Cutaneous Head and Neck Squamous Cell Carcinoma with Regional Metastases: The Prognostic Importance of Soft Tissue Metastases and Extranodal Spread

Clinicopathologic data from patients treated at the Sydney Head and Neck Cancer Institute, Royal Prince Alfred Hospital, Sydney, Australia, were recorded prospectively on a computerized database since 1987. The database contains information on patient demographics, clinical and pathologic staging, treatment details, histopathologic features, duration of follow-up, and status at last visit. All patients with cSCC metastatic to the parotid and/or neck treated by primary surgical resection with curative intent between 1987 and 2007 were identified. The pathology details recorded in the database were cross-checked with the original pathology reports and the database was updated where necessary. Slides of tumors from all selected patients were reexamined by a pathologist experienced in the examination of head and neck tumors (R.M.). ENS was defined as extension of lymph node metastases of SCC beyond the nodal capsule, and STMs were defined as free soft tissue tumor deposits lacking continuity with the primary tumor and without discernible associated lymph node tissue. The presence, size, and number of STM were measured and added to the existing database. To exclude the effect of bulky tumors, only patients with metastatic nodes ≤3 cm in size were included.

Data were collated and filtered by Microsoft Excel, and statistical analysis was performed by SPSS version 16.0 (SPSS, Chicago, IL). Categorical data were analyzed by chi-square test or Fisher’s exact test, normally distributed continuous data by t-test, and nonparametric data by Kruskal–Wallis test where appropriate. All statistics were two sided, and a P value of <0.05 was considered statistically significant. Overall survival was calculated from the date of surgery to date of death or last follow-up. Disease-free survival was calculated from the date of surgery to date of last follow-up including date of death from any cause if there were no recurrence or date of first disease recurrence. Differences in survival were determined by univariate Cox regression analysis, and survival curves were generated by the Kaplan–Meier method. A Cox proportional hazard model was used to adjust for the effect of other statistically significant covariates and potential confounders, including postoperative radiotherapy and the number of tumor deposits, by means of purposeful selection of covariates to develop a final multivariable model according to the method of Hosmer et al.17

The results of the present study suggest that the presence of STMs is associated with a worse prognosis than the presence of node metastases (with or without ENS). We were unable to confirm that ENS in node metastases ≤3 cm in size is associated with reduced survival after adjusting for the effect of STM and number of nodes involved. However, it is likely that the study is insufficiently powered to detect a statistically significant difference because the adverse effect of ENS was considerably less than that of STM (type II error). This lends support to the argument that STMs, rather than representing lymph nodes completely replaced by tumor, may instead represent a distinct biologic entity (namely deposits of tumor in soft tissue, not associated with lymph nodes).

Because number and size of tumor deposits are important prognostic factors and size of the tumor is related to the presence of ENS and STM, we tried to exclude the effect of bulky tumors by only selecting patients with tumors up to 3 cm as supported by the N1S3 and current tumor, node, metastasis staging systems.10,12,18 In this subgroup, the presence of STM was a statistically significant adverse prognostic factor, and the effect was even more pronounced in patients with both STM and ENS.

A limitation of this study is that primary tumor information is not evaluated. Other factors that could confound the effect of STM include perineural invasion, lymphovascular invasion, depth of invasion, tumor grade, and immune status of the patient.3,7 Many of these factors were adopted in the 7th edition of the American Joint Committee on Cancer/International Union Against Cancer staging system for cSCC. The prognostic significance of primary tumor factors in patients with node metastases is unknown. Patients in this study were only referred with node metastases, primary tumor data was often unavailable and many patients have either no identifiable primary or multiple potential primaries.

