J Plast Surg Hand Surg, 2014; Early Online: 1–5 © 2014 Informa Healthcare ISSN: 2000-656X print / 2000-6764 online DOI: 10.3109/2000656X.2014.944188
ORIGINAL ARTICLE
Basosquamous carcinoma: Is it an aggressive tumor? Yavuz Kececi1, Asuman Argon2, Tulug Kebat2, Emin Sir1, Melike Gungor1 & Enver Vardar2 Department of Plastic and Reconstructive Surgery and 2Department of Pathology, Izmir Education and Research Hospital, Izmir, Turkey
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1
Abstract Basosquamous carcinoma is a rare cutaneous tumour that is considered an aggressive type of basal cell carcinoma with an increased risk of recurrence and metastases. This impression has been perpetuated in the literature, despite limited scientific data and conflicting results of some authors. This present study was aimed to evaluate the clinical–pathological features of this tumour and follow-up of a series of basosquamous carcinoma. Basosquamous carcinoma patients who underwent surgical excision between January 2000 and February 2012 were analyzed retrospectively. Their medical files were reviewed and the corresponding routinely stained sections (with hematoxylin-eosin) were re-evaluated by two pathologists. Thirty-five patients with basosquamous carcinoma were operated on in this period. Most tumurs were located in the head and neck area (94%), and the mean age of the patients was 69.8 years. Margin involvements were seen in 11 patients (31.4%) and all of them underwent re-excision. There was only one local recurrence. There was neither regional lymph node nor distant metastasis in this series. The recurrence rate of basosquamous carcinoma is found as 4%, lower than that of most other similar studies. Further pathologic studies are needed to better classify basosquamous carcinoma and to increase consistency between the results of studies. Surgical excision and regular follow-up are considered as the treatment of choice. Key Words: Basosquamous carcinoma, basal cell carcinoma, skin carcinoma
Introduction Basosquamous cell carcinoma is a rare tumour with an estimated prevalence rate of 2% of all skin carcinomas [1,2]. It was initially described as a coexistence of basal cell carcinoma and squamous cell carcinoma without any transition zone between them. Subsequent studies reported that basosquamous carcinoma is a variant of basal cell carcinoma and it has areas of definitive basal cell carcinoma and squamous cell carcinoma with a transition zone between them, suggesting differentiation of one of the tumours into the other [3,4]. It is now believed that basal cell carcinoma cells, being pluripotential cells, differentiate into the more aggressive squamous cells [5]. Although basosquamous carcinoma is similar to the basal cell carcinoma clinically and morphologically, this tumour may behave more aggressively, with a propensity for local recurrence and a potential risk for distant metastatic spread. However, there is a disagreement about aggressiveness of this tumour. Studies reported local recurrence rates in a wide range, varying from 4–47.1% [1,2,6-8]. The rarity of this tumour and its particular histologic pattern may result in these variable results. This present study was aimed to evaluate the clinicalpathological features of this tumour and follow-up of a series of basosquamous carcinoma cases. Materials and methods This is a retrospective study of basosquamous carcinoma patients who underwent surgical excision between January 2000 and February 2013. Their medical files were reviewed and the corresponding routinely stained sections (with hematoxylin-eosin)
were re-evaluated by two pathologists. Histologic definition of basosquamous carcinoma was based on identifying areas of both basaloid cells which are larger, paler, and rounder than in solid basal cell carcinoma types and squamoid cells with abundant eosinophilic cytoplasm, and also intermediate cells with amphophilic cytoplasm, round nuclei, and occasional nucleoli [9] (Figure 1). Keratinizing basal cell carcinoma and collision lesions were excluded. Also, the number of patients presenting basal cell carcinomas and squamous cell carcinomas was determined in order to identify the prevalence of basosquamous carcinoma. The principles of the 1975 Declaration of Helsinki were followed in the study. Preoperative diagnosis of basosquamous carcinomas was never made, and the consequent choice of surgical margins was performed according to the suspected tumoural diagnosis. Decision for the safe surgical margin was given in accordance with the international guidelines. A lateral margin of 4–6 mm was indicatively chosen for suspected squamous cell carcinoma less than 2 cm in diameter and not located on the scalp, ears, eyelid, nose, or lips, and a margin wider than 6 mm for high risk locations [10,11]. A lateral margin of 3–4 mm was indicatively chosen for suspected superficial and nodular basal cell carcinomas in low risk areas and of at least 4–5 mm for infiltrative-morpheaform basal cell carcinomas [12]. The clinical data of the patients were analyzed with regard to age, gender, tumour site, tumour size, and disease recurrence. The pathologic parameters recorded were margin involvement, evidence of perineural invasion, stromal fibroplasia, stromal lymphocyte infiltration, loss of palisading and
Correspondence: Yavuz Kececi, MD, Attending Surgeon, Department of Plastic and Reconstructive Surgery, Izmir Education and Research Hospital, Saim Cikrikci Cad. Bozyaka Karabaglar, 35350 Izmir, Turkey. Tel: +90 532 382 5901. Fax: +90 232 261 4444. E-mail: [email protected] (Received 11 March 2014; accepted 9 July 2014)
