Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• Options for high-risk BCC lesions include:
  • Standard excision using wider margins with linear or delayed repair with standard reexcision
  • Mohs Mircrographic surgery (MMS)
  • Resection with complete circumferential peripheral and deep margen assessment (CCPDMA)
  • RT for nonsurgical candidates
  • Patients treated with MMS or resection with CCPDMA should receive adjuvant radiation if clear margins cannot be achieved
• Recommended adjuvant therapy options include:
  • Radiation and/or multidisciplinary consultation:
    • To consider systemic therapy with a hedgehog pathway inhibitor or involvement in a clinical trial:
      • In select cases, hedgehog inhibitors can be considered in a neoadjuvant fashion if there is a potential benefit of decreasing the lesion to spare surgical morbidity, as demonstrated here
  • Adjuvant RT is recommended for patients with negative margins after surgery:
    • But with large nerve or extensive perineural involvement

• Primary treatment options for low-risk BCC include:
  • Curettage and electrodesiccation:
    • In areas without hair growth:
      • Provided that the treatment be changed to excision if the adipose is reached
  • Standard excision:
    • With 4 mm clinical margins
  • RT for nonsurgical candidates:
    • If margins are positive after excision:
      • Patients should receive adjuvant therapy
  • Mohs micrographic surgery (MMS)
  • Resection with complete circumferential peripheral and deep margin assessment (CCPDMA) with frozen or permanent section
  • Standard reexcision for area L regions (trunk, extremities):
    • Is recommended:
      • Whereas radiation may be administered to nonsurgical candidates

• Several randomized studies and meta-analyses have compared superficial therapies for low-risk BCC, including:
  • Topical therapies such as imiquimod or 5-fluorouracil (5-FU)
  • Photodynamic therapy (PDT) with methyl aminolevulinate (MAL) or 5-aminolevulinic acid (ALA),
  • Cryotherapy
• 5-FU:
  • Is an antineoplastic antimetabolite
• Imiquimod:
  • Is a synthetic immune response modifier:
    • That enhances cell-mediated immune response via the induction of proinflammatory cytokines
• For the treatment of superficial BCC:
  • 5-FU can be applied daily to the tumor and several millimeters of surrounding skin for a period of at least 4 weeks:
    • After a 2- to 3-week interval:
      • The area is then evaluated, often by biopsy, to ensure adequate therapy
• PDT:
  • Involves the application of a photosensitizing agent on the skin, followed by irradiation with a light source
• Cryosurgery:
  • Destroys tumor cells by freeze-thaw cycles, but a key limitation is poorer cosmetic outcomes compared with other treatment options
  • Contraindications to cryosurgery for BCC include:
    • Indistinct borders
    • Recurrent tumor
    • Certain tumor location overlying nerves
    • Size greater than 1 cm on the face
    • Certain pathologic features of:
      • Morpheaform, sclerosing, infiltrative, or perineural invasion
    • Patient characteristics, including:
      • Dark skin type
      • Cosmetically sensitive patient
      • Previous poor response to cryotherapy
      • Raynaud phenomenon
  • Imiquimod and 5-FU:
    • Have been found to be effective in treating superficial BCC in randomized studies:
      • The efficacy and cosmetic results of some of these comparison studies are demonstrated in the table
      • One study indicates that PDT has similar efficacy as cryotherapy but better cosmetic outcomes
      • Another study demonstrates that PDT, imiquimod, and 5-FU have similar efficacy and cosmetic outcomes:
        • Although the risk of recurrence may be somewhat higher with PDT versus imiquimod
      • The National Comprehensive Cancer Network panel agrees that these superficial therapies:
        • May be effective for anatomically challenging locations where surgery or radiation is contraindicated or impractical:
          • But the cure rates of these approaches are lower compared with surgery

