Basosquamous carcinoma Carlos Garcia, MD,a Eduardo Poletti, MD,b and A. Neil Crowson, MDc Oklahoma City and Tulsa, Oklahoma, and Aguascalientes, Mexico Background: Basosquamous carcinoma is considered an aggressive type of basal cell carcinoma (BCC) with an increased risk of recurrence and metastases. This concept has been perpetuated in the literature in spite of confusing terminology, limited scientific data, and the contradictory surgical experiences of some observers. Methods: This is a narrative review based on a MEDLINE search of articles in English and a manual search of popular dermatology textbooks to define basosquamous carcinoma, its incidence, clinical behavior, and treatment of choice. Results: There are no specific clinical features to distinguish basosquamous carcinoma from other BCC types and the diagnosis is made only after biopsy. There are several histologic definitions of basosquamous carcinoma ranging from a characteristic combination of BCC and squamous cell carcinoma with or without a transition zone, to any BCC with evidence of keratinization. The authors confine the use of the term to an infiltrative growth BCC with areas of keratinization and/or intercellular bridge formation in the setting of a prototypic proliferative stromal reaction. The term ‘‘metatypical basal cell carcinoma’’ is considered a synonym but its use is discouraged for the reasons outlined. The reported incidence of basosquamous carcinoma ranges from 1.2% to 2.7%. Published recurrence rates are 12% to 51% for surgical excision and 4% for Mohs micrographic surgery. The incidence of metastasis is at least 5%. The aggressive biological behavior and clinical course distinguish basosquamous carcinoma from other forms of BCC. Limitations: This study is a literature review, contains a limited number of patients, and is mostly retrospective studies. Conclusion: The terminology surrounding basosquamous carcinoma is confusing and there is a need for more uniform language. Based on our review and personal experience, we propose a more precise and specific definition. Data regarding the incidence, recurrence, and metastasis rates of basosquamous carcinoma are based mostly on retrospective series with a limited number of cases. We conclude that although the incidence of basosquamous carcinoma is unknown, there is a literature precedent suggesting more aggressive biological behavior. We believe that complete surgical excision is the preferred approach, and that basosquamous carcinoma is an ideal candidate lesion for Mohs micrographic surgery. ( J Am Acad Dermatol 2009;60:137-43.)
B
asosquamous carcinoma was initially defined in the early 20th century as a neoplasm with a histomorphology intermediate between
From the Department of Dermatology at the Oklahoma University Health Sciences Center, Oklahoma Citya; Department of Dermatology, University of Aguascalientesb; and Departments of Dermatology, Pathology, and Surgery, Oklahoma University Health Sciences Center and Regional Medical Laboratory, Tulsa.c Funding sources: None. Conflicts of interest: None declared. Reprints not available from the authors. Correspondence to: Carlos Garcia, MD, Department of Dermatology, Oklahoma University Health Sciences Center, 619 NE 13 St, Oklahoma City, OK, 73104. E-mail:
[email protected]. 0190-9622/$36.00 ª 2008 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2008.09.036
basal cell carcinoma (BCC) and squamous cell carcinoma, which occupy opposite poles of a spectrum of differentiation. Later, 3 similar morphologic subtypes of BCC were described.1 Two of these were referred to as ‘‘metatypique mixte’’ and ‘‘metatypique intermediare’’ types. The former type was a mixture of typical BCC containing areas of conglomerate squamous cells with pale, eosinophilic cytoplasms, intercytoplasmic bridges, and keratohyalin granules. In the latter, the tumor cells were larger and paler than basaloid cells but smaller than squamoid cells, and often lacked intercellular bridges. So far, no attempt was made to assign a distinct behavior to these tumors. In 1928, basosquamous carcinoma was described as a distinct neoplasm with a particular histology and clinical behavior.2 Over time, the terminology became confusing with some authors 137
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Table I. Dermatology textbooks 1. James WD, Berger TG, Elston DM. Andrew’s diseases of the skin: clinical dermatology. 10th ed. Canada: Elsevier Saunders, 2006. p. 646-8.* 2. Rigel DS, Friedman RJ, Dzubow LM, Reintgen DS, Bystryn JC, Marks R. Cancer of the skin. 1st ed. Philadelphia: Elsevier Saunders, 2005. p. 104. 3. Elder DE, Elenitsas R, Johnson BL, Murphy GF. Lever’s histopathology of the skin. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 846. 4. Barnhill RL, Crowson AN. Textbook of dermatopathology. 2nd ed. New York: McGraw-Hill, 2004. p. 604. 5. Burns T, Breathnach S, Cox N, Griffiths C. Rook’s textbook of dermatology. 7th ed. UK: Blackwell Science, 2004. p. 36.24. 6. Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. 1st ed. Edinburgh: Mosby, 2003. p. 1686-8. 7. Freedberg IM, Eisen A, Wolff K, Austen KF, Goldsmith LA, Katz SI. Fitzpatrick’s dermatology in general medicine. 6th ed. New York: McGraw-Hill, 2003. p. 750-1.* 8. McKee PH, Colonje E, Granter SR. Pathology of the skin. Philadelphia: Elsevier, 2555. p. 1175-8. 9. Weedon D. Skin pathology. 2nd ed. London: Churchill Livingston, 2002. p. 769-70. *Do not recognize or mention basosquamous carcinoma.
