Recently, an increasing number of reports have described squamous cell carcinomas arising in free flaps used for maxillofacial reconstruction. Here, we report the case of a patient with second primary carcinoma arising in a free flap, and present a literature review of possible risk factors. A 59-year-old woman was referred to our department complaining of swelling in the lower gingiva in 2012. Her previous history included hypopharyngeal carcinoma for which she had undergone surgery and high-dose radiation therapy. We diagnosed her with osteoradionecrosis, and she underwent mandibular resection and simultaneous reconstruction with an anterolateral thigh flap. In 2016, the patient presented with an exophytic swelling with leucoderma on the free flap. We diagnosed the lesion as a second primary squamous cell carcinoma derived from the free flap used for the reconstruction. She underwent resection of the free flap under general anesthesia. Interestingly, we found mucosalization and hyphae-like Candida on the histopathological examination. Regarding factors of cancerization, it is reasonable to consider causes that lead to chronic inflammation, such as mucosalization (alteration in the environment), external stimuli in the oropharyngeal area, or candidasis .
A second primary carcinoma developed in a free flap used for reconstruction.
A 59-year-old woman was diagnosed with hypopharyngeal carcinoma.
She underwent mandibular resection and reconstruction with a thigh flap.
We found mucosalization and hyphae-like Candida on histopathological inspection.
Mucosalization, external stimulation, or Candida may lead to cancerization.
The use of free flaps in the maxillofacial region, such as radial forearm free flaps and anterolateral thigh (ALT) flaps, for reconstruction after tumor resection, such as squamous cell carcinoma (SCC), has become the gold standard for the oral rehabilitation of patients [ ]. These flaps allow better locoregional control in orofacial cancers and improve the functional and cosmetic outcomes. However, the number of reports on the occurrence of SCC in free flaps used for surgical reconstruction has been increasing. In these cases, it can be difficult to determine whether the carcinoma is a recurrence or a second primary carcinoma in the free flap. Furthermore, such carcinomas may be more prevalent among patients who undergo surgical reconstruction [ ]. In the present study, we report the rare case of a patient who was diagnosed with a second primary carcinoma in a free flap used for reconstruction after segmental mandibulectomy in the oral cavity.
Presentation of case
A 59-year-old woman was referred to our department complaining of swelling in the lower gingiva in 2009. Her previous history included hypopharyngeal carcinoma for which she had undergone left oropharynx partial resection (without neck dissection) surgery and high-dose radiation therapy (up to 70 Gy). She had no history of cigarette smoking or alcohol consumption.
Regarding the clinical picture, her left gonial angle showed swelling and sequestration around the left first molar ( Fig. 1 -A, B). Our clinical diagnosis was osteoradionecrosis. The possibility of cancer recurrence could not be excluded based on contrast-enhanced computed tomography and magnetic resonance imaging. She underwent a biopsy, and the results showed inflamed granulation tissue with infection. She was administered regular debridement and antibacterial treatment as a conservative therapy. However, no improvement in the symptoms was observed with this conservative therapy. Therefore, she underwent left mandible segmental resection and grafting with an ALT flap in 2012 ( Fig. 2 -A). The histological diagnosis was osteoradionecrosis. The possibility of cancer was not found from findings the specimen. She was followed up at our outpatient clinic. In 2016, 4 years after the reconstruction surgery, the patient presented with exophytic swelling with leucoderma on the free flap (30 × 20 mm; Fig. 2 -B). There was no regional lymphadenopathy. Based on the biopsy results, we diagnosed the patient with SCC of the left buccal mucosa. It was unclear if the tumor was present on a preoperative computed tomography image, because the image had a strong artifact due to the previous reconstruction surgery (data not shown). The patient underwent partial resection of the free flap under general anesthesia. Histopathological findings from the resected specimen confirmed that the carcinoma tissue showed irregular keratinization on the free flap side ( Fig. 3 -A, B). The border between the mucosa and free flap was clear at deeper levels, despite appearing unclear more superficially. The cancer cell nests were primarily localized within the free flap, and there were few cancer pearls in the oral mucosa ( Fig. 3 -C, D). According to these results, we diagnosed the patient with SCC derived from the free flap reconstruction. In addition, the p16 immunostaining was not positive ( Fig. 4 -B), and the cornfield layer revealed hyphae-like Candida ( Fig. 4 -A, C). The postsurgical course was uneventful, and there was no evidence of tumor recurrence in the 2-year postoperative follow up.
