Dermatology: Practical and Conceptual Research Letter | Dermatol Pract Concept. 2023;13(4):e2023254 1 An Aggressive Case of Infundibulocystic Squamous Cell Carcinoma on the Upper Lip: A Hybrid Pathology of Well-Differentiated and Infiltrative Variants Takumi Hasegawa1, Shiro Iino1, Shiori Sekine1, Kohei Kitakaze1, Natsuki Baba1, Noritaka Oyama1, Minoru Hasegawa1 1 Department of Dermatology, Division of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan Key words: squamous cell carcinoma, follicular differentiation, immunohistochemistry, chemoradiation therapy dermoscopy Citation: Hasegawa T, Iino S, Sekine S, et al. An Aggressive Case Of Infundibulocystic Squamous Cell Carcinoma On The Upper Lip: A Hybrid Pathology Of Well-Differentiated And Infiltrative Variants. Dermatol Pract Concept. 2023;13(4):e2023254. DOI: https://doi .org/10.5826/dpc.1304a254 Accepted: May 18, 2023; Published: October 2023 Copyright: ©2023 Hasegawa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Noritaka Oyama, MD and PhD, Division of Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji, Fukui 910-1193, Japan. Tel: +81-776-61-8367, Fax: +81-776-61-8112, E-mail: norider@u-fukui.ac.jp Introduction Infundibulocystic squamous cell carcinoma (icSCC) is a rare skin adnexal neoplasm, originating from the infun- dibulum of hair follicles. Histologically, it displays follic- ular differentiation and comprises three distinct variants; well- differentiated, less-differentiated, and infiltrative forms [1,2]. The highly differentiated pathology of icSCC may hold mild-to-moderate phenotype, but often possesses aggressive clinical presentation, alerting a prognostic and therapeutic perspective. We describe for the first time such a case of icSCC with a hybrid histology of well-differentiated and infiltrative variants, whose clinical course showed an aggressive behav- ior but prompt regression to a concurrent chemoradiation therapy, possibly retaining reminiscent of hair cycle. Case Presentation An 82-year-old Japanese man presented with a month- history of a small nodule on the upper lip, which rapidly enlarged after diagnostic skin biopsy. Examination revealed a 3 × 2 cm, reddish indurative plaque with keratotic surface on the upper lip (Figure 1A). Dermoscopy revealed reddish homogeneous area with tiny white cystic structures, resem- bling milia-like cysts (Figure 1B). Previous histological find- ings showed a keratin-filled cystic structure with irregular shaped, epithelial walls that invaded into the deep dermis, suggesting well-differentiated SCC, although the diagnosis of keratoacanthoma remains likely (Figure 2A). He underwent excisional biopsy with safety margin for the conclusive diagnosis. Histology revealed a volcano-like 2 Research Letter | Dermatol Pract Concept. 2023;13(4):e2023254 opening of the central keratin-filled plug invaginated by epi- dermal lipping that arose from the follicular infundibulum (Figure 2, B and C), similar to those of keratoacanthoma. The neighboring epidermis was irregularly thickened with various sized nests and endophytic infundibular cysts, invading into the deep dermis and peripheral nerve sheath (Figure 2, D- G). The tumour nests were mostly consisted of eosinophilic glassy-pale keratinocytes with slight-to-moderate nuclear atypia (Figure 2H). The former histopathology was compat- ible with well-differentiated icSCC and the latter was infil- trative one. Immunohistochemistry showed intense staining of CK16 (Figure 2I) and β-catenin (Figure 2J), follicular in- fundibulum markers [2], and Bcl-xL (Figure 2K), a candidate biomarker for distinguishing SCC from keratoacanthoma [3]. Three-weeks after resection, a local recurrence of the tumour developed and rapidly enlarged, which covered al- most the entire upper lip and part of the nostril (Figure 1C). Enhanced CT scanning showed no evidence of metastasis. Considering the aggressive clinical activity, age, and affected skin sites, we employed a combined chemoradiation ther- apy with docetaxel (25mg/m2 monthly) and electron beam, achieved a dramatic reduction and completed disappearance leaving a well-healed scar (Figure 1D). Conclusions To date, there have been only 5 case reports of icSCC, in- cluding ours (Table 1) [2,4,5]. Their affected skin sites were the exposed area. Recurrence or metastasis were unclearly stated. Our case displayed abrupt local recurrence within 3-weeks after complete resection and rapid regression during chemoradiation therapy. The bipolar clinical course may in part reflect a possible transition of two key life-stages of the hair follicle (eg, anagen and catagen). Figure 1. Time-course clinical view and dermoscopic findings. (A) A 3 cm × 2 cm, reddish indurative plaque with whitish keratotic surface on the upper lip. (B) A reddish homogeneous area with scattered tiny white cystic structures, similar to millia-like cysts. (C) Three weeks after marginal resection of the tumor, a local recurrence developed and rapidly enlarged, covering almost the entire upper lip and part of the nostril. (D) The tumor size and invasiveness were dramatically reduced and disappeared leaving a well- healed scar by four courses of chemotherapy with docetaxel and irradiation. Research Letter | Dermatol Pract Concept. 