separating basosquamous from metatypical carcinoma, others using the terms synonymously, and still others claiming that basosquamous carcinoma was only a keratotic variant of BCC.3,4 Today, most dermatologists recognize that basosquamous carcinoma is a subtype of BCC with aggressive behavior and higher tendency for recurrence and metastases.5 Herein, we present a review of the literature on basosquamous carcinoma/metatypical BCC and clarify its clinical and histologic definitions, incidence, behavior, and treatment of choice.
METHODS We conducted a MEDLINE search (1966-2007) of articles in English using the term ‘‘basal cell carcinoma’’ with the following subheadings: classification, diagnosis, mortality, and pathology. We also combined ‘‘basal cell carcinoma’’ with the terms ‘‘basosquamous’’ or ‘‘metatypical’’ of the skin in the article’s title. Articles were selected according to the following criteria. Inclusion criteria were: (1) prospective and retrospective case series of basosquamous carcinoma or metatypical BCC with at least 3 cases; (2) histologic reviews of BCC that included basosquamous carcinoma or metatypical BCC; and (3) commentary articles specific to basosquamous carcinoma or metatypical BCC. Exclusion criteria were: (1) case reports of basosquamous carcinoma or metatypical BCC with two or fewer cases; and (2) histologic reviews of BCC that did not include basosquamous carcinoma or metatypical BCC. In addition, a manual search of references in articles selected and of 9 popular dermatology textbooks was performed looking for ‘‘basosquamous carcinoma’’ and ‘‘metatypical basal cell carcinoma’’ (Table I).
RESULTS The MEDLINE search (1966-2007) of articles in English using the terms ‘‘basal cell carcinoma (BCC)’’ (classification, diagnosis, mortality, and pathology) yielded 1536 articles. Of those, 136 were listed as review articles but only 6 met inclusion criteria and were selected. The search for ‘‘metatypical BCC/skin’’ yielded 9 articles, 3 of which met inclusion criteria and were selected. The search for ‘‘basosquamous carcinoma/skin’’ yielded 30 articles, 13 of which met inclusion criteria and were selected. Two of 9 textbooks reviewed did not recognize ‘‘basosquamous carcinoma’’ or ‘‘metatypical basal cell carcinoma’’ as separate entities or did not mention them at all.6,7 The summary that follows is based on analysis of 6 textbooks and 22 articles (14 case series, 4 reviews, 3 about immunohistochemical stains, and 1 commentary) and references cited in those articles. Additional references to support the discussion of biologic behavior of aggressive BCC types were added from our personal files. Clinical features Most authors recognize that basosquamous carcinoma has a nonspecific clinical presentation and the diagnosis is made only after biopsy. The majority of lesions arise on the head and neck (80%) with the central face and perinasal areas being the most common locations (30%). Yet, the tumor can occur on the neck, trunk, and extremities, too. The location of tumors is similar to other types of BCC.8-10 Histologic definitions The term ‘‘basosquamous carcinoma’’ usually implies a BCC with areas of lineage differentiation into squamous cell carcinoma.11 This tumor has areas of BCC and squamous cell carcinoma plus a transition zone between them.12 The areas of BCC
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have small, uniform, hyperchromatic cells, with peripheral palisading, mitoses, and stromal collagen deposition with proliferative fibroblasts. In contrast to pure BCC, some basaloid cells in basosquamous carcinoma exhibit eosinophilic cytoplasms, often lack the characteristic peripheral palisading and retraction artifact, and have variable cytoplasmic keratinization.13-15 The areas of squamoid cell carcinoma are characterized by large polygonal squamoid cells with eosinophilic cytoplasms reflecting cytoplasmic keratinization, larger open nuclei with prominent nucleoli, frequent mitosis, dyskeratotic cells, and intercellular bridges. The use of immunohistochemical stains has added to the definition of basosquamous carcinoma.16 Areas of BCC are BerEP4, AE1, and AE3 positive, whereas areas of squamous cell carcinoma are AE1, AE3, and CAM5.2 positive and show variable staining with epithelial membrane antigen.17 Importantly, the transition zone shows a decline of staining with graded reactivity for Ber-EP4 as the