A Rare Case of Metastatic Squamous : A Case Presentation and Discussion of Updated Staging Guidelines and Prognostic Factors

Steven Brandon Nickle, DO,* Nicole Arnold, DO,** J Ryan Jackson, DO,*** Tracy Favreau, DO, FAOCD****

*Dermatology Resident, 2nd year, Broward Medical Center, Fort Lauderdale, FL **Dermatology Resident, 1st year, Beaumont Medical Center, Farmington Hills, MI ***Traditional Rotating Intern, Sampson Regional Medical Center, Clinton, NC ****Director/Chairman of Dermatology, Nova Southeastern University College of Osteopathic Medicine/Broward General Medical Center, Fort Lauderdale, FL

Abstract Cutaneous squamous cell carcinoma (cSCC) is well recognized in the literature as a fairly common that arises from a malignant proliferation of epidermal keratinocytes. Prognosis is typically favorable in cSCC, as it rarely metastasizes. However, the literature is unclear in regard to what defines “high risk” cSCC and what its prognostic indicators are. We report a case of a 68-year-old Caucasian female with metastatic cSCC and review the recent available guidelines regarding staging and major tumor characteristics associated with aggressive behavior and a poor outcome.

Introduction unknown duration. Cutaneous squamous cell carcinoma (cSCC) is Infectious disease was consulted for potential the second most common human , with superimposed infection of the left upper scapular an estimated annual incidence of 186,157 to mass. The patient was started on vancomycin 419,843 cases in the United States.1 While tumor and piperacillin/tazobactam with preliminary recurrence, , and death occasionally microbiology Gram stain for Gram-positive occur, prognosis is typically excellent, as these cocci and Gram-negative rods. We recommended complications only occur approximately in 1% a wide excision of the left upper-back mass to to 5% of cases.2-6 Current literature supports a rule out angiosarcoma versus squamous cell correlation between certain pathological and carcinoma, along with an excision of the right clinical features, aggressive tumor behavior, and upper-back mass to rule out . increased risk of metastasis. However, there Upon completion of the excisions, the histologic are disputes over the definition of “high-risk examination of the left upper-back wide- cSCC” and its appropriate prognostic indicators. excision specimen revealed a necrotic, poorly Without a prognostic model, clinicians lack differentiated neoplasm with epidermoid and evidence to guide decisions regarding appropriate sarcomatoid components with blood-vessel nodal staging and adjuvant therapy. We report invasion. The following stains were performed a 68-year-old Caucasian female with metastatic on the left upper-back tissue specimen: p63 (+), cutaneous SCC and review the most up-to- (+), Pan-K (+), HMB45 (-), MART1 (-), date guidelines regarding staging and major vimentin (+) (Figures 2, 3). The clinical and tumor characteristics associated with aggressive histopathologic exam favored a diagnosis of the behavior and a poor outcome. left upper-back as sarcomatoid squamous cell Figure 1. Left scapular fungating mass with carcinoma. Histologic examination of the right Case Report central erosions. upper-back lesion demonstrated malignant A 68-year-old Caucasian female presented to melanoma in situ with benign margins. After the emergency room (ER) with a left scapular mass on her left scapula (Figure 1) that was surgery, it was recommended that the patient mass that had been present for approximately tender to palpation and symmetrical with central be followed by oncology for further adjunctive six months per patient recollection. The initially erosion, surrounding erythema and malodorous therapy. small, pruritic papule had enlarged, become discharge; and a single, 3 cm x 2 cm, variegated Months later, the patient presented again to the tender and eventually ruptured. The rupture multi-toned brown to black, isolated patch ER due to extreme weakness and fatigue. The left produced a malodorous purulent discharge that with irregular borders, focal hyperpigmentation axillary mass measured 16 cm in size and had prompted her to seek medical attention. and slight elevation on the right upper back of become necrotic (Figure 4). A core of Past medical history was significant for 10 or more blistering without sunscreen as a child, hypertension, dyslipidemia and diabetes mellitus. Family history was significant for melanoma in two out of her six sisters. Surgical history consisted of a hysterectomy and cholecystectomy. The patient lived at home and was cared for by her son. The patient denied any weight change, fever or chills. On physical exam, temperature was 98.4 F (36.9 C), heart rate 66, respiratory rate 20, blood pressure 166/76 and oxygen saturation at 95% on room air. The patient had a firm, left axillary node that had been present for an unknown Figures 2 and 3. Left upper back tissue specimen: p63 (+), p16 (+), Pan-K (+), HMB45 (-), MART1 (-), vimentin (+). duration of time; a 12 cm x 10 cm fungating