2 Y. Kececi et al.
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clefting, localisation of squamous areas, and clearly presence of a transition zone. The patients who could be followed-up and those could not were compared in order to determine whether there were differences between them in terms of gender, margin involvement (Fisher’s exact test), age, and tumour size (Student t-test). Results Thirty-five patients with basosquamous carcinoma tumour were included in the study. There were 21 males and 14 females with a mean age of 69.8 years (range = 42–92 years). In this investigated period for the presented study, squamous cell carcinoma was found in 498 patients and basal cell carcinoma in 1149 patients. Basosquamous carcinoma composed 2.1% of all basal cell, squamous cell, and basosquamous carcinomas. Most tumours were located in the head and neck area (33 of 35 patients, 94%), mainly on the central face and perinasal area (19 patients, 54%) and auricular area (five patients, 14%). Only two tumours (4.4%) were located outside the head and neck area, in the upper extremity. Clinical tumour size was greater than 2 cm in five patients (14%). There were neither regional lymph node nor distant metastases. Local recurrence occurred in only one of 25 cases with available follow-up data (4%). In this case, there was no surgical margin involvement and tumour size was 10 mm. Recurrence occurred 14 months after the surgery. This patient was re-operated on, and his 60-months follow-up was free of problems. The mean of tumour size was 13 ± 9 mm. Surgical margin involvement was evident in 11 patients (31.4%), and those all underwent subsequent re-excision. Perineural invasion was not seen in any tumour. Squamoid differentiation was prominent in the base of the tumour in 16 patients, while it was diffused thoroughly across the tumour in the other 19 patients. There was not a clear transition zone in five of 35 tumours. Findings of other histological features are presented in Table I. There was not any follow-up data for 10 of the 35 patients. For the remaining 25 patients, the average follow-up period was 87 months (range = 12–168 months). When the 10 patients without any follow-up data were compared with the other 25 patients, there were no statistically significant differences for gender (p = 0.47, Fisher’s exact test), margin involvement (p = 0.26, Fisher’s exact test), age (p = 0.52, Student t-test), or tumour size (p = 0.88, Student t-test) variables.
Figure 1. General appearance of tumour in low-magnification. While basaloid cells were noticeable on the surface of the tumour, squamoid cells were observed deep in the tumour (40, H&E).
and neck region (Figure 2). Central face affinity makes surgical treatment of this tumour difficult, without leaving an aesthetic problem. The tendency for the head and neck location may be explained by higher sun exposure [6]. There is a significant male predominance in most series [6,13]. In this presented study, 60% of basosquamous carcinoma cases were males. Similar to previous reports [1,7,13], the age distribution was in a wide range (42–92 years), with a mean of 69 ± 11 years. The prevalence rate for basosquamous carcinoma was reported to be between 1.2–2.7% of all non-melanoma skin carcinomas [2,7,13,14]. In our report, basosquamous carcinoma prevalence was 2.1% in a total of 1682 skin carcinomas, confirming the relative rarity of this tumour. Histologically, there are areas of basal cell carcinoma and squamous cell carcinoma with or without a transition zone and a fibroblast-rich, collagenized stroma in basosquamous carcinoma
Discussion Basosquamous carcinoma is a rare skin carcinoma that is most commonly seen on the head and neck region, mainly involving the central face and perinasal areas [13]. The incidence of head and neck location for basosquamous carcinoma was reported between 82–97% [1,7,13]. The anatomic distribution in our series was similar, with 94% of tumours located on the head Table I. Histologic findings of the basosquamous tumours. Stromal fibroplasia Stromal lymphocyte infiltration Loss of palisading Loss of clefting
Prominent 18 23 21 22
Moderate 6 11 5 5
Weak 2 1 9 8
Figure 2. Anatomic locations of 33 cases of basosquamous carcinoma.
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Basosquamous carcinoma
Figure 3. Three cell component of tumour in high-magnification. The arrow on the upper left refers to squamoid cells with abundant eosinophilic cytoplasm, the one on the upper right intermediate cells with amphophilic cytoplasm, round nuclei and occasional nucleoli, the one on the lower left basaloid cells which are larger, paler, and rounder than in solid basal cell carcinoma (200, H&E).
(Figures 3 and 4). Stromal fibroplasia and stromal lymphocyte infiltration were prominent or moderate in almost all the patients, while loss of palisading and clefting were weak in approximately one fourth of the patients (Table I). The basaloid cells in this tumour are larger, paler, and rounder than in solid basal cell carcinoma. The squamoid cell component has larger, polygonal squamoid cells with eosinophilic cytoplasms, larger open nuclei with prominent nucleoli, frequent mitosis, dyskeratotic cells, and intercellular bridges. The intermediate cells reside between them with amphophilic cytoplasm, round nuclei, and occasional nucleoli [7,9,15]. The origin of these cells is unknown, but the pluripotential basal cell is a possible candidate [16]. Basosquamous carcinoma can mimic keratotic basal cell carcinoma which exhibits squamous differentiation in the centre of some nodules. Both basal and squamoid components are uniform and there is neither a transition zone nor the densely collagenized, fibroblast-rich stroma of aggressive growth basal
Figure 4. Dense fibroblastic proliferation in the tumour (100, H&E).
