Histological changes in intra-oral skin flaps
© Woolgar and Triantafyllou; licensee BioMed Central Ltd. 2009
Received: 09 October 2008
Accepted: 12 January 2009
Published: 12 January 2009
This review outlines the histological features of intra-oral skin flaps and their pathology as encountered in a routine head and neck diagnostic histopathology service. Problems in recognising and interpreting unfamiliar and complex appearances, and areas of diagnostic and prognostic uncertainty, are highlighted.
Free tissue transfer using vascularised skin flaps such as the radial forearm flap has become a routine part of the management and rehabilitation of patients with squamous cell carcinoma of the mouth and oropharynx (OSCC) [1, 2]. How the skin flap adapts to the oral environment has been researched in animal models  and in humans [4–10] with recent articles focusing on general performance status, sensory function, particular histological features and immunohistochemically assessed changes in the cornification process [11–13]. Grossly, the flaps often appear similar to the native oral mucosa  and a gradual "mucosalisation" of the transferred skin with loss of the stratum corneum and shrinkage of pilosebaceous units has been suggested [3, 8]. The notion of "mucosalisation" has, however, been challenged  and recent articles suggest that the cutaneous phenotypes are maintained unless there is chronic candidiasis [9, 12]; even when the more "alien" jejunal mucosa is transferred within the mouth, preservation of its phenotype is long-term . Such continued distinction between transferred and native tissues is not unexpected as it is the underlying stroma that influences the phenotype of the overlying epithelium . Many clinicians regard candidal infestation of the epidermis as an inevitable consequence of the wet oral environment and a frequent cause of clinical lesions [5, 6, 8, 16]. For example, chronic candidiasis was evident in 75% of punch biopsies in the study on the adaptive properties of the transferred skin reported by Katou et al . Hence, chronic candidiasis is often the preferred clinical diagnosis when localised erythematous, leukoplakic and erosive/ulcerative lesions are noted at the junction of the skin flap and the oral mucosa. Nevertheless, cancerous and precancerous lesions should always be considered in the clinical differential diagnosis since a study on survival and patterns of recurrence in 200 OSCC patients indicated that 5% of the patients developed a new primary tumour at the skin flap/mucosal junction . The clinical diagnostic uncertainty means that the management of such lesions usually involves biopsy and histological assessment. The latter, however, often presents difficulties. Information that may facilitate the pathologist's interpretation of the complex histological features of chronic candidiasis of the transferred skin is not readily available and the biopsy may be submitted with a complicated clinical history (such as widespread or multifocal dysplasia of the remaining oral mucosa, or previous radiotherapy), thus compounding the difficulty.
The present review aims to comment on the range of histopathological changes seen in skin flap biopsies, highlighting diagnostic difficulties and potential pitfalls. It is based on long-term experience gained on abundant routine diagnostic material and concentrates on the morphology and possible pathogenesis of lesions rather than their incidence and frequency. To begin, the histological features of skin flaps removed as part of subsequent reconstructive surgery will be described to illustrate "normal histological features", followed by an account of a range of pathological lesions including chronic candidiasis, squamous epithelial dysplasia and carcinoma, and miscellaneous acanthomas and adnexal tumours.
"Normal histological features"
When inflammation is present, the horny layer may be lost and, in most cases, a psoriasiform pattern is seen. This is explained by colonisation of the skin flap surface by Candida species. (For illustration, see the following section.) We have observed fibrinous exudate with inflammatory cells and cell debris (pseudomembranous coating) on the epidermis in around 20% of skin-flaps removed during a restructuring procedure, intra-epidermal hyphae in around 40% and involvement of the adjacent oral mucosa in around 50% of skin-infected cases. Hence, candidiasis is a common histological finding even when it is not noted clinically. Acute pseudomembranous and chronic candidiasis is common in oral cancer patients and is attributable to a combination of multiple local and systemic predisposing factors . It is likely that the skin-flap is at greater risk than the native oral mucosa since constant immersion in water is an important risk factor for cutaneous candidiasis .
Chronic hyperplastic candidiasis
Chronic hyperplastic candidiasis (CHC) is the most common histological diagnosis for lesions removed for diagnostic biopsy. Three different reaction patterns occur.
In the third "mixed" reaction pattern, cutaneous and mucosal patterns are present within different regions of the same lesion in roughly equal proportions. As in the "sub-clinical" infections seen in skin-flaps removed during restructuring procedure and mentioned above, infection of the native oral mucosa is seen in around 50% of CHC cases where the biopsy includes the adjacent oral mucosa.