characteristics of the tumor move from BCC to squamous cell carcinoma.18 The use of beta-2 microglobulin is not helpful.19 Metatypical BCC has been variably described as synonymous with basosquamous carcinoma,5,6 as a tumor having areas of BCC and a transition zone but without transformation into squamous cell carcinoma, or vaguely as any tumor with features of both BCC and squamous cell carcinoma.8,12,20 In addition, although typical BCCs express keratin 17 and often keratin 8, metatypical carcinomas have weak reactions to these antibodies.21 Some authors propose that basosquamous carcinoma is synonymous with mixed carcinoma5,22 but others have stated that mixed carcinoma exhibits no transition zone.8 In other reports, basosquamous carcinoma and keratotic BCC are considered synonymous and are described as masses of BCC with squamoid differentiation toward the center and with uniform appearance of both the BCC and squamous cell carcinoma areas.4,23 Others recommend avoidance of the terms ‘‘basosquamous’’ and ‘‘metatypical’’ BCC and call squamous cell carcinoma any BCC with significant squamoid differentiation based on a similar expected behavior.24 Incidence of basosquamous carcinoma Schuller et al15 reported 33 cases of basosquamous carcinoma from a total of 2565 nonmelanoma skin cancers of the head and neck (1.2%). Martin et al14 reviewed the medical records of all patients with skin cancer treated at the University of Louisvilleeaffiliated hospitals between 1985 and
1988. There were 2075 cases of skin carcinoma with 31 lesions in 28 patients given the diagnosis of basosquamous carcinoma of the skin (1.4%). Bowman et al25 reported on 1000 consecutive Mohs micrographic surgery cases performed at the Oschner Clinic in New Orleans, LA. There were 27 basosquamous cell carcinomas (2.7%). Clinical behavior and prognosis of basosquamous carcinoma Several authors suggest that basosquamous cell carcinoma has a worse prognosis and greater incidence of recurrence and metastases as compared with BCC and some authors equate its behavior to that of squamous cell carcinoma.5,13,14,18,26-28 Kazantseva et al21 described a high percentage of proliferating cells in metatypical cell carcinoma as compared with BCC and proposed that this increased activity may explain some cases of aggressive biologic behavior. Also, Kallioinen et al29 reported that local aggressive behavior of BCC and basosquamous carcinoma seems to be accompanied by discontinuity of the basement membrane zone. A retrospective review of 17 cases of metastatic BCC from the Armed Forces Institute of Pathology30 described 10 lesions that had a primary lesion available for analysis. Eight of those cases (80%) had a basosquamous or metatypical histology and the authors concluded that metatypical features in BCCs are associated with an ability to metastasize. In contrast, a larger review of 170 cases of metastatic BCCs found that only 15% of cases exhibited foci of squamous differentiation.31 In other reports, authors15,32 describe a recurrence rate of 12% to 51% for basosquamous carcinomas of the head and neck and calculated a metastatic rate of 5% at 0 to 30 years. Treatment of basosquamous carcinoma Borel23 reported a local disease recurrence rate of 45.7% after wide excision for metatypical cell carcinoma in 35 patients with a follow-up of 1 year. Martin et al14 found 9 (32.1%) posttreatment disease recurrences in 28 patients with a median follow-up period of 5 years. Schuller et al15 reported a 12.1% recurrence rate in 33 patients with metatypical cell carcinoma treated with surgical excision. Karatas et al33 reported a 17% recurrence rate after excision in 35 patients with periocular metatypical cell carcinoma. Bowman et al25 reported their experience with 1000 Mohs micrographic surgical cases: 745 BCCs, 228 squamous cell carcinomas, and 27 basosquamous carcinomas. The average number of stages needed to achieve clear margins was 1.6, 1.5, and 2.0, respectively. Basosquamous carcinoma displayed tissue invasion similar to BCC and squamous cell carcinoma
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Fig 1. Infiltrative growth subtype of basal cell carcinoma (BCC) that shows areas of BCC and squamous cell carcinoma with transition zone and collagenized stroma containing prominent fibroblasts intimately opposed to tumor nests (arrows). (Hematoxylin-eosin stain; original magnification: 310.)