3
cell carcinomas [13]. Differential diagnosis of basosquamous carcinoma from keratotic basal cell carcinoma will prevent unduly aggressive surgery for what is really a nodular form of basal cell carcinoma [3]. An incorrect histopathologic diagnosis is not uncommon, especially if only a superficial biopsy is obtained. Leibovitch et al. [6] reported that initial biopsy before total excision could only correctly diagnose basosquamous carcinoma in 13.7% of their patients and that basosquamous carcinoma diagnosis was made only by total excision of the lesions. This entity should be kept in mind when a simple curettage or fulguration therapy is chosen as the therapy method based on a biopsy result. Immunohistochemical staining can be used in confirming the diagnosis. Even though no specific marker for basosquamous carcinoma exists, the anti-HEA (human epithelial antigen) mouse monoclonal antibody Ber-EP4 labels the basaloid component of basosquamous carcinoma and allows visualization of a transition zone, showing progressive fading of HEA expression within the same tumour mass. HEA immunostaining is therefore helpful in excluding collision tumours consisting of basal cell carcinoma and squamous cell carcinoma [17,18]. Mougel et al. [19] informed that, in their 15 basosquamous carcinoma patient series, three lesions initially reported as basosquamous carcinoma were eventually diagnosed as squamous cell carcinoma after Ber EP4 immunostaining was used. Therefore, immunohistochemical staining would be helpful in separating more aggressive tumours from basosquamous carcinomas. Literature data about recurrence rate and aggressiveness of basosquamous carcinoma is conflicting. Several authors suggest that basosquamous carcinoma has a worse prognosis and greater incidence of recurrences and metastases as compared with basal cell carcinoma, and some authors equate its behaviour to that of squamous cell carcinoma [4,5,7]. Borel [1] reported a local disease recurrence rate of 45.7% in 35 patients with a follow-up of 1 year. Martin et al. [7] reported a 32.1% recurrence rate and five (17.9%) regional lymph node metastases in a series of 28 patients. Schuller et al. [2] found four recurrences (12.1%) in a series of 33 patients. Karatas et al. [8] reported a 17% recurrence rate and a 14% lymph node metastasis rate in 35 patients. Skaria [20] stated an 8.9% recurrence rate in a series of 56 patients. Also, Bowman et al. [13] declared distant metastases in two patients (7.4%) in a series of 27 patients. Betti et al. [14] found two recurrences (5.7%) and one pulmonary metastasis in 35 patients who completed 5 years follow-up. On the other hand, local disease recurrence rate was 4% and neither lymph node nor distant metastases occurred in the presented study. Leibovitch et al. [6] reported local disease recurrence in four of 98 patients without any metastases. In addition, Mougel et al. [19] declared that there was no recurrence or metastases in 12 basosquamous patients with transplanted organs. They linked this result to that their patients with transplanted organs undergo regular dermatologic examination, and tumour diagnosis is usually made at an early stage of tumour development. However, early diagnosis could not elucidate this inconsistency in the results about recurrence rate and aggressiveness of the tumour. Probably, this inconsistency may result from the broad histologic definition of the tumour. The term of metatypical basal cell carcinoma is used by some authors as a
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4 Y. Kececi et al. synonym for basosquamous carcinoma [21-23]. On the other hand, Patterson and Wick [24] and Weedon and Strutton [25] classified basosquamous carcinoma and metatypical basal cell carcinoma as distinct types of basal cell carcinoma. Separating these two types of basal cell carcinoma from each other probably will increase consistency between the results of the studies. Margin involvement, perineural invasion and male gender are reported as significant prognostic indicators for recurrence [7]. There was not any perineural invasion in our series. The incidence of perineural invasion in basosquamous carcinoma was reported as varying from 0–7.9% [6,19]. Leibovitch et al. [6] reported that basosquamous carcinoma recurrence occurred in one of six (16.7%) patients with perineural invasion compared to in three of 92 (3.2%) patients without perineural invasion, demonstrating the more aggressive nature of tumours with perineural invasion. The absence of perineural invasion might contribute to the low rate of local recurrence in our series. Margin involvement is a problem in basosquamous carcinoma surgery. Most surgeons make a decision about the size of the safe surgical margin according to the suspected tumour diagnosis. However, there are no clinical features to distinguish basosquamous carcinoma which presents in the same locations with similar clinical characteristics as other basal cell carcinomas. In the presented series, preoperative diagnosis of basosquamous carcinomas was never made and the tumour was found in the surgical margin in 11 patients (31%). Margin involvement incidence was reported to vary from 9.6%–16.7% for basal cell carcinoma [26,27]. This difference most likely resulted from the invasiveness of this tumour, despite its relatively quiescent clinical appearance. Giacomel et al. [28] investigated the dermoscopic patterns of basosquamous carcinoma in order to facilitate early diagnosis and accurate management of this tumour. They reported that this tumour exhibited at least one basal cell carcinoma-related plus one squamous cell carcinoma-related dermoscopic feature. Therefore, it can be considered that a dermoscopic pre-surgical evaluation of tumour margins may ameliorate the traditional surgical performance in the primary treatment of basosquamous carcinoma. Skaria [20] used Mohs micrographic surgery in the treatment of 56 basosquamous carcinoma patients and found a 8.9% recurrence rate. Therefore, he recommended an additional 2–3 mm margin removal once the excision is complete. However, all the patients with margin involvement underwent re-excision and none of them had a disease recurrence in this presented study. Only 71.4% of the patients in our series could be followedup. This lack of follow-up is certainly a possible bias, as some of the patients might have disease recurrence. Although these missing data are certainly important, we found no significant differences between the patients who could be followed-up and those who could not. There is no generally accepted guideline for the treatment of basosquamous carcinoma, depending on its rarity or debates about histological definition. Wide local excision with clear surgical margins seems to be the treatment of choice. It is very important to identify indicators of recurrence: positive surgical margins, and perineural invasion. A regular follow-up would allow early detection of disease recurrence.
