Abstract
Purpose
The aim of the study was to update the experience treating cutaneous squamous cell and basal cell carcinomas of the head and neck with incidental or clinical perineural invasion (PNI) with radiotherapy (RT).
Materials and methods
From 1965 to 2007, 216 patients received RT alone or with surgery and/or chemotherapy.
Results
The 5-year overall, cause-specific, and disease-free survivals for incidental and clinical PNIs were 55% vs 54%, 73% vs 64%, and 67% vs 51%. The 5-year local control, local-regional control, and freedom from distant metastases for incidental and clinical PNIs were 80% vs 54%, 70% vs 51%, and 90% vs 94%. On univariate and multivariate ( P = .0038 and .0047) analyses, clinical PNI was a poor prognostic factor for local control. The rates of grade 3 or higher complication in the incidental and clinical PNI groups were 16% and 36%, respectively.
Conclusions
Radiotherapy plays a critical role in the treatment of this disease. Clinical PNI should be adequately irradiated to include the involved nerves to the skull base.
1
Introduction
Skin carcinoma with perineural invasion (PNI) is relatively uncommon, occurring in approximately 2% of cutaneous basal cell carcinomas (BCCs) and 3% of squamous cell carcinomas (SCCs) of the head and neck . The cancer cells surround the nerve sheath and spread proximally down the length of the nerve toward the skull base, although distal spread is also possible .
Perineural invasion is grouped into incidental and clinical. Incidental PNI includes asymptomatic patients with evidence of microscopic invasion of the nerve detected only by histopathology. Clinical PNI includes patients with evidence of a cranial neuropathy (most commonly cranial nerve [CN] V or VII) on physical examination and/or radiographic evidence of gross tumor involvement along the tract of a nerve . Magnetic resonance imaging (MRI) is used to detect and define the extent of PNI. Positron emission tomography computed tomography (PET-CT) is unlikely to define the extent of gross PNI as accurately as MRI. Of note, it is rare to observe radiographic evidence of PNI in an asymptomatic patient. Perineural invasion associated with SCC increases the risk of metastases to the regional lymph nodes, which should be evaluated with contrast-enhanced CT.
Patients may experience a subtle feeling of ants crawling underneath the skin (formication), which may progress to pain, numbness, and/or facial weakness over 6 months to 2 years before diagnosis . There is an increased risk of PNI with midface location, male sex, increasing tumor size, recurrence after prior treatment, and poor histologic differentiation . Although PNI is a result of direct extension along a nerve, it may be associated with apparent “skip” lesions along the nerve, which increases the risk of a recurrence after resection even if negative margins are obtained on surgical pathology . Patients with PNI have a poorer prognosis compared with those who do not have PNI .
Patients with incidental PNI typically receive a wide local excision of the primary lesion before the diagnosis and are then considered for postoperative radiotherapy (RT). Patients with minimal focal PNI, particularly those with BCC, may be considered for surgery alone depending on the primary site and the reliability of the patient for close follow-up . Patients with completely resectable clinical PNI cancers usually undergo surgery followed by postoperative RT to reduce the risk of local-regional recurrence. Patients with incompletely resectable clinical PNI cancers are treated with definitive RT. The RT clinical target volume includes the involved nerves to the base of skull because the extent of subclinical disease is often difficult to define. Hyperfractionation is preferred to once-daily fractionation to reduce the risk of damage to the visual apparatus when the retina, optic nerve(s), and/or chiasm receive high-dose RT . Extrapolating from patients treated with mucosal head and neck SCCs, concurrent chemotherapy may be considered in the treatment to improve the likelihood of local control for patients with SCC and clinical PNI . However, there is no definitive evidence that the probability of cure is enhanced by the addition of chemotherapy. Clinically negative regional lymph nodes should also be electively treated in patients with SCC because of the 15% to 20% risk of subclinical disease . Patients with CN deficits and/or pain before treatment usually do not experience amelioration of these problems after RT even if the cancer has been eradicated .
The purpose of this study is to update the University of Florida experience using RT to treat cutaneous SCCs and BCCs of the head and neck with either incidental or clinical PNI.