2023;13(4):e2023254 3 An infundibulocystic biology towards carcinogenic tran- sition proposes the involvement of two major molecular cas- cades, namely oncogenic RAS and Wnt/β-catenin pathways [6]. An imbalance of two signaling pathways may affect the stability of hair infundibulum regeneration, responsible for the carcino- genic state and possibly aggressive clinical behavior in our case. The overall prognosis and definitive diagnosis of icSCC remain inconclusive. The aggressive clinical behavior in our case may be attributed to a rare pathological hybrid pos- sessing well-differentiated and infiltrative characters, with direct activation of the oncogenic Wnt signaling pathway by β-catenin overexpression. Figure 2. Histopathological features (hematoxylin-eosin and immunohistopathological staining). (A) A punch biopsy pathology showing a keratin-filled cystic structure with irregular shaped, epithelial walls that invaded into the deep dermis (original magnification, x20). (B) A volcano-like opening of the central keratin-filled plug invaginated by a thinner epidermal lipping architecture similar to that of keratoacanthoma (x20). (C) Tumor nests and infundibular cysts arose from the follicular infundibulum (x40). (D) Numerous micro- or dilated infundibular cysts of various shapes that infiltrated into the deep dermis (x40). (E) Irregularly and asymmetrically thickening of the epidermis with various sized neoplastic cords or nests from the wall of the follicular infundibulum throughout the dermis (x40). (F and G) The tumor nests invaded into the deep dermis (x100) and peripheral nerve sheath (x200), respectively. (H) The nests were mostly consisted of eosinophilic glassy and pale keratinocytes with slight to moderate nuclear atypia (x200). (I) Broad and intense expression of CK16 in the deeply situated neoplastic components (x100). (J) Membrane-dominated staining of b-catenin with jigsaw-like nuclear/cytoplasmic pattern in the whole neoplas- tic components (x100). (K) Cytoplasmic staining of antiapoptotic protein Bcl-xL was observed in the nest (x100). 4 Research Letter | Dermatol Pract Concept. 2023;13(4):e2023254 Ta b le 1 . S um m ar y of in fu nd ib ul oc ys ti c sq ua m ou s ce ll ca rc in om a a th us f ar r ep or te d in t he li te ra tu re . C as e A u th o rs A g e/ Se x Si te Si ze (c m ) Tr ea tm en t Lo ca l re cu rr en ce M et as ta si s C lin ic al f ea tu re s Fo llo w -u p ( yr ) R ef er en ce s 1 M is ag o N , e t al 79 /M U pp er li p 3 N .D . N on e N on e E ry th em at ou s ke ra to ti c pl aq ue 1. 5 2 2 M is ag o N , e t al 56 /M U pp er li p 2. 5 N .D . N on e N on e E ry th em at ou s ke ra to ti c pl aq ue 2 2 3 K im S M , e t al 67 /M Po st er io r ea r 2 E xc ic io n N .D . N on e Fl at n od ul e, ke ra to ti c pl aq ue N .D . 4 4 Su m a A , e t al 72 /M L ef t he lix of e ar 2 E xc ic io n an d po st op er at iv e ex te rn al b ea m ra di ot he ra py N on e N on e So lit ar y, c ru st ed , fle sh -c ol or ed , ru bb ey m as s 3. 5 5 5 O ur c as e 82 /M U pp er li p 3 M ar gi na l r es ec ti on , ch em or ad ia ti on th er ap y + N on e R ed di sh in du ra ti ve pl aq ue w it h a w hi ti sh k er at ot ic su rf ac e 1 th is r ep or t N .D ., no t de sc ri be d. To d at e, t he re h av e be en o nl y 5 ca se r ep or ts o f ic SC C , i nc lu di ng o ur s. T he ir a ff ec te d sk in s it es w er e th e ex po se d ar ea . R ec ur re nc e or m et as ta si s w er e un cl ea rl y st at ed . Research Letter | Dermatol Pract Concept. 2023;13(4):e2023254 5 Int J Cancer. 2009;124(10):2361-2366. DOI: 10.1002/ijc.24197. PMID: 19165861. 4. Kim SM, Kim H, Kim HS, Cho SH, Lee JD. Infundibulocystic Squamous Cell Carcinoma. Ann Dermatol. 2015;(3):319-321. DOI: 10.5021/ad.2015.27.3.319. PMID: 26082591. PMCID: PMC4466287. 5. Suma A, Ando Y, Yahata Y. A case of infundibulocystic squamous cell carcinoma, initially made a diagnosis of milia en plaque. Skin Cancer (Japanese). 2015;30:1-5. 6. Kossard S. Keratoacanthoma, committed stem cells and neoplas- tic aberrant infundibulogenesis integral to formulating a concep- tual model for an infundibulocystic pathway to squamous cell carcinoma. J Cutan Pathol. 2021;48(1):184-191. DOI: 10.1111 /cup.13861. PMID: 32881028. PMCID: PMC7821248. References 1. Kossard S, Tan KB, Choy C. Keratoacanthoma and infundibu- locystic squamous cell carcinoma. Am J Dermatopathol. 2008; 30(2):127-134. DOI: 10.1097/DAD.0b013e318161310c. PMID: 18360115. 2. Misago N, Inoue T, Toda S, Narisawa Y. Infundibular (Follicular) and Infundibulocystic Squamous Cell Carcinoma: A Clinicopath- ological and Immunohistochemical Study. Am J Dermatopathol. 2011;33(7):687-964. DOI: 10.1097/DAD.0b013e318205b2c5. PMID: 21937907. 3. Vasiljevic N, Andersson K, Bjelkenkrantz K, et al. The Bcl-xL in- hibitor of apoptosis is preferentially expressed in cutaneous squa- mous cell carcinoma compared with that in keratoacanthoma.