Conclusion The recurrence rate of basosquamous carcinoma was found as 4%, lower than that of most other similar studies. Different assessment about the aggressiveness of basosquamous carcinoma might depend on the broad histologic definition. Further pathologic studies are needed to better define basosquamous carcinoma and to increase consistency between the results of the studies. The incidence of marginal involvement was higher than that of basal cell carcinoma, so a surgical safe margin should be kept wider when preoperative diagnosis is available. Surgical excision and regular follow-up are considered as the treatment of choice. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References [1] Borel DM. Cutaneous basosquamous carcinoma. Arch Pathol Lab Med 1973;95:293–7. [2] Schuller DE, Berg JW, Sherman G, Krause CJ. Cutaneous basosquamous carcinoma of the head and neck: a comparative analysis. Otolaryngol Head Neck Surg 1979; 87:420–7. [3] Maloney ML. What is basosquamous carcinoma? Dermatol Surg 2000;26:505–6. [4] Jones MS, Helm KF, Maloney ME. The immunohistochemical characteristics of the basosquamous cell carcinoma. Dermatol Surg 1997;23:181–4. [5] Lopes de Faria J, Nunes PH. Basosquamous cell carcinoma of the skin with metastases. Histopathology 1988;12:85–94. [6] Leibovitch I, Huilgol SC, Selva D, et al. Basosquamous carcinoma: treatment with Mohs micrographic surgery. Cancer 2005; 104:170–5. [7] Martin RC II, Edwards MJ, Cawte TG, et al. Basosquamous carcinoma: analysis of prognostic factors influencing recurrence. Cancer 2000;88:1365–9. [8] Karatas SO, Ayhan M, Aytug Z, et al. Periocular metatypical cell carcinoma: clinicopathologic correlation, management, and follow-up in 35 patients. J Plast Reconstr Aesthet Surg 2006;59: 1280–7. [9] Weedon D. Skin pathology. 2nd ed. New York: Churchill Livingstone; 1997. p 650. [10] Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol 1992;27:241–8. [11] French Society of Dermatology. Guideline for the diagnosis and treatment of cutaneous squamous cell carcinoma and precursor lesions. Ann Dermatol Venereol 2009;136:166–86. [12] Telfer NR, Colver GB, Morton CA; British Association of Dermatologists CA. Guidelines for the management of basal cell carcinoma. Br J Dermatol 2008;159:35–48. [13] Bowman PH, Ratz JL, Knoepp TG, et al. Basosquamous carcinoma. Dermatol Surg 2003;29:830–3. [14] Betti R, Crosti C, Ghiozzi S, et al. Basosquamous cell carcinoma: a survey of 76 patients and a comparative analysis of basal cell carcinomas and squamous cell carcinomas. Eur J Dermatol 2013;23:83–6. [15] Garcia C, Poletti E, Crowson AN. Basosquamous carcinoma. J am Acad Dermatol 2009;60:137–43. [16] Lopes de Faria J. Basal cell carcinoma of the skin with areas of squamous cell carcinoma: a basosquamous cell carcinoma? J Clin Pathol 1985;38:1273–7. [17] Beer TW, Shepherd P, Theaker JM. Ber EP4 and epithelial membrane antigen aid distinction of basal cell, squamous cell and basosquamous carcinomas of the skin. Histopathology 2000;37:218–23.
Basosquamous carcinoma
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[18] Jones MS, Helm KF, Maloney ME. The immunohistochemical characteristics of the basosquamous cell carcinoma. Dermatol Surg 1997;23:181–4. [19] Mougel F, Kanitakis J, Faure M, Euvrard S. Basosquamous cell carcinoma in organ transplant patients: a clinicopathologic study. J Am Acad Dermatol 2012;66:151–7. [20] Skaria AM. Recurrence of basosquamous carcinoma after Mohs micrographic surgery. Dermatology 2010;221:352–5. [21] LeBoit PE, Burg G, Weedon D, Sarasin A. editors. World Health Organisation classification of tumors. Pathology and genetics of skin tumors. Lyon: IARC Press; 2006. p 10–33. [22] Emett AJJ. Surgical analysis and biological behavior of 2277 basal cell carcinomas. Aust NZ J Surg 1990;60:855–63.
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[23] Rosai J. Rosai and Ackermans Surgical Pathology. Edinburgh: Mosby; 2004. p 136–9. [24] Patterson JW, Wick MR. Nonmelanocytic tumors of the skin. Atlas of tumor pathology. Series 4, Fascicle 4 Washington DC: Armed Forces Institute of Pathology; 2006. p 46–68. [25] Weedon D, Strutton G. Skin pathology. Edinburgh: Churchill Livingstone; 2002. p 765–72. [26] Longhi P, Serra MP, Robotti E. Incompletely excised basal cell carcinomas: our guidelines. Onco Targets Ther 2008;1:1–4. [27] Betti R, Radaelli G, Crosti C, et al. Margin involvement and clinical pattern of basal cell carcinoma with mixed histology. J Eur Acad Dermatol Venereol 2012;26:483–7. [28] Giacomel J, Lallas A, Argenziano G, et al. Dermoscopy of basosquamous carcinoma. Br J Dermatol 2013;169:358–64.