2
Materials and methods
The charts of all patients treated with RT for cutaneous SCC and BCC at the University of Florida from January 1965 to November 2007 were retrospectively reviewed under an institutional review board–approved protocol. Patients with metatypical BCCs (basosquamous carcinomas) were included. The pathology was routinely reviewed at the time of consultation to determine the presence of PNI. Patients were excluded if they had received prior RT to the same location. A total of 848 patients treated with curative intent were identified: 216 (25%) had PNI, including 107 patients with incidental PNI, and 109 patients with clinical PNI. Fourteen patients were immunosupressed, including 11 patients with incidental PNI and 3 patients with clinical PNI. Patients were routinely evaluated with contrast-enhanced CT beginning in 1983; 186 patients (86%) were treated after January 1, 1983, including 98 patients with incidental PNI and 88 patients with clinical PNI. Patients with clinical PNI routinely underwent MRI before treatment beginning in 1986; 179 patients (83%) were treated after January 1, 1986, including 95 patients with incidental PNI and 84 patients with clinical PNI. Intensity-modulated RT has been used for patients with head and neck cancers at our institution since 2001; 77 patients (36%) were treated after January 1, 2001, including 48 patients with incidental PNI and 29 patients with clinical PNI, and many of those with fields extending to the skull base were treated with this technique. Fourteen patients received an interstitial implant as part of their treatment, including 6 patients with incidental PNI and 8 patients with clinical PNI. All patients who received brachytherapy also received external-beam RT. All living patients had a minimum follow-up of 2 years. The median follow-up for all patients was 4 years (range, 0.2–26 years), and for living patients, it was 6.6 years (range, 0.6–23 years). Fourteen patients (6%) were lost to follow-up with a median follow-up of 35.0 months (range, 7.8–168.1 months). Patient and tumor characteristics are described in Table 1 . The median ages of the overall, incidental, and clinical perineural patient populations were 64 years (range, 26 to >89 years), 64 years (range, 32 to >89 years), and 64 years (range, 26 to >89 years), respectively. The overall male-to-female ratio was approximately 5:1.
| Characteristic | No. of patients | |
|---|---|---|
| Clinical PNI (%) n = 109 | Incidental PNI (%) n = 107 | |
| Sex | ||
| Male | 82 (75%) | 94 (88%) |
| Female | 27 (25%) | 13 (12%) |
| cT stage | ||
| Tx | N/A | 13 (12%) |
| T1 | N/A | 16 (15%) |
| T2 | N/A | 23 (21%) |
| T3 | N/A | 9 (8%) |
| T4 | 109 (100%) | 46 (43%) |
| N stage | ||
| N0 | 94 (86%) | 81 (76%) |
| N1 | 15 (14%) | 26 (24%) |
| Histology | ||
| SCC | 88 (81%) | 97 (91%) |
| BCC | 13 (12%) | 7 (7%) |
| BSCC | 8 (7%) | 3 (3%) |
| Differentiation | ||
| Well differentiated | 15 (14%) | 7 (7%) |
| Moderately differentiated | 26 (24%) | 33 (31%) |
| Poorly differentiated | 26 (24%) | 32 (30%) |
| NOS | 42 (39%) | 35 (33%) |
| De novo or recurrent | ||
| De novo | 31 (28%) | 52 (49%) |
| Recurrent | 46 (42%) | 25 (23%) |
| Multiply recurrent | 32 (29%) | 30 (28%) |
On multivariate analysis of the entire cohort of 216 patients, the only parameter that was statistically significant for local control was incidental vs clinical PNI. Therefore, for the purpose of this analysis, the data on these 2 entities will be presented separately.
2.1
Incidental PNI
Initial sites of disease for the 107 patients are depicted in Table 2 . The most common sites of disease were the skin of the temple, ear, scalp, and forehead. Most lesions were SCCs (91%), and the rest were BCCs (7%) or metatypical BCCs (3%). Approximately 61% were either moderately or poorly differentiated; differentiation was not otherwise specified for 33% of the lesions. Primary lesions and regional nodal status were clinically staged according to the 1997 American Joint Committee on Cancer (AJCC) staging system (see Table 1 ). As depicted in Table 3 , 85% of the lesions were treated with postoperative RT. Fifty-two patients (49%) had previously untreated lesions, 25 (23%) were recurrent for the first time, and 30 (28%) were multiply recurrent. Skin margins were positive in 41 (40%) of 103 patients and close (<5 mm) in 8 patients (8%).