but significantly increased incidence of metastases. Specifically, pulmonary metastases occurred in 7.4% of basosquamous carcinomas compared with 0.87% of squamous cell carcinomas (P \.001). In a recent prospective multicenter trial, the authors reported all the basosquamous carcinomas treated with Mohs micrographic surgery in Australia between 1993 and 2002.34 There were 178 cases (85 recurrent) most of which were located on the head and neck (95%). The most common location was the nose (33%). The incidence of perineural invasion was 7.9%. The average number of Mohs layers needed to achieve clear margins was 1.6. Followup of at least 5 years was available for 98 patients (51%). There were 4 local recurrences (4%) and two lymph node metastases (2%). Only one of 6 patients with perineural invasion and 5-year follow-up had a recurrence. The authors concluded that their low recurrence rate after Mohs micrographic surgery supports the importance of margin control when treating basosquamous carcinoma.
DISCUSSION There are no clinical features to distinguish basosquamous carcinoma and the diagnosis is made only after biopsy. It presents in the same locations and with similar clinical characteristics as other BCCs. Approximately 80% of basosquamous carcinomas occur on the head and neck. The most frequent locations are the central face and perinasal skin (30%). In our hands, and in the hands of Australian observers, the indolent growth variants are found widely distributed on both sun-exposed and sun-protected skin, whereas the aggressive growth variants such as infiltrative and morpheaform BCC are more frequent in sun-exposed skin.35,36
Fig 2. Peripheral palisading and clefting are variable (same lesion). (Hematoxylin-eosin stain; original magnification: 320.)
The histologic definitions of basosquamous carcinoma are confusing and some clarification is needed. We propose the following nomenclature based on our review of the literature. Basosquamous carcinoma is an infiltrative growth subtype of BCC that shows areas of BCC and squamous cell carcinoma with or without a transition zone and a fibroblast-rich, collagenized stroma (Fig 1). The basaloid cells in this tumor are more mitotically active than indolent growth (superficial and nodular) BCCs with greater numbers of apoptotic nuclei. Peripheral palisading and clefting are variable (Fig 2). 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 (Fig 3). Like infiltrative growth and morpheiform BCC, basosquamous carcinoma has an aggressive-growth infiltrative pattern with tongues of tumor cells embedded in a dense stroma containing prominent fibroblasts (Fig 4). With immunostains, the areas of BCC are Ber-EP4, AE1, and AE3 positive, whereas areas of squamous cell carcinoma are AE1, AE3, and CAM.52 positive and show variable staining with epithelial membrane antigen. Characteristically, the transition zone shows a decline of staining with graded reactivity for Ber-EP4 as the morphology of the tumor moves from BCC to squamous cell carcinoma. The use of the term ‘‘metatypical’’ is inconsistent with modern concepts of biology, whereby ‘‘metaplasia’’ is defined as a change of one mature cell type to another. As BCC is derived from germinative progenitor epithelia as opposed to a mature cell line,5 its change to a different lineage cannot be logically construed to represent metaplasia or metatypia and we prefer to avoid the term ‘‘metatypical BCC.’’ Keratotic BCC is a nodular BCC that exhibits squamous differentiation in the center of some
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Fig 3. Squamoid cell component has larger, polygonal squamoid cells with eosinophilic cytoplasms, larger nuclei with prominent nucleoli, frequent mitosis, dyskeratotic cells (arrow), and intercellular bridges (same lesion). (Hematoxylin-eosin stain; original magnification: 360.)
Fig 4. Basosquamous carcinoma has aggressive-growth infiltrative pattern with tongues of tumor cells embedded in dense stroma containing proplastic fibroblasts (same lesion). (Hematoxylin-eosin stain; original magnification: 320.)