ORIGINAL ARTICLE
Basosquamous carcinoma: Is it an aggressive tumor? Yavuz Kececi1, Asuman Argon2, Tulug Kebat2, Emin Sir1, Melike Gungor1 & Enver Vardar2 Department of Plastic and Reconstructive Surgery and 2Department of Pathology, Izmir Education and Research Hospital, Izmir, Turkey
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1
Abstract Basosquamous carcinoma is a rare cutaneous tumour that is considered an aggressive type of basal cell carcinoma with an increased risk of recurrence and metastases. This impression has been perpetuated in the literature, despite limited scientific data and conflicting results of some authors. This present study was aimed to evaluate the clinical–pathological features of this tumour and follow-up of a series of basosquamous carcinoma. Basosquamous carcinoma patients who underwent surgical excision between January 2000 and February 2012 were analyzed retrospectively. Their medical files were reviewed and the corresponding routinely stained sections (with hematoxylin-eosin) were re-evaluated by two pathologists. Thirty-five patients with basosquamous carcinoma were operated on in this period. Most tumurs were located in the head and neck area (94%), and the mean age of the patients was 69.8 years. Margin involvements were seen in 11 patients (31.4%) and all of them underwent re-excision. There was only one local recurrence. There was neither regional lymph node nor distant metastasis in this series. The recurrence rate of basosquamous carcinoma is found as 4%, lower than that of most other similar studies. Further pathologic studies are needed to better classify basosquamous carcinoma and to increase consistency between the results of studies. Surgical excision and regular follow-up are considered as the treatment of choice. Key Words: Basosquamous carcinoma, basal cell carcinoma, skin carcinoma
Introduction Basosquamous cell carcinoma is a rare tumour with an estimated prevalence rate of 2% of all skin carcinomas [1,2]. It was initially described as a coexistence of basal cell carcinoma and squamous cell carcinoma without any transition zone between them. Subsequent studies reported that basosquamous carcinoma is a variant of basal cell carcinoma and it has areas of definitive basal cell carcinoma and squamous cell carcinoma with a transition zone between them, suggesting differentiation of one of the tumours into the other [3,4]. It is now believed that basal cell carcinoma cells, being pluripotential cells, differentiate into the more aggressive squamous cells [5]. Although basosquamous carcinoma is similar to the basal cell carcinoma clinically and morphologically, this tumour may behave more aggressively, with a propensity for local recurrence and a potential risk for distant metastatic spread. However, there is a disagreement about aggressiveness of this tumour. Studies reported local recurrence rates in a wide range, varying from 4–47.1% [1,2,6-8]. The rarity of this tumour and its particular histologic pattern may result in these variable results. This present study was aimed to evaluate the clinicalpathological features of this tumour and follow-up of a series of basosquamous carcinoma cases. Materials and methods This is a retrospective study of basosquamous carcinoma patients who underwent surgical excision between January 2000 and February 2013. Their medical files were reviewed and the corresponding routinely stained sections (with hematoxylin-eosin)
were re-evaluated by two pathologists. Histologic definition of basosquamous carcinoma was based on identifying areas of both basaloid cells which are larger, paler, and rounder than in solid basal cell carcinoma types and squamoid cells with abundant eosinophilic cytoplasm, and also intermediate cells with amphophilic cytoplasm, round nuclei, and occasional nucleoli [9] (Figure 1). Keratinizing basal cell carcinoma and collision lesions were excluded. Also, the number of patients presenting basal cell carcinomas and squamous cell carcinomas was determined in order to identify the prevalence of basosquamous carcinoma. The principles of the 1975 Declaration of Helsinki were followed in the study. Preoperative diagnosis of basosquamous carcinomas was never made, and the consequent choice of surgical margins was performed according to the suspected tumoural diagnosis. Decision for the safe surgical margin was given in accordance with the international guidelines. A lateral margin of 4–6 mm was indicatively chosen for suspected squamous cell carcinoma less than 2 cm in diameter and not located on the scalp, ears, eyelid, nose, or lips, and a margin wider than 6 mm for high risk locations [10,11]. A lateral margin of 3–4 mm was indicatively chosen for suspected superficial and nodular basal cell carcinomas in low risk areas and of at least 4–5 mm for infiltrative-morpheaform basal cell carcinomas [12]. The clinical data of the patients were analyzed with regard to age, gender, tumour site, tumour size, and disease recurrence. The pathologic parameters recorded were margin involvement, evidence of perineural invasion, stromal fibroplasia, stromal lymphocyte infiltration, loss of palisading and
Correspondence: Yavuz Kececi, MD, Attending Surgeon, Department of Plastic and Reconstructive Surgery, Izmir Education and Research Hospital, Saim Cikrikci Cad. Bozyaka Karabaglar, 35350 Izmir, Turkey. Tel: +90 532 382 5901. Fax: +90 232 261 4444. E-mail: [email protected] (Received 11 March 2014; accepted 9 July 2014)