| Tumor site | No. of patients | |
|---|---|---|
| Clinical PNI n = 109 | Incidental PNI n = 107 | |
| Forehead | 13 | 10 |
| Medial canthus | 4 | 1 |
| Lateral canthus | 2 | 1 |
| Infraorbital | 5 | 1 |
| Temple | 7 | 19 |
| Nasolabial fold | 11 | 2 |
| Nasal vestibule | 6 | 8 |
| Maxilla | 19 | 7 |
| Preauricular | 6 | 2 |
| Postauricular | 2 | 7 |
| Mandible | 0 | 0 |
| Lip | 11 | 8 |
| Ear | 7 | 16 |
| Chin | 2 | 0 |
| Nasal ala | 4 | 4 |
| Scalp | 2 | 14 |
| Unknown | 6 | 5 |
| Other | 2 | 2 |
| Treatment | No. of patients | |
|---|---|---|
| Clinical PNI (%) n = 109 | Incidental PNI (%) n = 107 | |
| Postoperative RT | 52 (48%) | 91 (85%) |
| Postoperative RT + chemotherapy | 6 (6%) | 8 (7%) |
| RT | 36 (33%) | 4 (4%) |
| RT + chemotherapy | 13 (12%) | 0 (0%) |
| Preoperative RT | 2 (2%) | 4 (4%) |
The median RT dose with external-beam RT with and without an interstitial implant was 65 (range, 40–135.2 Gy) and 64.8 Gy (range, 32–76.8 Gy), respectively. Seventy-four percent of the patients were treated with once-daily fractionation, whereas the remaining 26% of patients were treated with twice-daily fractionation. A variety of RT techniques and beam energies was used, including orthovoltage x-rays, megavoltage x-rays, and/or electrons. Treatment techniques have been previously described . Thirty-six percent of the patients were treated with local fields only (primary site plus a margin), 43% of the patients were treated with extended fields (>2 cm margin), and 21% of the patients were treated to the base of skull. Regional nodes were treated electively in 29 (37%) of 79 node-negative patients, all of whom had SCC.
2.2
Clinical PNI
Initial sites of disease for the 109 patients are depicted in Table 2 . The most common sites were the skin of the maxilla and cheek, forehead, nasolabial fold, and lip. Most lesions were SCCs (88/109, or 81%) with the remainder being BCCs (12%) or metatypical BCCs (7%). Forty-eight percent were either moderately or poorly differentiated; differentiation was not otherwise specified for 39% of the lesions.
All tumors were AJCC clinical stage T4 by definition (see Table 1 ). Distribution by primary tumor size was as follows: 2 cm or less, 18 patients; 2.1 to 5 cm, 35 patients; greater than 5 cm, 13 patients; and size not specified, 43 patients. Patients in whom the precise tumor size was indeterminate included those with ill-defined tumors and enlarged CNs.
Thirty-one lesions were previously untreated, 46 were recurrent for the first time, and 32 were multiply recurrent. As depicted in Table 3 , 48% of patients were treated with surgery and postoperative RT, 33% were treated with RT alone, 12% received concurrent chemoradiotherapy, 6% were treated with postoperative RT and chemotherapy, and 2% received preoperative RT. Patients selected for RT alone or with concurrent chemotherapy had more advanced incompletely resectable tumors usually because of tumor extension to the skull base. Skin margins were positive in 30 (50%) of 60 patients and close (<5 mm) in 6 (10%) of 60 patients.
The primary and secondary CNs involved is shown in Table 4 . Primary refers to a nerve that was initially involved by the cancer, and secondary refers to nerves that were subsequently invaded. Multiple nerves were primarily or secondarily involved in some patients. The most common primary CNs involved were CN V2 (47%) and CN VII (26%). Clinical symptoms at presentation included sensory deficits (72%), pain (46%), motor deficits (33%), and/or formication (10%).
| Involvement | No. of patients |
|---|---|
| Primarily involved | |
| CN V1 | 22 |
| CN V2 | 51 |
| CN V3 | 12 |
| CN VII | 28 |
| Other | 3 |
| Secondarily involved | |
| CN V1 | 17 |
| CN V2 | 8 |
| CN V3 | 19 |
| CN VII | 15 |
| Other | 32 |
| Radiographic PNI | |
| CN V1 | 10 |
| CN V2 | 35 |
| CN V3 | 13 |
| CN VII | 12 |
| Other | 4 |
The median RT dose of external-beam RT with or without an interstitial implant was 74.9 (range, 63.3–100 Gy) and 70.2 Gy (range, 33.3–79.5 Gy), respectively. Patients were treated with either once-daily fractionation (54%) or twice-daily fractionation (46%). Radiotherapy techniques have been previously described . Approximately 65% of the patients were treated with large fields extending to the skull base. Twenty-three percent of patients were treated with extended fields (defined as RT fields larger than local but not extending to the base of the skull), whereas the remaining 12% of patients were treated with local fields only (primary site plus a margin). Regional nodes were treated electively in 52 (55%) of 94 node-negative patients. Of these 52 patients, most were SCC (50 patients) with 1 metatypical BCC and 1 BCC.