• SENTINA Trial:
  • Was a 4-arm, prospective, multicenter cohort study:
    • Of 1,737 patients:
      • That evaluated the role of sentinel lymph node biopsy (SLNB) in patients who had undergone neoadjuvant chemotherapy (NAC) for invasive breast cancer
    • Clinical node status:
      • Was determined by palpation and ultrasound in all patients
    • Ultrasound guided fine-needle aspiration or core biopsy:
      • Was recommended but not mandatory
    • Patients with clinically node-negative (cN-) disease:
      • Underwent SLNB before NAC (Arm A)
    • If the sentinel node (SN) was positive:
      • A second SLNB and axillary lymph node dissection (ALND) was performed after NAC (Arm B)
    • Women who were clinically node positive (cN+) underwent NAC, and those who converted to being cN- also had SLNB and axillary lymph node dissection (Arm C)
    • Only patients whose clinical nodal status remained positive (ycN1) underwent axillary dissection without sentinel lymph node biopsy (arm D)
• When SLNB was done before NAC:
  • No difference in the detection rate was found between the combined (radiocolloid and blue dye) and single agent (radiocolloid alone) detection techniques:
    • 99.5% vs. 98.8%
• However, when SLNB was done after NAC:
  • The addition of blue dye increased the detection rate and the number of nodes retrieved
  • Dual tracer detection rate was:
    • 76% after chemotherapy in patients who also had SLNB prior to chemotherapy and 88% in those who converted from cN+ to cN- with NAC and had only one SLNB
• For patients who were confirmed node positive by SLNB biopsy prior to NAC:
  • The FNR of repeat SLNB after NAC was 51.6%
• For patients who converted from cN+ to cN- with NAC:
  • FNR of SLNB after NAC was 14.2%:
    • However, in the cN+ to cN- group:
      • The FNR was below 10%, for patients who had 3 or more lymph nodes removed and if both blue dye and radiocolloid were used
        • In these cases, the FNR was 8.6%
• References
  • Kuehn T, Bauerfeind I, Fehm T, Fleige B, Hausschild M, Helms G, et al. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncol.2013;14(7):609-618.
  • Schwentner L, Helms G, Nekljudova V, Ataseven B, Bauerfeind I, Ditsch N, et al. Using ultrasound and palpation for predicting axillary lymph node status following neoadjuvant chemotherapy – Results from the multi-center SENTINA trial. Breast. 2017;31:202-207.

• In the NSABP B-27 trial:
  • 2,411 women with operable breast cancer were randomly assigned to receive:
    • Preoperative AC followed by surgery
    • Preoperative AC followed by docetaxel then surgery
    • AC followed by surgery and then docetaxel
      • Tamoxifen was initiated concurrently with chemotherapy
  • The addition of docetaxel, preoperatively or postoperatively:
    • Did not significantly improve OS or DFS
  • The sample size of the study:
    • Was deemed insufficient to yield significance for the moderate improved DFS:
      • However, in the subset of patients with a clinical partial response to AC:
        • The addition of preoperative docetaxel (but not postoperative docetaxel):
          • Resulted in a significant increase in DFS compared with AC alone:
            • Hazard ratio, 0.71; 95% confidence interval, 0.55–0.91; P=.007
  • There was a significant decrease in the cumulative incidence of all local recurrence as first events:
    • In the two groups treated with docetaxel:
      • Approximately half of which was accounted for by ipsilateral breast tumor recurrences in women treated with breast-conserving therapy

References

1. Bear HD, Anderson S, Smith RE, Geyer Jr CE, Mamounas EP, Fisher B, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006;24(13):2019-2027.

2. NSABP clinical trials overview. Protocol B-27. A randomized trial comparing preoperative doxorubicin (adriamycin) cyclophosphamide (AC) to preoperative AC followed by preoperative docetaxel (taxotere) and to preoperative ac followed by postoperative docetaxel in patients with operable carcinoma of the breast. National Surgical Adjuvant Breast and Bowel Project website. http://www.nsabp.pitt.edu/B-27.asp. Accessed May 15, 2020.