2 Y. Kececi et al.
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clefting, localisation of squamous areas, and clearly presence of a transition zone. The patients who could be followed-up and those could not were compared in order to determine whether there were differences between them in terms of gender, margin involvement (Fisher’s exact test), age, and tumour size (Student t-test). Results Thirty-five patients with basosquamous carcinoma tumour were included in the study. There were 21 males and 14 females with a mean age of 69.8 years (range = 42–92 years). In this investigated period for the presented study, squamous cell carcinoma was found in 498 patients and basal cell carcinoma in 1149 patients. Basosquamous carcinoma composed 2.1% of all basal cell, squamous cell, and basosquamous carcinomas. Most tumours were located in the head and neck area (33 of 35 patients, 94%), mainly on the central face and perinasal area (19 patients, 54%) and auricular area (five patients, 14%). Only two tumours (4.4%) were located outside the head and neck area, in the upper extremity. Clinical tumour size was greater than 2 cm in five patients (14%). There were neither regional lymph node nor distant metastases. Local recurrence occurred in only one of 25 cases with available follow-up data (4%). In this case, there was no surgical margin involvement and tumour size was 10 mm. Recurrence occurred 14 months after the surgery. This patient was re-operated on, and his 60-months follow-up was free of problems. The mean of tumour size was 13 ± 9 mm. Surgical margin involvement was evident in 11 patients (31.4%), and those all underwent subsequent re-excision. Perineural invasion was not seen in any tumour. Squamoid differentiation was prominent in the base of the tumour in 16 patients, while it was diffused thoroughly across the tumour in the other 19 patients. There was not a clear transition zone in five of 35 tumours. Findings of other histological features are presented in Table I. There was not any follow-up data for 10 of the 35 patients. For the remaining 25 patients, the average follow-up period was 87 months (range = 12–168 months). When the 10 patients without any follow-up data were compared with the other 25 patients, there were no statistically significant differences for gender (p = 0.47, Fisher’s exact test), margin involvement (p = 0.26, Fisher’s exact test), age (p = 0.52, Student t-test), or tumour size (p = 0.88, Student t-test) variables.
Figure 1. General appearance of tumour in low-magnification. While basaloid cells were noticeable on the surface of the tumour, squamoid cells were observed deep in the tumour (40, H&E).
and neck region (Figure 2). Central face affinity makes surgical treatment of this tumour difficult, without leaving an aesthetic problem. The tendency for the head and neck location may be explained by higher sun exposure [6]. There is a significant male predominance in most series [6,13]. In this presented study, 60% of basosquamous carcinoma cases were males. Similar to previous reports [1,7,13], the age distribution was in a wide range (42–92 years), with a mean of 69 ± 11 years. The prevalence rate for basosquamous carcinoma was reported to be between 1.2–2.7% of all non-melanoma skin carcinomas [2,7,13,14]. In our report, basosquamous carcinoma prevalence was 2.1% in a total of 1682 skin carcinomas, confirming the relative rarity of this tumour. Histologically, there are areas of basal cell carcinoma and squamous cell carcinoma with or without a transition zone and a fibroblast-rich, collagenized stroma in basosquamous carcinoma
Discussion Basosquamous carcinoma is a rare skin carcinoma that is most commonly seen on the head and neck region, mainly involving the central face and perinasal areas [13]. The incidence of head and neck location for basosquamous carcinoma was reported between 82–97% [1,7,13]. The anatomic distribution in our series was similar, with 94% of tumours located on the head Table I. Histologic findings of the basosquamous tumours. Stromal fibroplasia Stromal lymphocyte infiltration Loss of palisading Loss of clefting
Prominent 18 23 21 22
Moderate 6 11 5 5
Weak 2 1 9 8
Figure 2. Anatomic locations of 33 cases of basosquamous carcinoma.
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Basosquamous carcinoma
Figure 3. Three cell component of tumour in high-magnification. The arrow on the upper left refers to squamoid cells with abundant eosinophilic cytoplasm, the one on the upper right intermediate cells with amphophilic cytoplasm, round nuclei and occasional nucleoli, the one on the lower left basaloid cells which are larger, paler, and rounder than in solid basal cell carcinoma (200, H&E).
(Figures 3 and 4). Stromal fibroplasia and stromal lymphocyte infiltration were prominent or moderate in almost all the patients, while loss of palisading and clefting were weak in approximately one fourth of the patients (Table I). The basaloid cells in this tumour are larger, paler, and rounder than in solid basal cell carcinoma. The squamoid cell component has larger, polygonal squamoid cells with eosinophilic cytoplasms, larger open nuclei with prominent nucleoli, frequent mitosis, dyskeratotic cells, and intercellular bridges. The intermediate cells reside between them with amphophilic cytoplasm, round nuclei, and occasional nucleoli [7,9,15]. The origin of these cells is unknown, but the pluripotential basal cell is a possible candidate [16]. Basosquamous carcinoma can mimic keratotic basal cell carcinoma which exhibits squamous differentiation in the centre of some nodules. Both basal and squamoid components are uniform and there is neither a transition zone nor the densely collagenized, fibroblast-rich stroma of aggressive growth basal
Figure 4. Dense fibroblastic proliferation in the tumour (100, H&E).