Page 12 A RARE CASE OF METASTATIC SQUAMOUS CELL CARCINOMA: A CASE PRESENTATION AND DISCUSSION OF UPDATED STAGING GUIDELINES AND PROGNOSTIC FACTORS the left axillary mass was conducted and revealed High-risk Characteristics overexpression have shown aggressive metastasis.7 metastatic squamous cell carcinoma with an The American Joint Committee on Cancer H&E stain that demonstrated multiple spindle- (AJCC) substantially altered the staging of Prognosis shaped, atypical cells (Figure 5). The axillary cSCC in 2010 with the 7th edition of its staging Currently, the nodal classification used in staging mass most likely represented an enlargement manual.10 The new edition aimed to create is divided into N1, N2, and N3, with further of the initial left axillary node, which had now congruence by replicating the staging system for subdivision of the N2 component into a, b, and infiltrated into major blood vessels and other the mucosal squamous cell cancer variant. The c based on ipsilateral vs. contralateral nodes. structures, making surgical treatment impractical. TNM classification and staging system remains From a retrospective study of 603 patients, Clark The patient elected at that time for palliative with many changes. Perhaps the most important et al. found that stages N2a, N2c, and N3 of the radiation therapy. of these components is the high- and low-risk AJCC staging system contained less than 10% of 10 designations. T1 and T2 are defined as a lesion patients exclusive of any prognostic relevance. < 2 cm or > 2 cm, respectively. However, if there This assessment calls into question the validity are more than two high-risk characteristics, of the classification and the overall utility of the regardless of tumor size, it is designated as system. T2 and stage 2. These characteristics include: Further research on patient outcomes from clinical tumor diameter 2 cm or greater, Breslow cutaneous SCC will prove useful for verifying thickness greater than 2 mm, poor differentiation, which adjustments to the AJCC staging system perineural invasion, Clark level IV or higher, and are indicated. Histologic features consisting of primary location on the external ear or non- 3,7,9,11,12 a poorly differentiated tumor, Breslow depth glabrous lip. However, in a prospective greater than 2 mm, and the presence of nerve study, Veness et al. examined 266 patients with involvement negatively influence the prognosis.14 cSCC that metastasized to parotid or cervical Approximately 75% of recurrences or metastases lymph nodes and found that 70% of the lesions of cSCC occur within two years after therapy, and measured ≤ 2 cm, indicating that factors other Figure 4. Left axillary necrotic mass with approximately 95% occur within five years. Thus, than tumor size likely contribute to metastatic 5 purulent discharge. 13 close follow-up is indicated. The risks for local risk. A review by Matorell-Calatayud et al. recurrence and distant metastasis are impacted by suggests other high-risk cSCC characteristics to tumor characteristics and patient characteristics. be included in the discussion of prognosis and Both regional lymph node and distant metastases treatment. These high-risk cSCC characteristics are associated with a markedly increased risk of include: genetic disorders (xeroderma disease-related mortality. Overall survival rates pigmentosum, epidermodysplasia verruciformis, for patients with regional lymph node metastases oculocutaneous albinism, dyskeratosis congenita, are about 25% to 35% at five years and less than and recessive dystrophic epidermolysis bullosa.), 20% at 10 years.5,15-18 In patients with distant cSCC arising at the site of a pre-existing lesion metastases, the five-year survival rate is less than (scars, burn sites, ulcers that are slow growing, 10%.5,18 chronic radiation dermatitis), immunosuppression and transplantation, and molecular markers. Sentinel lymph node (SLN) biopsy is a surgical For example, EFGR overexpression has been procedure utilized to detect subclinical nodal linked to early metastasis, and lesions with p16 metastasis . High-quality studies

Figure 5. Core biopsy from left axillary mass Table 1. AJCC tumor (T) staging and “high risk” features (H&E): Multiple spindled-shaped atypical cells present. Designation Description TX Primary tumor cannot be assessed T0 No evidence of primary tumor Discussion Cutaneous squamous cell carcinoma (cSCC) Tis is a fairly common with an average T1 Tumor 2 cm or less in greatest dimension with fewer than 2,7 lifetime incidence greater than 10%. The two high-risk features majority of patients with cSCC present with a localized disease that is cured with local treatment; T2 Tumor > 2 cm in greatest dimension, or tumor of any size however, tumor recurrence, metastasis, and death with two or more high-risk features from this disease occasionally occur. Tumors that T3 Tumor with invasion of maxilla, mandible, orbit or are associated with an increased risk of aggressive temporal bone behavior and demonstrate clinical or histological features have been termed “high-risk.” T4 Tumor with invasion of skeleton (axial or appendicular) or The mortality rate for disease-specific death perineural invasion of skull base from cSCC is 2.1%, with more deaths occurring High-risk Features annually from cSCC than melanoma due to the 8,9 Designation Description higher prevalence of the disease. Adequate > 2 mm classification and staging of cSCC is necessary Depth/Invasion in order to accurately predict a prognosis and Clark level ≥ IV appropriately develop a treatment plan. The Perineural invasion difficulties lay in the controversy regarding the Primary site: ear newest staging system and a lack of conclusive, Anatomic Location evidence-based research regarding high- Primary site: hair-bearing lip risk characteristics, prognosis, and treatment Differentiation Poorly differentiated or undifferentiated efficacy.2,9

