
Miscellaneous

Medicolegal Pitfalls
Malpractice suits are uncommon following the diagnosis and treatment of squamous cell
carcinoma because, in most cases, both are straightforward and readily accomplished.
Nonetheless, squamous cell carcinoma is a lesion with the potential to cause substantial morbidity
and even mortality, and physicians who diagnose and treat squamous cell carcinoma are held
legally accountable for actions that are taken (or not taken) that fall outside the standard of care.

Failure to diagnose squamous cell carcinoma may lead to substantial morbidity and occasionally
mortality. Large court awards have been set for cases in which failure to diagnose squamous cell
carcinoma has led to death.

Failure to treat and perceived inadequate treatment are common causes of malpractice claims
against physicians. These cases occur most frequently when physicians fail to use an adequately
aggressive primary treatment or fail to recognize a high-risk lesion. Recognizing that high-risk
squamous cell carcinoma may metastasize and lead to death is important. Therefore,
appropriately aggressive and prompt treatment is indicated in such cases. However, because
defined prognostic criteria and models have not been developed, little information is available to
guide clinicians in the most appropriate staging and treatment for individuals with high-risk
squamous cell carcinoma. Because of a lack of data, care standards regarding nodal staging,
radiologic imaging, and postsurgical adjuvant therapy have not been developed. Subsequently, a
lack of uniformity exists among experienced physicians in the treatment of high-risk squamous cell
carcinoma.32,33

Failure to provide appropriate follow-up is a potential pitfall. The courts hold the physician, not the
patient, responsible for appropriate follow-up. Because primary treatment of squamous cell
carcinoma is not a guarantee of cure, ensuring adequate patient follow-up is essential. Failure to
inform patients of the potential morbidity associated with squamous cell carcinoma may lead to the
lesion being regarded as trivial and not requiring follow-up. Missed appointments may indicate the
patient is worried or angry. Thus, patients with a history of squamous cell carcinoma who miss
follow-up appointments should be contacted by phone (or when necessary, with a certified letter)
to reschedule. All medical staff are advised to document phone calls in writing and to save certified
letter documentation.

Failure to explain all possible risks and complications of surgery is another legal pitfall. Surgery for
squamous cell carcinoma may cause bleeding, infection, scar formation, physical deformity, and
nerve damage. The removal of deeply invasive lesions may lead to substantial morbidity, including
paralysis and pain syndromes. Explaining all possible risks prior to surgery is essential. Such
explanations should ideally be documented in written consent forms signed by the treating
physician and the patient. Additionally, the physician should not treat lesions outside the realm of
his or her comfort zone. If a surgical complication develops, the physician who performed the
primary procedure is held legally responsible, regardless of who handles the complication.



Multimedia

                                                               Media file 1:
                                      Large sun-induced squamous cell carcinoma on the forehead/temple.




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                                                                 Media file 2:

                                   Squamous cell carcinoma in situ, Bowen disease. Courtesy of Hon Pak, MD.




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                                                      Media file 3:
                                   Squamous cell carcinoma. Courtesy of Hon Pak, MD.




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                                                      Media file 4:
                                   Squamous cell carcinoma. Courtesy of Hon Pak, MD.




             (Enlarge Image)