3
cell carcinomas [13]. Differential diagnosis of basosquamous carcinoma from keratotic basal cell carcinoma will prevent unduly aggressive surgery for what is really a nodular form of basal cell carcinoma [3]. An incorrect histopathologic diagnosis is not uncommon, especially if only a superficial biopsy is obtained. Leibovitch et al. [6] reported that initial biopsy before total excision could only correctly diagnose basosquamous carcinoma in 13.7% of their patients and that basosquamous carcinoma diagnosis was made only by total excision of the lesions. This entity should be kept in mind when a simple curettage or fulguration therapy is chosen as the therapy method based on a biopsy result. Immunohistochemical staining can be used in confirming the diagnosis. Even though no specific marker for basosquamous carcinoma exists, the anti-HEA (human epithelial antigen) mouse monoclonal antibody Ber-EP4 labels the basaloid component of basosquamous carcinoma and allows visualization of a transition zone, showing progressive fading of HEA expression within the same tumour mass. HEA immunostaining is therefore helpful in excluding collision tumours consisting of basal cell carcinoma and squamous cell carcinoma [17,18]. Mougel et al. [19] informed that, in their 15 basosquamous carcinoma patient series, three lesions initially reported as basosquamous carcinoma were eventually diagnosed as squamous cell carcinoma after Ber EP4 immunostaining was used. Therefore, immunohistochemical staining would be helpful in separating more aggressive tumours from basosquamous carcinomas. Literature data about recurrence rate and aggressiveness of basosquamous carcinoma is conflicting. Several authors suggest that basosquamous carcinoma has a worse prognosis and greater incidence of recurrences and metastases as compared with basal cell carcinoma, and some authors equate its behaviour to that of squamous cell carcinoma [4,5,7]. Borel [1] reported a local disease recurrence rate of 45.7% in 35 patients with a follow-up of 1 year. Martin et al. [7] reported a 32.1% recurrence rate and five (17.9%) regional lymph node metastases in a series of 28 patients. Schuller et al. [2] found four recurrences (12.1%) in a series of 33 patients. Karatas et al. [8] reported a 17% recurrence rate and a 14% lymph node metastasis rate in 35 patients. Skaria [20] stated an 8.9% recurrence rate in a series of 56 patients. Also, Bowman et al. [13] declared distant metastases in two patients (7.4%) in a series of 27 patients. Betti et al. [14] found two recurrences (5.7%) and one pulmonary metastasis in 35 patients who completed 5 years follow-up. On the other hand, local disease recurrence rate was 4% and neither lymph node nor distant metastases occurred in the presented study. Leibovitch et al. [6] reported local disease recurrence in four of 98 patients without any metastases. In addition, Mougel et al. [19] declared that there was no recurrence or metastases in 12 basosquamous patients with transplanted organs. They linked this result to that their patients with transplanted organs undergo regular dermatologic examination, and tumour diagnosis is usually made at an early stage of tumour development. However, early diagnosis could not elucidate this inconsistency in the results about recurrence rate and aggressiveness of the tumour. Probably, this inconsistency may result from the broad histologic definition of the tumour. The term of metatypical basal cell carcinoma is used by some authors as a
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4 Y. Kececi et al. synonym for basosquamous carcinoma [21-23]. On the other hand, Patterson and Wick [24] and Weedon and Strutton [25] classified basosquamous carcinoma and metatypical basal cell carcinoma as distinct types of basal cell carcinoma. Separating these two types of basal cell carcinoma from each other probably will increase consistency between the results of the studies. Margin involvement, perineural invasion and male gender are reported as significant prognostic indicators for recurrence [7]. There was not any perineural invasion in our series. The incidence of perineural invasion in basosquamous carcinoma was reported as varying from 0–7.9% [6,19]. Leibovitch et al. [6] reported that basosquamous carcinoma recurrence occurred in one of six (16.7%) patients with perineural invasion compared to in three of 92 (3.2%) patients without perineural invasion, demonstrating the more aggressive nature of tumours with perineural invasion. The absence of perineural invasion might contribute to the low rate of local recurrence in our series. Margin involvement is a problem in basosquamous carcinoma surgery. Most surgeons make a decision about the size of the safe surgical margin according to the suspected tumour diagnosis. However, there are no clinical features to distinguish basosquamous carcinoma which presents in the same locations with similar clinical characteristics as other basal cell carcinomas. In the presented series, preoperative diagnosis of basosquamous carcinomas was never made and the tumour was found in the surgical margin in 11 patients (31%). Margin involvement incidence was reported to vary from 9.6%–16.7% for basal cell carcinoma [26,27]. This difference most likely resulted from the invasiveness of this tumour, despite its relatively quiescent clinical appearance. Giacomel et al. [28] investigated the dermoscopic patterns of basosquamous carcinoma in order to facilitate early diagnosis and accurate management of this tumour. They reported that this tumour exhibited at least one basal cell carcinoma-related plus one squamous cell carcinoma-related dermoscopic feature. Therefore, it can be considered that a dermoscopic pre-surgical evaluation of tumour margins may ameliorate the traditional surgical performance in the primary treatment of basosquamous carcinoma. Skaria [20] used Mohs micrographic surgery in the treatment of 56 basosquamous carcinoma patients and found a 8.9% recurrence rate. Therefore, he recommended an additional 2–3 mm margin removal once the excision is complete. However, all the patients with margin involvement underwent re-excision and none of them had a disease recurrence in this presented study. Only 71.4% of the patients in our series could be followedup. This lack of follow-up is certainly a possible bias, as some of the patients might have disease recurrence. Although these missing data are certainly important, we found no significant differences between the patients who could be followed-up and those who could not. There is no generally accepted guideline for the treatment of basosquamous carcinoma, depending on its rarity or debates about histological definition. Wide local excision with clear surgical margins seems to be the treatment of choice. It is very important to identify indicators of recurrence: positive surgical margins, and perineural invasion. A regular follow-up would allow early detection of disease recurrence.