• The NSABP B-51 / RTOG 1304 trial:
  • Is a phase 3 randomized clinical trial currently accruing patients:
    • The trial is designed to evaluate the role of regional nodal radiotherapy (RT) in patients who had documented positive axillary lymph nodes prior to undergoing NAC who subsequently convert to pathologically negative axillary nodes after the administration of NAC
  • The primary endpoint:
    • Is to determine if regional nodal RT significantly reduces the rate of in-breast cancer recurrence free interval
  • Node positivity:
    • Will be documented by either FNA or core needle biopsy prior to the administration of NAC
  • Patients will undergo standard NAC with the addition of anti-HER2 therapy for patients with HER2-positive tumors
  • Patients can have either mastectomy or breast-conserving therapy:
    • Mastectomy patients will be randomized to either no RT or regional nodal RT and chest wall RT
    • Breast conservation patients will be randomized to either whole-breast RT or whole-breast RT plus regional nodal RT
• A companion trial is being undertaken by The Alliance for Clinical Trials in Oncology:
  • The A11202 trial is enrolling patients that were axillary node positive prior to NAC, have a normal axilla on physical exam after NAC, but have microscopic disease on sentinel lymph node biopsy:
    • This trial randomizes patients to completion axillary node dissection or sentinel lymph node biopsy only in addition to radiation therapy for both arms

References

1. NSABP clinical trials overview. Protocol B-27. A randomized trial comparing preoperative doxorubicin (adriamycin) cyclophosphamide (ac) to preoperative ac followed by preoperative docetaxel (taxotere) and to preoperative ac followed by postoperative docetaxel in patients with operable carcinoma of the breast. National Surgical Adjuvant Breast and Bowel Project website. http://www.nsabp.pitt.edu/b-51.asp. Accessed May 15, 2020.

2. NRG-alias protocol information. https://www.nrgoncology.org/Clinical-Trials/Protocol/nsabp-b-51-rtog-1304?filter=nsabp-b-51-rtog-1304. Accessed September 11, 2020.

3. Comparison of axillary lymph node dissection with axillary radiation for patients with node-positive breast cancer treated with chemotherapy. NIH ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT01901094. Accessed May 15, 2020.

• Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) constitute the majority of nonmelanoma skin cancers (NMSCs):
  • Which are also referred to as “keratinocyte cancer”
• Keratinocyte cancer:
  • Represents about 95% of malignant skin tumors estimated at greater than 5.8 million cases annually
• While BCC (3.6 million cases annually) is four to five times more common than SCC (1.8 million cases annually):
  • The incidence of both tumor types continues to rise despite growing awareness of the risk factors for these skin cancers
• The overall incidence increases with age:
  • Is known to be higher in men than in women
• Development of NMSC is multifactorial and is related to various genotypic, phenotypic, and environmental risk factors:
  • Ultraviolet (UV) solar radiation:
    • Is considered to be the dominant risk factor for the development of both BCC and SCC:
      • Supported by the fact that most of these tumors tend to present on sun-exposed areas of the body
    • The development of BCC is thought to arise from intense intermittent sun exposure:
      • Leading to burns
    • Whereas SCC appears to be linked to the cumulative dose of UV solar radiation over time
    • Sun exposure earlier in life appears to be more influential in skin cancer development than that received later in life
    • Markers of UV sensitivity (e.g., fair skin, light eyes, blond or red hair) and intensity of exposure (i.e., increased incidence for individuals living in proximity to the equator):
      • Are associated with increased NMSC risk as is additional UV exposure from recreational tanning booths and UV light therapy:
        • One case-controlled study demonstrated that the use of tanning devices was associated with an estimated twofold risk for both SCC (odds ratio = 2.5) and BCC (odds ratio = 1.5)
        • Karagas et al. reported that treatment of psoriasis with oral psoralen in combination with light treatment (PUVA therapy) resulted in an increased adjusted relative risk of 8.6 for SCC while the risk for BCC was much lower
        • UV-induced mutations in the p53 tumor suppressor gene is thought to be a common event in NMSC development
  • Another important risk factor for both BCC and SCC:
    • Is immunosuppression:
      • Long-term immunosuppression therapy such as that used for solid organ transplant has been shown to increase the risk of SCC over 100-fold and for BCC about 10-fold
      • SCC in immunosuppressed patients tend to be behave more aggressively and are associated with greater tumor depth, higher risk of recurrence, and more frequently associated with perineural or lymphovascular invasion:
        • However, BCCs have not been found to be more aggressive in solid organ transplant recipients than the general population
    • Patients with acquired immunodeficiency syndrome also have an increased incidence of NMSC, and factors such as persistent human papilloma virus (HPV) infection may act synergistically with UV exposure to increase risk:
      • Moreover, HPV infection, especially HPV 16 and 18, has been implicated in the development of anogenital SCC
  • Exposure to ionizing radiation:
    • Increases the risk of NMSC threefold and often presents decades after initial exposure
      • This risk has been shown to be dose dependent
  • Chemical exposures:
    • Such as arsenic, tar, soot, tobacco, asphalt, and mineral oil:
      • Have all been associated with an increased risk of SCC
  • SCC can also arise from areas of chronic inflammation and healing such as from:
    • Scars, burn sites, or ulcers:
      • This type of SCC is also known as a Marjolin ulcer
  • Patients with genetic syndromes including:
    • Xeroderma pigmentosum, albinism, Muir–Torre syndrome, dystrophic epidermolysis bullosa, Fanconi anemia, Werner syndrome, nevoid basal cell syndrome, and Li–Fraumeni syndrome have an increased incidence of NMSC:
      • Xeroderma pigmentosum:
        • Is a rare autosomal recessive disease characterized by:
          • Photophobia, severe sun sensitivity, and advanced sun damage:
            • Affected individuals have defective DNA excision repair, and when exposed to UV radiation, develop malignancies of the skin and eyes at a rate 1,000 times that of the general population
        • Aggressive sun protection in the form of full-body sun suits and regular skin examinations are critical for patients with xeroderma pigmentosum
        • Ideally, these patients should only go outside at night
    • Nevoid basal cell syndrome:
      • Is an autosomal dominant disorder characterized by the development of multiple BCCs:
        • BCCs in patients with nevoid basal cell syndrome are often quite small but can number in the hundreds on any given skin surface
      • The sonic hedgehog signaling pathway (PTCH1 gene, chromosome 9q):
        • Has been recognized as having a significant etiologic role in nevoid BCC syndrome, and is also present in 90% of sporadic BCC
      • These patients are exquisitely sensitive to radiation and should avoid excessive sun exposure and radiation therapy
    • Regular follow-up is important, as such tumors are difficult to monitor and treat
• Similar to other tumor types, a previous diagnosis of cutaneous carcinoma:
  • Increases the risk of future NMSCs to as high as 35% at 3 years and 50% at 5 years

• BCC is the most common cancer in humans and the most common type of skin cancer
• BCCs are believed to arise from hair follicle cells and are therefore found almost exclusively on hair-bearing skin
• Most lesions are found on sun-exposed mask areas of the head and neck, but non–sun-exposed areas are also at risk
• These tumors tend to grow slowly, but when untreated can lead to invasion of local structures including muscle, cartilage, and bone.
• Although the biologic behavior of BCC is characterized by local and sometimes disfiguring invasiveness:
  • Metastasis is rare, occurring in less than 0.05% of cases
• There are multiple histologic subtypes of BCC, and subtype is predictive of its behavior:
  • Less aggressive subtypes include:
    • Nodular BCC
    • Superficial BCC
    • Keratotic variant of BCC
    • Infundibulocystic variant of BCC
    • Fibroepithelioma of Pinkus
• Higher-risk subtypes include:
  • Sclerosing variant of BCC
  • Infiltrating variant of BCC
  • Micronodular variant of BCC
  • Morpheaform (or desmoplastic) variant of BCC
  • Basosquamous carcinoma
• The higher-risk subtypes tend to have subclinical extension exceeding the visible borders of the lesion:
  • Making treatment more difficult
• Nodular BCC is the classic lesion of this type of non melanoma skin cancers (NMSC):
  • It appears as a pink translucent nodule with rolled edges and is often described as “pearly”:
    • In dark-skinned individuals, these tumors are often pigmented and can resemble melanoma
  • Overlying telangiectasias and ulceration are common:
    • They occur predominantly on the face