NICKLE, HACKERT, JACKSON, FAVREAU Page 13 Table 2. NCCN guidelines for “high-risk” cSCC24 • Poorly differentiated histologic characteristics Factors indicating “high-risk” cSCC* • Perineural invasion (of any caliber) Area M ≥ 10 mm** • Tumor invasion beyond the subcutaneous fat Area H ≥ 6 mm*** (excluding bone invasion, which automatically upstages tumors to alternative stage T3). Poorly defined This alternative T-staging system differs from Recurrence 2010 AJCC tumor staging in the following Immunosuppression regards: Site of prior RT or chronic inflammatory process • Stage T1 comprises tumors that have no risk Rapidly growing tumor factors. Neurologic symptoms • Stage T2 tumors are categorized into two Moderately or poorly differentiated substages based on number of risk factors. Acantholytic, adenosquamous, or desmoplastic subtypes • Stage T3 includes all cases of bone invasion as well as tumors without bone invasion but Depth: ≥ 2 mm or Clark levels IV, V with all four risk factors. Perineural or vascular involvement • There is no stage T4 in the alternative staging. • Location on the ear and vermillion lip are not *High-risk = ≥1 of 12 risk factors considered risk factors. **M = Medium risk: forehead, scalp, cheek, neck ***H = High risk: “masked areas” of face, central face, ears, periauricular, eyelids, periorbital, nose, • Breslow (millimeter) tumor depth was not temple, lips used as a risk factor. Note: Low risk: trunk and extremities • Invasion beyond subcutaneous fat was the best prognostic cutpoint in this data set evaluating the use of SLN biopsy in high-risk skin, 9% presented with more than one cSCC, defining elevated risk of poor outcomes. cutaneous SCC are lacking.19,20 The effect of this and 33% had known risk factors such as , procedure on patient survival is unclear. lymphoma, radiation dermatitis, and arsenic • Stage T2b tumors are responsible for most exposure. poor outcomes. Treatment efficacy The proposed alternative tumor-staging system The most appropriate management of high- Tumors have been classified according to the 2010 AJCC T-stage guidelines (Table 1).23 provides improved prognostic discernment via risk cSCC remains unknown. However, stratification of stage T2 tumors. However, current treatment guidelines from the Along with the AJCC, the National validation in other cohorts is still needed. National Comprehensive Cancer Network, Comprehensive Cancer Network (NCCN) established in 2010, use a similar list of high- guidelines (Table 2) have been proposed to help risk criteria to determine appropriateness of in the assessment and classification of “high- Conclusion excision and the necessary margins, including risk” cSCCs.24 However, analysis from Melinda Cutaneous squamous cell carcinoma is a previous radiation, chronic inflammation, and et al. demonstrates discordance between their challenging neoplasm to classify and treat. This immunosuppression.7,21 If a lesion has one of these definitions of “high-risk” cSCC.25 challenge is largely due to the lack of substantial characteristics, excision with 10 mm margins or prospective studies regarding disease-specific In a retrospective cohort study, Jambusaria- survival. It is necessary for practitioner to be is indicated. The National Cancer Pahlajani et al. proposed an alternative tumor- Institute recommends the use of 6 mm to 10 mm vigilant regarding these high-risk characteristics staging system to identify risk factors for poor by promoting close follow-up with these margins for lesions > 20 mm or exhibiting high- outcomes in cSCC and evaluate the 2010 risk characteristics.22 patients due to the higher risks of recurrence and AJCC tumor-staging system’s ability to stratify metastasis. Although Mohs surgery is recommended for occurrence of these outcomes.12 The results for high-risk cSCC cases, ideal management has AJCC tumor stages T2 to T4 were statistically not yet been defined for this group, and a lack indistinguishable. Consequently, the majority of of randomized controlled trials subsequently poor outcomes occurred in AJCC stage T2 cases. leads to the management of patients not being The Jambusaria-Pahlajani et al. staging system uniform. 22 A retrospective study by Mullen et (Table 3) prognostically stratifies the stage T2 al. suggests that favorable outcomes can result in group, since most outcomes of interest (87%) patients with advanced disease or drastic surgical occurred in AJCC stage T2. 12 The alternative procedures (e.g., extremity amputation and/or tumor-staging system is based on four risk factors lymph node dissection).2 From this study, a list of that were highly predictive of at least two end characteristics that increase metastatic potential points of interest. These risk factors include: was developed. In individuals with metastasis, • Tumor diameter of 2 cm or greater 12.5% had primary lesions in previously injured

12 Table 3. Alternative T-staging system by Jambusaria-Pahlajani, et al. Alternative T-staging System Definition T0 In situ SCC T1 0 risk factors T2a 1 risk factor T2b 2-3 risk factors T3 4 risk factors or bone invasion

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