Conclusion The recurrence rate of basosquamous carcinoma was found as 4%, lower than that of most other similar studies. Different assessment about the aggressiveness of basosquamous carcinoma might depend on the broad histologic definition. Further pathologic studies are needed to better define basosquamous carcinoma and to increase consistency between the results of the studies. The incidence of marginal involvement was higher than that of basal cell carcinoma, so a surgical safe margin should be kept wider when preoperative diagnosis is available. Surgical excision and regular follow-up are considered as the treatment of choice. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References [1] Borel DM. Cutaneous basosquamous carcinoma. Arch Pathol Lab Med 1973;95:293–7. [2] Schuller DE, Berg JW, Sherman G, Krause CJ. Cutaneous basosquamous carcinoma of the head and neck: a comparative analysis. Otolaryngol Head Neck Surg 1979; 87:420–7. [3] Maloney ML. What is basosquamous carcinoma? Dermatol Surg 2000;26:505–6. [4] Jones MS, Helm KF, Maloney ME. The immunohistochemical characteristics of the basosquamous cell carcinoma. Dermatol Surg 1997;23:181–4. [5] Lopes de Faria J, Nunes PH. Basosquamous cell carcinoma of the skin with metastases. Histopathology 1988;12:85–94. [6] Leibovitch I, Huilgol SC, Selva D, et al. Basosquamous carcinoma: treatment with Mohs micrographic surgery. Cancer 2005; 104:170–5. [7] Martin RC II, Edwards MJ, Cawte TG, et al. Basosquamous carcinoma: analysis of prognostic factors influencing recurrence. Cancer 2000;88:1365–9. [8] Karatas SO, Ayhan M, Aytug Z, et al. Periocular metatypical cell carcinoma: clinicopathologic correlation, management, and follow-up in 35 patients. J Plast Reconstr Aesthet Surg 2006;59: 1280–7. [9] Weedon D. Skin pathology. 2nd ed. New York: Churchill Livingstone; 1997. p 650. [10] Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol 1992;27:241–8. [11] French Society of Dermatology. Guideline for the diagnosis and treatment of cutaneous squamous cell carcinoma and precursor lesions. Ann Dermatol Venereol 2009;136:166–86. [12] Telfer NR, Colver GB, Morton CA; British Association of Dermatologists CA. Guidelines for the management of basal cell carcinoma. Br J Dermatol 2008;159:35–48. [13] Bowman PH, Ratz JL, Knoepp TG, et al. Basosquamous carcinoma. Dermatol Surg 2003;29:830–3. [14] Betti R, Crosti C, Ghiozzi S, et al. Basosquamous cell carcinoma: a survey of 76 patients and a comparative analysis of basal cell carcinomas and squamous cell carcinomas. Eur J Dermatol 2013;23:83–6. [15] Garcia C, Poletti E, Crowson AN. Basosquamous carcinoma. J am Acad Dermatol 2009;60:137–43. [16] Lopes de Faria J. Basal cell carcinoma of the skin with areas of squamous cell carcinoma: a basosquamous cell carcinoma? J Clin Pathol 1985;38:1273–7. [17] Beer TW, Shepherd P, Theaker JM. Ber EP4 and epithelial membrane antigen aid distinction of basal cell, squamous cell and basosquamous carcinomas of the skin. Histopathology 2000;37:218–23.
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[18] Jones MS, Helm KF, Maloney ME. The immunohistochemical characteristics of the basosquamous cell carcinoma. Dermatol Surg 1997;23:181–4. [19] Mougel F, Kanitakis J, Faure M, Euvrard S. Basosquamous cell carcinoma in organ transplant patients: a clinicopathologic study. J Am Acad Dermatol 2012;66:151–7. [20] Skaria AM. Recurrence of basosquamous carcinoma after Mohs micrographic surgery. Dermatology 2010;221:352–5. [21] LeBoit PE, Burg G, Weedon D, Sarasin A. editors. World Health Organisation classification of tumors. Pathology and genetics of skin tumors. Lyon: IARC Press; 2006. p 10–33. [22] Emett AJJ. Surgical analysis and biological behavior of 2277 basal cell carcinomas. Aust NZ J Surg 1990;60:855–63.
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[23] Rosai J. Rosai and Ackermans Surgical Pathology. Edinburgh: Mosby; 2004. p 136–9. [24] Patterson JW, Wick MR. Nonmelanocytic tumors of the skin. Atlas of tumor pathology. Series 4, Fascicle 4 Washington DC: Armed Forces Institute of Pathology; 2006. p 46–68. [25] Weedon D, Strutton G. Skin pathology. Edinburgh: Churchill Livingstone; 2002. p 765–72. [26] Longhi P, Serra MP, Robotti E. Incompletely excised basal cell carcinomas: our guidelines. Onco Targets Ther 2008;1:1–4. [27] Betti R, Radaelli G, Crosti C, et al. Margin involvement and clinical pattern of basal cell carcinoma with mixed histology. J Eur Acad Dermatol Venereol 2012;26:483–7. [28] Giacomel J, Lallas A, Argenziano G, et al. Dermoscopy of basosquamous carcinoma. Br J Dermatol 2013;169:358–64.