2.3
Statistical analysis
All statistical calculations were accomplished with SAS and JMP software (SAS Institute, Cary, NC). A local failure was defined as a treatment failure at the site of the primary skin lesion, along the course of an at-risk nerve (including the skull base), or in the central nervous system (defined to include the cerebrospinal fluid, brainstem, and brain) if tumor reached the brain by direct extension. Nearly all local recurrences occurred within the high-dose treatment volume at the site of gross disease. A regional failure was defined as a recurrence in a lymph node region of the head and neck (including the parotid area). Recurrences elsewhere were defined as distant failures . Hematogenous brain metastases were coded as distant metastases. The Kaplan-Meier product limit method provided estimates of local control, local-regional control, distant metastases, cause-specific survival, and overall survival . The log-rank test provided estimates of statistical significance between strata of selected prognostic factors for each end point. A multivariate analysis was performed using Cox regression for each end point for the following variables: type of PNI (microscopic vs clinical), sex, histology, type of treatment, disease status, field extent, T stage, clinical symptoms, and number of nerves involved .
2
Materials and methods
The charts of all patients treated with RT for cutaneous SCC and BCC at the University of Florida from January 1965 to November 2007 were retrospectively reviewed under an institutional review board–approved protocol. Patients with metatypical BCCs (basosquamous carcinomas) were included. The pathology was routinely reviewed at the time of consultation to determine the presence of PNI. Patients were excluded if they had received prior RT to the same location. A total of 848 patients treated with curative intent were identified: 216 (25%) had PNI, including 107 patients with incidental PNI, and 109 patients with clinical PNI. Fourteen patients were immunosupressed, including 11 patients with incidental PNI and 3 patients with clinical PNI. Patients were routinely evaluated with contrast-enhanced CT beginning in 1983; 186 patients (86%) were treated after January 1, 1983, including 98 patients with incidental PNI and 88 patients with clinical PNI. Patients with clinical PNI routinely underwent MRI before treatment beginning in 1986; 179 patients (83%) were treated after January 1, 1986, including 95 patients with incidental PNI and 84 patients with clinical PNI. Intensity-modulated RT has been used for patients with head and neck cancers at our institution since 2001; 77 patients (36%) were treated after January 1, 2001, including 48 patients with incidental PNI and 29 patients with clinical PNI, and many of those with fields extending to the skull base were treated with this technique. Fourteen patients received an interstitial implant as part of their treatment, including 6 patients with incidental PNI and 8 patients with clinical PNI. All patients who received brachytherapy also received external-beam RT. All living patients had a minimum follow-up of 2 years. The median follow-up for all patients was 4 years (range, 0.2–26 years), and for living patients, it was 6.6 years (range, 0.6–23 years). Fourteen patients (6%) were lost to follow-up with a median follow-up of 35.0 months (range, 7.8–168.1 months). Patient and tumor characteristics are described in Table 1 . The median ages of the overall, incidental, and clinical perineural patient populations were 64 years (range, 26 to >89 years), 64 years (range, 32 to >89 years), and 64 years (range, 26 to >89 years), respectively. The overall male-to-female ratio was approximately 5:1.
| Characteristic | No. of patients | |
|---|---|---|
| Clinical PNI (%) n = 109 | Incidental PNI (%) n = 107 | |
| Sex | ||
| Male | 82 (75%) | 94 (88%) |
| Female | 27 (25%) | 13 (12%) |
| cT stage | ||
| Tx | N/A | 13 (12%) |
| T1 | N/A | 16 (15%) |
| T2 | N/A | 23 (21%) |
| T3 | N/A | 9 (8%) |
| T4 | 109 (100%) | 46 (43%) |
| N stage | ||
| N0 | 94 (86%) | 81 (76%) |
| N1 | 15 (14%) | 26 (24%) |
| Histology | ||
| SCC | 88 (81%) | 97 (91%) |
| BCC | 13 (12%) | 7 (7%) |
| BSCC | 8 (7%) | 3 (3%) |
| Differentiation | ||
| Well differentiated | 15 (14%) | 7 (7%) |
| Moderately differentiated | 26 (24%) | 33 (31%) |
| Poorly differentiated | 26 (24%) | 32 (30%) |
| NOS | 42 (39%) | 35 (33%) |
| De novo or recurrent | ||
| De novo | 31 (28%) | 52 (49%) |
| Recurrent | 46 (42%) | 25 (23%) |
| Multiply recurrent | 32 (29%) | 30 (28%) |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