It seems likely that the range of changes seen in intra-oral skin flaps reflects a similar sequence of events to that occurring in cutaneous candidal infections . While compact hyperorthokeratosis probably characterises lesions of longer duration, the loss of the horny layer and other features of the mucosal reaction pattern seem to represent changes occurring early in the infection. The species of Candida involved and differences in the immune response may be further factors in determining the reaction pattern.
The diagnosis of CHC is not always straightforward. The mucosal reaction pattern (Figs 4, 5) is well known to oral pathologists and also, to general pathologists since it is seen in superficial, acute and sub-acute infections of skin. In contrast, the cutaneous reaction pattern with its striking compact hyperorthokeratosis (Fig. 3) can be problematical. In infections of the skin and nail beds, compact hyperorthokeratosis is the hallmark of chronicity , but is often unfamiliar to pathologists since chronic cutaneous infections are not common and are often diagnosed by clinical assessment or scrapings rather than biopsy. The grouping of candidal hyphae and their tendency to detach along with clumps of horny layer, and the absence of intra-epithelial microabscesses add to the diagnostic difficulty. Furthermore, the unfamiliarity of compact hyperorthokeratosis in intra-oral biopsy specimens may lead to an erroneous diagnosis. Care is needed also when the rete hyperplasia characterising the mucosal reaction pattern is marked and accompanied by "reactive" cytological atypia since it could be mistaken for microinvasive SCC, but see the following section.
Chronic candidiasis and squamous epithelial dysplasia
Our experience suggests that around 25% of skin flap lesions diagnosed as CHC show features of squamous epithelial dysplasia, mild or moderate grade. The dysplasia tends to be focal, with sharply defined margins and associated with parakeratosis and marked desquamation. The most conspicuous features are nuclear hyperchromatism, basal cell hyperplasia, drop-shaped rete processes, and in some cases, dyskeratosis affecting all the keratinocytic cell layers. The appearance and degree of the atypia can be such that they cannot readily be explained solely as reactive or regenerative features, and their precise status and prognosis are uncertain. The possibility that the candidal infection is superimposed on an inherent dysplastic lesion must be considered and, hence, re-biopsy after antifungal therapy is advisable. Often, however, the pathogenesis and prognosis remain uncertain and it is important to convey this uncertainty to the clinician. Such lesions have to be managed on an individual basis until the results of long-term follow up studies become available.
There are numerous reports of dysplasia occurring in CHC of the oral mucosa [21–23], but this is not mentioned in accounts of chronic cutaneous candidiasis . The distinction between "reactive" cytological atypia in response to candidal infection and inflammation from inherent dysplasia with malignant potential is difficult. The appearance and degree of the individual cellular and architectural atypia must be considered firstly followed by consideration of the numbers and depth of intra-epithelial hyphae and the intensity of the inflammatory response, and any erosion or ulceration. Nevertheless, the final decision may be subjective and largely based on experience.
In-situand invasive squamous cell carcinoma
The development of carcinoma in-situ and SCC of the skin flap is difficult to explain. It is possible that the skin may have been affected by ultra-violet irradiation or other carcinogens, such as tar, prior to its transfer to the mouth; or the skin flap may have been affected by carcinogens such as tobacco and alcohol following its transfer to the mouth. The role of chronic candidal infection is uncertain. Another possibility is that the epidermis of the skin-flap can become colonised by oral epithelial cells (showing inherent abnormalities) by either a "creeping" or "seeding" mechanism. The creeping mechanism seems unlikely when step sectioning confirms evident and well defined junctional zone between the affected epidermis and oral epithelium, in cases of pathology centrally located within the skin flap and well away from the junctional zone, and when there is no evidence of dysplasia of the native oral mucosa. Creeping, however, may be a factor in lesions occurring at the junctional zone, and in patients with field cancerisation or multiple and multifocal tumours of the native oral mucosa. The seeding mechanism should be considered particularly when erosion/ulceration with florid granulation tissue are noted at the junction of the skin flap and the native oral mucosa (Fig. 1i), there being similarities with the epithelialisation of dental pulp polyps . The viable desquamated oral keratinocytes showing inherent abnormalities and seeding the granulation tissue could originate from sub-clinical field cancerisation, persistent or residual tumour and a new primary.
Hyperkeratotic plaque, acanthomas and appendage tumours
A diagnosis of hyperkeratotic plaque is made when there is localised hyperorthokeratosis without evidence of fungal infection, dysplasia or inflammation. The lesion probably represents a frictional callus, due, for example, to denture trauma.