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 BCCs, including basosquamous carcinoma (Fig 5). A collision tumor has geographically distinct basal cell and squamous cell tumors without transition zone and with distinct and independent origin in the epidermis (Fig 6). We term these neoplasms ‘‘mixed basal cell-squamous cell carcinoma.’’4,5 The incidence of basosquamous carcinoma is unknown. The literature suggests that this neoplasm represents from 1.2% to 2.7% of all BCCs but these figures come from a few retrospective series and no definite conclusions can be drawn from the data. In terms of clinical behavior, the literature suggests that basosquamous carcinoma has significantly greater risk of local recurrence and metastasis. Although this information comes mostly from
Fig 5. Keratotic basal cell carcinoma (BCC) is nodular BCC that exhibits squamous differentiation in center of some nodules (arrow). Both basal and squamoid components are uniform and there is neither a transition zone nor the densely collagenized, proplastic stroma of aggressive growth BCCs, including basosquamous carcinoma. (Hematoxylin-eosin stain; original magnification: 310.)
Fig 6. Collision tumor has geographically distinct basal cell (small arrow) and squamous cell (large arrow) tumors without transition zone and with distinct and independent origin in epidermis. (Hematoxylin-eosin stain; original magnification: 34.)
retrospective reviews, there appears to be enough evidence and significant number of cases to support this notion. In addition, basosquamous carcinoma should be considered one of the most aggressive BCC types based on its infiltrative growth and stromal reaction patterns. We have previously shown that aggressive growth variants of sporadic BCC are associated with stromal fibroplasia and over expression of what is likely mutant p53.37,38 It is this stromal response to tumor that makes the aggressive growth BCC less amenable to local therapy and control.39 Loss of basement membrane material around individual tumor cell nests occurs with progression from indolent to aggressive growth neoplasms.40 The indolent growth variants of BCC are surrounded by a continuous basement membrane zone comprising collagens type IV and V admixed with laminin. The
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aggressive growth variants manifest an absent basement membrane.41 Although formerly held to constitute a barrier to invasion,30 it appears that basement membrane material is first be secreted by and later dissolved by neoplastic cell systems, such as in the case of up-regulated transmembrane metalloproteinase activity in vertical growth phase melanoma-derived cell lines in vitro,42 a biologic function that has specific implications. In particular, the basement membrane zone may act as a trap for cytokines derived from tumor cells, stromal cells, and inflammatory cells. These cytokines, when liberated by a transmembrane or other matrix metalloproteinase, may then be bioavailable to promote tumor growth. There are no prospective trials available to compare therapies for basosquamous carcinoma and, therefore, no specific treatment of choice. Yet, it seems logical to treat basosquamous carcinoma according to protocols followed for aggressive histologic BCC subtypes. Excision is probably best and Mohs micrographic surgery should be indicated for high-risk locations, recurrent or large tumors, and tissue preservation. Radiation is a good alternative in selected cases. In our view, the aggressive growth variants of BCC (infiltrative, morpheaform, basosquamous) manifesting pronounced stromal desmoplasia should not be treated by simple curettage and fulguration.
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35. Crowson AN, Magro CM, Kadin M, Stranc M. Differential expression of bcl2 oncogene in human basal cell carcinoma. Hum Pathol 1996;27:355-9. 36. McCormack CJ, Kelly JW, Dorevitch AP. Differences in age and body site distribution of the histological subtypes of basal cell carcinoma: a possible indicator of different causes. Arch Dermatol 1997;133:593-6. 37. Crowson AN, Pilavdzic D, Stranc M, Magro CM. Expression of p21WAF1/CIP1 in aggressive- versus non-aggressive-growth basal cell carcinoma: a comparative study [abstract]. Lab Invest 1999;79:56A. 38. Crowson AN, Magro CM, Pilavdzic D, Stranc M. Differential stromal p53 expression in human basal cell carcinoma [abstract]. Lab Invest 1997;76:43A.
39. Sexton M, Jones DB, Maloney ME. Histologic pattern analysis of basal cell carcinoma. J Am Acad Dermatol 1990;23: 1118-26. 40. Hayakawa TJ, Pilavdzic D, Magro CM, Stranc M, Crowson AN. The ultrastructure of aggressive-versus indolent-growth basal cell carcinoma: a comparative study [abstract]. Lab Invest 1998;78:50A. 41. Barsky SH, Grossman DA, Bhuta S. Desmoplastic basal cell carcinomas possess unique basement membrane-degrading properties. J Invest Dermatol 1987;88:324-9. 42. Iida J, Wilhelmson KL, Price MA, Wilson CM, Pei D, Furcht LT, McCarthy JB. Membrane type-I matrix metalloproteinase promotes human melanoma invasion and growth. J Invest Dermatol 2004;122:167-76.