References

   1.   Johnson TM, Rowe DE, Nelson BR, Swanson NA. Squamous cell carcinoma of the skin
        (excluding lip and oral mucosa). J Am Acad Dermatol. Mar 1992;26(3 Pt 2):467-
        84. [Medline].
   2.   Leiter U, Garbe C. Epidemiology of melanoma and nonmelanoma skin cancer--the role of
        sunlight. Adv Exp Med Biol. 2008;624:89-103. [Medline].
   3.   Masini C, Fuchs PG, Gabrielli F, et al. Evidence for the association of human
        papillomavirus infection and cutaneous squamous cell carcinoma in immunocompetent
        individuals. Arch Dermatol. Jul 2003;139(7):890-4. [Medline].
   4.   Wong SS, Tan KC, Goh CL. Cutaneous manifestations of chronic arsenicism: review of
        seventeen cases. J Am Acad Dermatol. Feb 1998;38(2 Pt 1):179-85. [Medline].
   5.   Herman S, Rogers HD, Ratner D. Immunosuppression and squamous cell carcinoma: a
        focus on solid organ transplant recipients. Skinmed. Sep-Oct 2007;6(5):234-8. [Medline].
   6.   Mehrany K, Weenig RH, Pittelkow MR, Roenigk RK, Otley CC. High recurrence rates of
        squamous cell carcinoma after Mohs' surgery in patients with chronic lymphocytic
        leukemia. Dermatol Surg. Jan 2005;31(1):38-42; discussion 42. [Medline].
7.   Nguyen P, Vin-Christian K, Ming ME, Berger T. Aggressive squamous cell carcinomas in
     persons infected with the human immunodeficiency virus. Arch
     Dermatol. Jun 2002;138(6):758-63. [Medline].
8.   Mallipeddi R. Epidermolysis bullosa and cancer. Clin Exp Dermatol. Nov 2002;27(8):616-
     23. [Medline].
9.   Newman MD, Weinberg JM. Topical therapy in the treatment of actinic keratosis and
     basal cell carcinoma. Cutis. Apr 2007;79(4 Suppl):18-28. [Medline].
10. Miller DL, Weinstock MA. Nonmelanoma skin cancer in the United States: incidence. J Am
    Acad Dermatol. May 1994;30(5 Pt 1):774-8. [Medline].
11. Gray DT, Suman VJ, Su WP, Clay RP, Harmsen WS, Roenigk RK. Trends in the
    population-based incidence of squamous cell carcinoma of the skin first diagnosed
    between 1984 and 1992. Arch Dermatol. Jun 1997;133(6):735-40. [Medline].
12. Hampton T. Skin cancer's ranks rise: immunosuppression to blame. JAMA. Sep
    28 2005;294(12):1476-80. [Medline].
13. Buettner PG, Raasch BA. Incidence rates of skin cancer in Townsville, Australia. Int J
    Cancer. Nov 23 1998;78(5):587-93. [Medline].
14. Veness MJ, Morgan GJ, Palme CE, Gebski V. Surgery and adjuvant radiotherapy in
    patients with cutaneous head and neck squamous cell carcinoma metastatic to lymph
    nodes: combined treatment should be considered best
    practice. Laryngoscope. May 2005;115(5):870-5. [Medline].
15. McCall CO, Chen SC. Squamous cell carcinoma of the legs in African Americans. J Am
    Acad Dermatol. Oct 2002;47(4):524-9. [Medline].
16. Williams LS, Mancuso AA, Mendenhall WM. Perineural spread of cutaneous squamous
    and basal cell carcinoma: CT and MR detection and its impact on patient management
    and prognosis. Int J Radiat Oncol Biol Phys. Mar 15 2001;49(4):1061-9. [Medline].
17. de Gruijl FR, Rebel H. Early events in UV carcinogenesis--DNA damage, target cells and
    mutant p53 foci. Photochem Photobiol. Mar-Apr 2008;84(2):382-7. [Medline].
18. Katiyar SK. UV-induced immune suppression and photocarcinogenesis: chemoprevention
    by dietary botanical agents. Cancer Lett. 2007;255:1-11. [Medline].
19. Ziegler A, Jonason AS, Leffell DJ, et al. Sunburn and p53 in the onset of skin
    cancer. Nature. Dec 22-29 1994;372(6508):773-6. [Medline].
20. Brown VL, Harwood CA, Crook T, Cronin JG, Kelsell DP, Proby CM. p16INK4a and
    p14ARF tumor suppressor genes are commonly inactivated in cutaneous squamous cell
    carcinoma. J Invest Dermatol. May 2004;122(5):1284-92. [Medline].
21. Ziegler A, Jonason AS, Leffell DJ, et al. Sunburn and p53 in the onset of skin
    cancer. Nature. Dec 22-29 1994;372(6508):773-6. [Medline].
22. Perry PK, Silverberg NB. Cutaneous malignancy in albinism. Cutis. May 2001;67(5):427-
    30. [Medline].
23. Karagas MR, Nelson HH, Zens MS, et al. Squamous cell and basal cell carcinoma of the
    skin in relation to radiation therapy and potential modification of risk by sun
    exposure. Epidemiology. Nov 2007;18(6):776-84. [Medline].
24. Zghal M, El-Fekih N, Fazaa B, et al. [Xeroderma pigmentosum. Cutaneous, ocular, and