Extranodal spread and soft tissue metastases are common findings in patients with metastatic cutaneous and mucosal SCC, one or the other being present in most patients.6, 11‐16 Generally, the distinction has been ignored by pathologists and clinicians and both have been grouped together. Studies in mucosal SCC have shown that the presence of both STM and/or ENS is related to reduced survival, but it is not clear from those studies whether STM and ENS are identical.11‐16 Partly this is because the term “soft tissue deposit or metastasis” is used rather imprecisely and may include direct extension of tumor cells from the primary site or even ENS of tumor from the lymph node into the soft tissues of the neck. In an attempt to be more specific we defined STM as “free soft tissue tumor deposits lacking continuity with the primary tumor and without discernible associated lymph node tissue.” In melanoma, “microscopic satellitosis” represents a parallel adverse prognostic factor that has been more extensively studied and strictly defined as “any discontinuous nest of metastatic cells more than 0.05 mm in diameter that are clearly separated by normal dermis from the main invasive component of melanoma by a distance of at least 0.3 mm.”19 Despite the similarity, we believe that these are different biologic entities as STM mainly occur in node basins rather than as dermal deposits within close proximity to the primary tumor. Regardless, a strict definition such as that adopted for microscopic satellitosis would enable reliable and reproducible estimates of STM’s prognostic significance in future studies.20‐22

STM could occur via spread of tumor cells through lymphatic channels draining the primary tumor or through perineural or vascular routes. Tumor cells that spread through lymphatics eventually reach lymph nodes, where they will either be contained by the local immune system or will overcome the local host defense and may eventually replace the whole lymph node with tumor. It has been demonstrated in animal models that some tumor cells escape the lymphatics or travel through small vessels and end up as free tumor deposits in the soft tissues.23 Tumors escaping lymphatic channels may possess cellular properties that promote growth and dissemination and may avoid some of the immune regulation that normally occurs in lymph nodes, whereas tumors with direct vascular invasion may be more prone to distant spread. The real explanation is likely to be complicated and multifactorial, and merits further study.

In this series, the predominant site of recurrence was within the parotid and neck suggesting that the focus of treatment should remain on optimizing locoregional control. There is good evidence that combined modality treatment with surgery and adjuvant radiotherapy improves locoregional control and survival in head and neck cSCC.5,24‐26 However, radiotherapy is associated with marked acute and long-term toxicity, and a recent multicenter study involving our institution suggests there is a low-risk group of patients with N1S3 stage I disease (single lymph node ≤3 cm) and no ENS or STM that may be suitable for treatment with surgery alone.10,27,28 Conversely, the results of the Trans-Tasman Radiation Oncology Group trial (Postoperative Skin Trial 05.01; http://​www.​trog.​com.​au/​) are awaited to determine whether intensification of treatment regimens with adjuvant chemoradiation may be beneficial for high-risk metastatic cSCC of the head and neck. Hence, accurate prognostic information remains critical to making decisions regarding deescalation or intensification of adjuvant therapy.

Soft tissue metastases have a comparable adverse effect on survival to multiple lymph node metastases. Therefore, adjuvant radiotherapy should be administered to all patients with STM, even if the metastasis is a small single deposit. We are cautious about making recommendations for patients with ENS, despite being unable to demonstrate a marked effect. Therefore, conventional multimodal therapy should be considered standard on the basis of evidence from multiple studies which have shown ENS to be an adverse prognostic factor, even though they are likely to have grouped ENS and STM together.6,7,10

The pathologic examination and reporting of parotid and neck dissection specimens is paramount to obtaining reliable prognostic information on which to base treatment decisions. It is essential that examination of all tumor deposits and lymph nodes (including the smallest nodes) is performed for the presence of ENS and STM, along with measurement of the size and number of metastases.10 This approach has also been recommended in other solid tumors, for example colorectal cancers, in which the majority of metastases are found in lymph nodes that are smaller than 5 mm in size, and even small metastatic tumor deposits have a negative prognostic impact.29‐31 As in many solid tumors, a low number of examined nodes probably represents understaging, and is associated with poorer prognosis.31 Clearly, adequate staging requires not only a meticulous surgical technique but also a detailed pathologic evaluation.

In conclusion, in metastatic cSCC of the head and neck, the presence of STM (with or without associated ENS) is a statistically significant independent predictor of reduced survival and is associated with more unfavorable outcomes than the presence of ENS alone. Further work is required to determine the biologic mechanisms underlying this finding. Similar to the guidelines in melanoma, pathology reports of head and neck cSCC should include the number and size of affected nodes, the presence of ENS, as well as the presence, number, and size of STMs. The threshold for aggressive multimodal treatment should be low in the presence of STM.