• Superficial BCC:
  • Is a variant that is more common on the limbs and trunk, and on other areas with little or no sun exposure:
    • It presents as a slow-growing, scaly pink plaque and can easily be confused with psoriasis, superficial SCC or SCC in situ (Bowen disease):
      • Gentle traction on the periphery of the lesion:
        • Often demonstrates a shiny translucent surface characteristic of BCC which can assist with diagnosis
• The histologic subtype of BCC:
  • Is highly predictive of its behavior
• Less aggressive subtypes include:
  • Nodular BCC
  • Superficial BCC
  • Keratotic variant
  • Infundibulocystic variant BCC
  • Fibroepithelioma of Pinkus
• Higher-risk subtypes include:
  • Sclerosing BCC
  • Morpheaform BCC
  • Infiltrative BCC
  • Micronodular BCC
  • Basosquamous carcinoma,
• Nodular BCC:
  • Which represents approximately 60% of cases:
    • Is the most common type
  • It appears as a pink, translucent nodule with rolled edges:
    • Often described as “pearly”
  • Overlying telangiectasias and ulceration are common
  • BCCs:
    • Most commonly occur on the face (Head and Neck Region)
  • Histologically, nodular BCC consists of:
    • Peripheral palisading of cells and chaotic arrangement of cells in the central region
• The sclerosing variant:
  • Has increased fibroblasts and the presence of fibrotic desmoplastic stroma

• Workup begins with a history and physical examination:
  • For patients with a suspicious lesion
• At the time of diagnosis, patients with BCC:
  • Should be given a full-body skin examination:
    • Because these individuals often have additional, concurrent cancers at other locations
  • A shave, punch, or excisional skin biopsy:
    • May be used for diagnosis of any suspicious lesion:
      • The biopsy should include deep reticular dermis:
        • Because infiltrative histology will often be present only at the deeper, advancing margins of a tumor
    • A punch biopsy:
      • Ranges in size from 2 to 8 mm and involves removing a cylinder of tissue to the level of the subcutaneous fat
    • A shave biopsy:
      • Involves injecting local anesthesia into the epidermis and upper dermis and performing a tangential sample at the base of the wheal
    • Excisional biopsy:
      • Involves removal of the entire lesion with a margin of clinically clear tissue
• Imaging studies:
  • Should be performed when extensive disease:
    • Such as bone involvement, perineural invasion, or deep soft tissue involvement, is suspected

• Location, independent of size, may constitute high risk, and these areas are defined as L, M, and H

• BCCs are the most common cancer in the United States, and the incidence is rapidly rising
• It is estimated that BCCs occur in 2 million Americans annually:
  • Exceeding the incidence of all other cancers
• BCCs are at least two times more common than squamous cell carcinomas (SCCs):
  • The second most common type of skin cancer
• The exact number of cases is difficult to estimate because these cases are not required to be reported to cancer registries
• BCCs generally have a good prognosis due to the low rate of metastasis (0.05%)
• In the U.S., more than 9,500 people are diagnosed with skin cancer every day
  • More than two people die of the disease every hour
• More people are diagnosed with skin cancer each year in the U.S. than all other cancers combined
• At least one in five Americans will develop skin cancer by the age of 70
• Actinic keratosis is the most common precancer:
  • It affects more than 58 million Americans
• Non-melanoma skin cancer:
  • The diagnosis and treatment of nonmelanoma skin cancers in the U.S:
    • Increased by 77% between 1994 and 2014
  • About 90% of nonmelanoma skin cancers are associated with exposure to ultraviolet (UV) radiation from the sun
  • Basal cell carcinoma (BCC):
    • Is the most common form of skin cancer:
      • An estimated 3.6 million cases of BCC are diagnosed in the U.S. each year
  • Squamous cell carcinoma (SCC):
    • Is the second most common form of skin cancer:
      • An estimated 1.8 million cases of SCC are diagnosed in the U.S. each year
  • More than 5,400 people worldwide die of nonmelanoma skin cancer every month
  • Organ transplant patients:
    • Are approximately 100 times more likely than the general public to develop squamous cell carcinoma
  • Regular daily use of an SPF 15 or higher sunscreen reduces the risk of developing squamous cell carcinoma:
    • By about 40^%