    neurologic abnormalities in 49 Tunisian cases]. Tunis Med. Dec 2005;83(12):760-
    3. [Medline].
25. Berg D, Otley CC. Skin cancer in organ transplant recipients: Epidemiology,
    pathogenesis, and management. J Am Acad Dermatol. Jul 2002;47(1):1-17; quiz 18-
    20. [Medline].
26. Black AP, Bailey A, Jones L, Turner RJ, Hollowood K, Ogg GS. p53-specific CD8+ T-cell
    responses in individuals with cutaneous squamous cell carcinoma. Br J
    Dermatol. Nov 2005;153(5):987-91. [Medline].
27. Alam M, Caldwell JB, Eliezri YD. Human papillomavirus-associated digital squamous cell
    carcinoma: literature review and report of 21 new cases. J Am Acad
    Dermatol. Mar 2003;48(3):385-93. [Medline].
28. Della Torre G, Donghi R, Longoni A, et al. HPV DNA in intraepithelial neoplasia and
    carcinoma of the vulva and penis. Diagn Mol Pathol. Mar 1992;1(1):25-30. [Medline].
29. Stockfleth E, Nindl I, Sterry W, Ulrich C, Schmook T, Meyer T. Human papillomaviruses in
    transplant-associated skin cancers. Dermatol Surg. Apr 2004;30(4 Pt 2):604-9. [Medline].
30. Mallipeddi R, Keane FM, McGrath JA, Mayou BJ, Eady RA. Increased risk of squamous
    cell carcinoma in junctional epidermolysis bullosa. J Eur Acad Dermatol
    Venereol. Sep 2004;18(5):521-6. [Medline].
31. Arbiser JL, Fan CY, Su X, et al. Involvement of p53 and p16 tumor suppressor genes in
    recessive dystrophic epidermolysis bullosa-associated squamous cell carcinoma. J Invest
    Dermatol. Oct 2004;123(4):788-90. [Medline].
32. Jambusaria-Pahlajani A, Hess S, Berg D, Schmults CD. Equipoise exists in the peri-
    operative management of cutaneous squamous cell carcinoma with perineural invasion: A
    survey study of American College of Mohs Surgery surgeons. Manuscript under review.
33. Hess SD, Jambusaria A, Katz K, Schmults CD. Clinical equipoise exists in the peri-
    operative management of high-risk cutaneous squamous cell carcinoma: A survey study
    of American College of Mohs Surgery surgeons. Manuscript under review.
34. Williams LS, Mancuso AA, Mendenhall WM. Perineural spread of cutaneous squamous
    and basal cell carcinoma: CT and MR detection and its impact on patient management
    and prognosis. Int J Radiat Oncol Biol Phys. Mar 15 2001;49(4):1061-9. [Medline].
35. Land R, Herod J, Moskovic E, et al. Routine computerized tomography scanning, groin
    ultrasound with or without fine needle aspiration cytology in the surgical management of
    primary squamous cell carcinoma of the vulva. Int J Gynecol Cancer. Jan-
    Feb 2006;16(1):312-7. [Medline].
36. Cho SB, Chung WG, Yun M, Lee JD, Lee MG, Chung KY. Fluorodeoxyglucose positron
    emission tomography in cutaneous squamous cell carcinoma: retrospective analysis of 12
    patients. Dermatol Surg. Apr 2005;31(4):442-6; discussion 446-7. [Medline].
37. Brantsch KD, Meisner C, Schonfisch B, et al. Analysis of risk factors determining
    prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet
    Oncol. Aug 2008;9(8):713-20. [Medline].
38. Ross AS, Schmults CD. Sentinel lymph node biopsy in cutaneous squamous cell
    carcinoma: a systematic review of the English literature. Dermatol
    Surg. Nov 2006;32(11):1309-21. [Medline].
39. Bargman H, Hochman J. Topical treatment of Bowen's disease with 5-Fluorouracil. J
    Cutan Med Surg. Mar-Apr 2003;7(2):101-5. [Medline].
40. Mackenzie-Wood A, Kossard S, de Launey J, Wilkinson B, Owens ML. Imiquimod 5%
    cream in the treatment of Bowen's disease. J Am Acad Dermatol. Mar 2001;44(3):462-
    70. [Medline].
41. Smith KJ, Hamza S, Skelton H. Topical imidazoquinoline therapy of cutaneous squamous
    cell carcinoma polarizes lymphoid and monocyte/macrophage populations to a Th1 and
    M1 cytokine pattern. Clin Exp Dermatol. Sep 2004;29(5):505-12. [Medline].
42. Marmur ES, Schmults CD, Goldberg DJ. A review of laser and photodynamic therapy for
    the treatment of nonmelanoma skin cancer. Dermatol Surg. Feb 2004;30(2 Pt 2):264-
    71. [Medline].
43. Jambusaria-Pahlajani A, Miller C, Quon H. Surgical monotherapy versus surgery plus
    radiotherapy in high risk cutaneous squamous cell carcinoma: A systematic review of
    outcomes. Dermatol Surg. In press.
44. Wollina U, Hansel G, Koch A, Kostler E. Oral capecitabine plus subcutaneous interferon