Inchoate or established seborrhoeic keratoses can be seen in around 15% of skin-flap lesions sent for diagnostic biopsy (Fig. 1h), with acanthotic (solid) and hyperkeratotic (papillomatous) patterns in around equal frequency. We have seen one case of adnexal tumour resembling eccrine syringofibroadenoma. It is tempting to speculate that, when the skin flap did not show clinically evident pathology prior its transfer within the mouth, the acanthomas/appendage tumours are secondary to this event. This would suggest that the transferred skin develops and exhibits typical cutaneous histopathology in an "alien" environment, and would be a further argument against mucosalisation. On the other hand, the possibility that subclinical acanthomas/appendage tumours were present in the flap prior to transferring cannot be excluded. This is supported by the aforementioned finding of small melanocytic naevi in the flaps.
Although skin flaps have been routinely used to reconstruct the oral cavity for more than 20 years, little is known about adaptive events and disease potential. The present review has highlighted areas of uncertainty and drawn attention to the relatively high proportion of biopsies, especially those at the edge of the skin flap, showing squamous epithelial dysplasia or worse. On this basis, it is recommended that clinicians biopsy any lesions where the clinical diagnosisis in doubt and which do not respond fully to antifungal therapy. It is hoped that long-term clinical and histological studies will be undertaken to assess the accuracy of recognising and interpreting infections, reactive processes, and potential and frank malignancies of the transferred epidermis.
- Soutar DS, McGregor IA: The radial forearm flap in intraoral reconstruction: the experience of 60 consecutive cases. Plast Reconstruct Surg. 1986, 78: 1-8. 10.1097/00006534-198607000-00001.View ArticleGoogle Scholar
- Vaughan ED: The radial forearm flap in orofacial reconstruction. Int J Oral Maxillofac Surg. 1994, 23: 194-204. 10.1016/S0901-5027(05)80370-4.View ArticlePubMedGoogle Scholar
- Eliachar I, Sebek BA, Levine S, Tucker HM: Histologic changes in skin implanted into the larynx and trachea by myocutaneous flap reconstruction. Otolaryngol Head Neck Surg. 1985, 93: 754-758.PubMedGoogle Scholar
- Dellon AL, Tarpley TM, Chretien PB: Histologic evaluation of intraoral skin grafts and pedicle flaps in humans. J Oral Surg. 1976, 34: 789-794.PubMedGoogle Scholar
- Beahm EK, Evans GR, Colome-Grimmer MI: Histologic changes of intraoral free skin flaps. Am J Surg. 1997, 174: 492-494. 10.1016/S0002-9610(97)00154-2.View ArticlePubMedGoogle Scholar
- Katou F, Motegi K, Tagami H, Shirai N, Echigo S, Nagura H: Unique inflammatory features noted in intraorally transferred skin flaps: correlation with candida albicans infection. Oral Surg Oral Med Oral Pathol Radiol Endod. 1999, 87: 676-684. 10.1016/S1079-2104(99)70160-5.View ArticleGoogle Scholar
- Badran D, Soutar DS, Robertson AG, Reid O, Milne EW, McDonald SW, Scothorne RJ: Behavior of radial forearm skin flaps transplanted into the oral cavity. Clin Anat. 1998, 11: 379-389. 10.1002/(SICI)1098-2353(1998)11:6<379::AID-CA3>3.0.CO;2-H.View ArticlePubMedGoogle Scholar
- Shibahara T, Noma H, Takeda E, Hashimoto S: Morphologic changes in forearm flaps of the oral cavity. J Oral Maxillofac Surg. 2000, 58: 495-499. 10.1016/S0278-2391(00)90009-0.View ArticlePubMedGoogle Scholar
- Khan AL, Cloke DJ, Hodgkinson PD, McLean NR, Soames JV: Do intraoral radial forearm free flaps re-mucosalise and is candida infection relevant?. Br J Plast Surg. 2001, 54: 299-302. 10.1054/bjps.2001.3574.View ArticlePubMedGoogle Scholar
- Sinclair A, Johnston E, Badran DH, Soutar DS, Robertson AG, McDonald SW: Histological changes in radial forearm skin flaps in the oral cavity. Clin Anat. 2004, 17: 227-232. 10.1002/ca.10180.View ArticlePubMedGoogle Scholar