Discussion and conclusions
When SCC arises in a free flap, it is difficult to determine whether it is a recurrent or second primary carcinoma. Tokita et al. [ ] have reported that to diagnose a second primary carcinoma arising in a free flap, the following conditions should be met: 1) the tumor should be limited to the free flap and be far from the oral mucosa; 2) there should be no tumor remnant after the initial treatment; 3) at least 3 years should have elapsed since the end of the initial treatment [ ]; 4) SCC should be confirmed by histopathologic examination; and 5) there should be no skin malignancies elsewhere on the body [ ]. In this case, the carcinoma met the conditions specified above. Therefore, we concluded that it was a second primary carcinoma, not a recurrence. Furthermore, the patient in our case underwent reconstruction for osteoradionecrosis, which constituted further evidence that the lesion was a second primary carcinoma. A review of the literature showed 20 similar cases that involved tumors that occurred in flaps used for reconstruction after resection of the oral cavity or head and neck cancers ( Table 1 ). Among these cases, patients who underwent reconstruction ranged in age from 28 to 80 years (mean, 55 years), and the age at recurrence ranged from 61 to 88 years (mean, 69.3 years). These intervals ranged from 3.5 to 39 years (mean, 14.3 years). Interestingly, the characteristics of second primary cancers may be present regardless of the time that has passed since the reconstruction [ ]. The ratio of male to female patients was 1.5:1 in these prior reports. Hypopharynx was most often seen at the expression site (5/20 cases). Radial forearm free flaps were most commonly used (7/20 cases) and the cancers were exophytic in most of these cases (10/17 cases). Histological diagnosis was SCC in all cases.
|Case number||Author||Gender||Reconstruction (Age)||Recurrence (Age)||Interval (Year)||Site||Type of reconstruction||Clinical appearance||Histology|
|1||Yoshino et al., 1989 [ ]||F||65||74||9||Hypopharynx||Local skin flap, DP flap||Exophytic||SCC|
|2||Yoshino et al., 1989 [ ]||F||72||78||6||Hypopharynx||Door flap||–||SCC|
|3||Yoshino et al., 1989 [ ]||F||60||76||16||Hypopharynx||DP flap||–||SCC|
|4||Deans et al., 1990 [ ]||M||37||61||24||Larynx||DP flap||Exophytic||SCC|
|5||Scott and Klassen, 1992 [ ]||M||28||67||39||Floor of mouth||Acromiothoracic tube pedicle||Exophytic||SCC|
|6||Montgomery et al., 1993 [ ]||M||52||58||6||Floor of mouth||PMMC flap||Ulcer||SCC|
|7||Sa’do et al., 1994 [ ]||F||61||70||9||Buccal mucosa||Free skin flap||Shallow ulcer||SCC|
|8||Sakamoto et al., 1998 [ ]||M||63||73||10||Hypopharynx||Radial forearm free flap||Scattered lesion||SCC|
|9||Ohtsuka et al., 1998 [ ]||F||64||72||8||Lower gum/Upper gum||PMMC flap||Exophytic||SCC|
|10||Iseli et al., 2002 [ ]||M||40||67||27||Larynx||DP flap||Exophytic||SCC|
|11||Monnier et al., 2008 [ ]||M||58||62||3.5||Tonsil||Radial forearm free flap||Exophytic||SCC|
|12||Monnier et al., 2008 [ ]||M||54||64||10||Tonsil/Transglottics||DP flap||White thickening||SCC|
|13||Ho et al., 2011 [ ]||M||53||65||12||Tongue||PMMC flap||Necrotic nodule||SCC|
|14||Zemann et al., 2011 [ ]||F||32||62||30||Palate cleft||Free skin flap||Exophytic||SCC|
|15||Yamasaki et al., 2011 [ ]||M||70||75||5||Hypopharynx||Radial forearm free flap||Exophytic||SCC|
|16||Nasu et al., 2012 [ ]||M||59||75||16||Tongue||Radial forearm free flap||Exophytic||SCC|
|17||Tokita et al., 2013 [ ]||M||80||86||5.5||Lower gum||Radial forearm free flap||Erythroplakia||SCC|
|18||Cymerman et al., 2013 [ ]||M||39||62||23||Floor of mouth||Radial forearm free flap||Hyper plastic nodule||SCC|
|19||Valentini et al., 2016 [ ]||F||51||72||21||Tongue||Radial forearm free flap||White patch||SCC|
|20||Present case||F||62||67||5||Buccal mucosa||ALT flap||Exophytic||SCC|