    alpha in advanced squamous cell carcinoma of the skin. J Cancer Res Clin
    Oncol. May 2005;131(5):300-4. [Medline].
45. Otley CC, Cherikh WS, Salasche SJ, McBride MA, Christenson LJ, Kauffman HM. Skin
    cancer in organ transplant recipients: effect of pretransplant end-organ disease. J Am
    Acad Dermatol. Nov 2005;53(5):783-90. [Medline].
46. Kuflik EG, Gage AA. The five-year cure rate achieved by cryosurgery for skin cancer. J
    Am Acad Dermatol. Jun 1991;24(6 Pt 1):1002-4. [Medline].
47. Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell
    carcinoma. J Am Acad Dermatol. Aug 1992;27(2 Pt 1):241-8. [Medline].
48. Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and
    survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for
    treatment modality selection. J Am Acad Dermatol. Jun 1992;26(6):976-90. [Medline].
49. Holmkvist KA, Roenigk RK. Squamous cell carcinoma of the lip treated with Mohs
    micrographic surgery: outcome at 5 years. J Am Acad Dermatol. Jun 1998;38(6 Pt 1):960-
    6. [Medline].
50. Robins P, Dzubow LM, Rigel DS. Squamous-cell carcinoma treated by Mohs' surgery: an
    experience with 414 cases in a period of 15 years. J Dermatol Surg
    Oncol. Oct 1981;7(10):800-1. [Medline].
51. Harwood CA, Leedham-Green M, Leigh IM, Proby CM. Low-dose retinoids in the
    prevention of cutaneous squamous cell carcinomas in organ transplant recipients: a 16-
    year retrospective study. Arch Dermatol. Apr 2005;141(4):456-64. [Medline].
52. Tan PY, Ek E, Su S, Giorlando F, Dieu T. Incomplete excision of squamous cell
    carcinoma of the skin: a prospective observational study. Plast Reconstr Surg. Sep
    15 2007;120(4):910-6. [Medline].
53. Chen K, Craig JC, Shumack S. Oral retinoids for the prevention of skin cancers in solid
    organ transplant recipients: a systematic review of randomized controlled trials. Br J
    Dermatol. Mar 2005;152(3):518-23. [Medline].
54. Mrass P, Rendl M, Mildner M, et al. Retinoic acid increases the expression of p53 and
    proapoptotic caspases and sensitizes keratinocytes to apoptosis: a possible explanation
    for tumor preventive action of retinoids. Cancer Res. Sep 15 2004;64(18):6542-
    8. [Medline].
55. Papoutsaki M, Lanza M, Marinari B, et al. The p73 gene is an anti-tumoral target of the
    RARbeta/gamma-selective retinoid tazarotene. J Invest Dermatol. Dec 2004;123(6):1162-
    8. [Medline].
56. Clayman GL, Lee JJ, Holsinger FC, et al. Mortality risk from squamous cell skin cancer. J
    Clin Oncol. Feb 1 2005;23(4):759-65. [Medline].
57. Brantsch KD, Meisner C, Schonfisch B, et al. Analysis of risk factors determining
    prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet
    Oncol. Aug 2008;9(8):713-20. [Medline].
58. Ross AS , Miller F, Elenitsas R, Xu X, Troxel AB, Schmults CD. Diameter of involved
    nerves predicts outcome in cutaneous squamous cell carcinoma with perineural invasion:
    an investigative-blinded retrospective cohort study. Under review.
59. Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients
    and different long-term immunosuppressive therapy regimens. J Am Acad
    Dermatol. Feb 1999;40(2 Pt 1):177-86. [Medline].
60. Euvrard S, Kanitakis J, Decullier E, et al. Subsequent skin cancers in kidney and heart
    transplant recipients after the first squamous cell carcinoma. Transplantation. Apr
    27 2006;81(8):1093-100. [Medline].
61. Veness MJ, Quinn DI, Ong CS, et al. Aggressive cutaneous malignancies following
    cardiothoracic transplantation: the Australian experience. Cancer. Apr
    15 1999;85(8):1758-64. [Medline].
62. Mehrany K, Weenig RH, Pittelkow MR, Roenigk RK, Otley CC. High recurrence rates of
    squamous cell carcinoma after Mohs' surgery in patients with chronic lymphocytic
    leukemia. Dermatol Surg. Jan 2005;31(1):38-42; discussion 42. [Medline].
63. Frierson HF Jr, Deutsch BD, Levine PA. Clinicopathologic features of cutaneous
    squamous cell carcinomas of the head and neck in patients with chronic lymphocytic
    leukemia/small lymphocytic lymphoma. Hum Pathol. Dec 1988;19(12):1397-
    402. [Medline].
64. Lobo DV, Chu P, Grekin RC, Berger TG. Nonmelanoma skin cancers and infection with
    the human immunodeficiency virus. Arch Dermatol. May 1992;128(5):623-7. [Medline].

								
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