- Shibahara T, Mohammed AF, Katkura A, Nomura T: Long-term functional results of free radial forearm flap used for oral reconstruction: functional and histological evaluation. J Oral Maxillofac Surg. 2006, 64: 1255-1260. 10.1016/j.joms.2006.04.022.View ArticlePubMedGoogle Scholar
- Rubino C, Dessy LA, Farace F, Ena P, Mazarello V: Microscopic and immunohistochemical analysis of the skin changes of free forearm flaps in intraoral reconstruction. Ann Plast Surg. 2002, 49: 362-368. 10.1097/00000637-200210000-00005.View ArticlePubMedGoogle Scholar
- Katou F, Shirai N, Kamakura S, Tagami H, Nagura H, Motegi K: Differential expression of cornified cell precursors in normal skin, intraorally transplanted skin and normal oral mucosa. Br J Dermatol. 2003, 148: 898-905. 10.1046/j.1365-2133.2003.05288.x.View ArticlePubMedGoogle Scholar
- Reichart P, Lonning T, Hausamen JE, Becker J: Morphologic study of jejunal mucosal transplants for the replacement of oral mucosa. J Oral Pathol. 1984, 13: 595-603. 10.1111/j.1600-0714.1984.tb01461.x.View ArticlePubMedGoogle Scholar
- Krikos GA: Dermo-epidermal interactions. Oral Surg Oral Med Oral Pathol. 1971, 32: 744-751. 10.1016/0030-4220(71)90300-8.View ArticlePubMedGoogle Scholar
- Wei WI, Lam KH, Lau WF: Fate of skin element of pectoralis major flap in intraoral reconstruction. Head Neck. 1989, 115 (3): 360-363.Google Scholar
- Woolgar JA, Rogers S, West CR, Errington RD, Brown JS, Vaughan ED: Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection. Oral Oncology. 1999, 35: 257-265. 10.1016/S1368-8375(98)00113-4.View ArticlePubMedGoogle Scholar
- Reichart PA, Samaranayake LP, Philipsen HP: Pathology and clinical correlates in oral candidiasis and its variants: a review. Oral Diseases. 2000, 6: 85-89.View ArticlePubMedGoogle Scholar
- Odds FC: Pathogenesis of Candidal infections. J Am Acad Dermatol. 1994, 31: 52-55. 10.1016/S0190-9622(08)81257-1.View ArticleGoogle Scholar
- Ollague J, Ackerman AB: Compact hyperorthokeratosis as a clue to chronic dermatophytosis and candidiasis. Am J Dermatopathol. 1982, 4: 359-363.View ArticlePubMedGoogle Scholar
- Cawson RA, Binnie WH: Candida leukoplakia and carcinoma: a possible relationship. Oral premalignancy. Proceedings of the first Dow Symposium. Iowa. Edited by: Mackenzie IC, Dabelsteen E, Squier CA. 1980, Iowa: University of Iowa, 59-66.Google Scholar
- Reibel J: Prognosis of oral pre-malignant lesions: significance of clinical, histopathological, and molecular biological characteristics. Crit Rev Oral Biol Med. 2003, 14: 47-62. 10.1177/154411130301400105.View ArticlePubMedGoogle Scholar
- McCullough M, Jaber M, Barrett AW, Bain L, Speight PM, Porter SR: Oral yeast carriage correlates with presence of oral epithelial dysplasia. Oral Oncol. 2002, 38: 391-393. 10.1016/S1368-8375(01)00079-3.View ArticlePubMedGoogle Scholar
- Woolgar JA, Triantafyllou A: Pitfalls and procedures in the histopathological diagnosis of oral and oropharyngeal squamous cell carcinoma and a review of the role of pathology in prognosis. Oral Oncol. 2008,Google Scholar
- Sa'do B, Nakamura N, Higuchi Y, Ozeki S, Harada H, Tashiro H: Squamous cell carcinoma of the oral cavity derived from a skin graft: a case report. Head & Neck. 1994, 16: 79-82. 10.1002/hed.2880160116.View ArticleGoogle Scholar
- Cassarino DS, Derienzo DP, Barr RJ: Cutaneous squamous cell carcinoma: a comprehensive clinico-pathologic classification. Part one. J Cutan Pathol. 2006, 33 (3): 191-206. 10.1111/j.0303-6987.2006.00516_1.x.PubMedGoogle Scholar
- Southam JC, Hodson JJ: The growth of epithelium, melanocytes, and Langerhans cells on human and experimental dental pulp polyps. Oral Surg Oral Med Oral Pathol. 1974, 37: 546-555. 10.1016/0030-4220(74)90286-2.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.