The unique histopathological features seen in a given SCC lesion are tremendously important in predicting its malignant potential. There are several other critical features, however, which may have equal if not greater prognostic value and must be assessed when evaluating tumor risk. These include tumor size and depth of invasion, degree of differentiation, anatomical location, perineural, and perivascular invasion, and immunosuppression [33
]. These are not necessarily mutually independent variables in that certain histologic subtypes of SCC are strongly associated with a specific set of secondary prognostic features. The primary histological differences between low-grade and high-grade SCC are summarized in .
Histological differences between low-grade and high-grade SCC.
Size and depth of invasion are perhaps the most important determinants of the likelihood of tumor recurrence and metastasis [33
]. As a broad rule, tumors less than 2
cm in size will only rarely metastasize and are unlikely to recur whereas those greater than 2
cm in size pose a significant threat of metastasis and recurrence [63
]. Similarly, tumors that exceed 4
mm in depth or Clark's level III, showing involvement of both the deeper levels of the dermis as well as the subcutaneous tissue, have a much more aggressive course of action and over a seven-fold increase in the probability of metastasis [64
]. Skin lesions greater than 8 mm in depth or Clark's level V pose such a significant threat of metastasis that nodal involvement and prophylactic node dissection should be seriously considered [65
]. As expected, SCCI, which is derived largely from a superficial precursor lesion, is considered to be an indolent tumor. In contrast, SCC with single cell infiltrates, which is defined predominantly by dermal activity, is considered to be a more aggressive tumor type.
The degree of histologic differentiation, as well as the anatomic site of the lesion, will also play a role in SCC evaluation and prognosis. Poorly differentiated tumors, particularly from the ear or the lip, will be three times more likely to metastasize, and twice as likely to recur when compared to tumors that are well differentiated [33
]. Despite this, the majority of metastatic tumors will be moderately to well differentiated, highlighting the importance of assessing all the prognostic factors in the evaluation of metastatic potential [33
Another essential component in assessing the malignant potential of a tumor is the presence of perineural and perivascular spread. Perineural involvement (PNI) is thought to occur in approximately 14% of all SCC tumors arising on the head or neck [66
], and is indicative of the inherently aggressive nature of the tumor. Accordingly, tumors with PNI will show a much greater likelihood of local recurrence (23%) relative to those without (9%) [67
]. They will also be associated with a worse overall outcome, and a significant increase in the disease-specific mortality rate. Clinically, perineural involvement can present as conventional SCC with an associated numbness, facial muscle weakness, twitching, or visual change. However, there are often no clinical symptoms of nerve involvement, and PNI is most frequently diagnosed microscopically [66
Similarly, invasion of capillary lymphatics signifies a more aggressive tumor nature and is correlated with an increased incidence of metastases, local recurrence, and disease-specific death [67
]. Additionally, SCC metastasis occurs predominantly via local lymphatics and often deposits in the lymph nodes of the neck [68
]. Although invasion tends to remain localized to regional nodes, prognosis remains extremely poor with only a 34.4% cure rate [33
Histopathologically, PNI and perivascular invasion will appear as an overlying SCC with atypical tumor cells which have penetrated the nerve or vascular tissue (). This can present in a variety of different invasion patterns, most frequently involving a complete encircling of the nerve or vessel by tumor cells. An incomplete, crescent-like pattern of atypical cells is also commonly seen. Occasionally, tangential contact, permeation, and lamination can be observed. Invasion almost always occurs contiguous to the main body of the tumor; however, it has been known on occasion to affect more distant nerve and vascular sites. Usually, tumor cells arranged in solid or sheet-like patterns are less invasive, and will pass around the nerve or vessel. In contrast, individual tumor cells will generally penetrate and track along associated structures [66
Figure 10 Poor prognostic factors. (a) Perineural invasion: the arrow indicates a large peripheral nerve that has been surrounded by tumor cells (200x). (b) Vascular invasion: the arrow indicates a small cluster of atypical squamous cells in a small vessel (200x). (more ...)
Finally, host immunosuppression can greatly increase the likelihood of SCC development, recurrence, and malignant spread [69
]. Suppression may be due to an underlying malignancy, the active use of immunosuppresive agents during transplant therapy, or infection with HIV. In fact, NMSC is considered to be one of the most common side effects of long-term immunosuppressant use seen in transplant recipients. Unlike the general population, these patients are more likely to present with SCCs than BCCs [73
]. These lesions will typically emerge on the sun-exposed surfaces of the body, and will be found more frequently in patients with histories of sun exposure [75
] and HPV infection [76
]. Immunosuppressed patients will usually present with multiple SCC lesions, and while the risk of each individual lesion metastasizing is not markedly elevated, the presence of so many will have the effect of increasing the overall risk of metastasis [77
Several methods of treatment exist for SCCs, most of which have been shown to be extremely effective in the management of these lesions. These include cryotherapy, curettage, electrodesiccation, radiation, surgical excision, and Mohs micrographic surgery [33
]. While most non-Mohs modalities have equal cure rates for low-risk, indolent SCC's, they have relatively poor outcomes when dealing with more aggressive tumors [33
]. Mohs micrographic surgery remains the treatment of choice for SCC lesions associated with any high-risk prognostic factor. When this therapy is not suitable for use, as is often the case with tumors located on the face, radiation and chemotherapy prove to be viable alternatives.