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Poorly differentiated squamous cell carcinoma arising from an intraepidermal epithelioma
Pathology – Research and Practice 209 (2013) 260–263
Contents lists available at SciVerse ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.com/locate/prp
Teaching cases
Poorly differentiated squamous cell carcinoma arising from an intraepidermal epithelioma Alan S. Boyd a,b,∗ , Lloyd E. King Jr. a a b
Department of Medicine (Dermatology), Vanderbilt University, Nashville, TN, United States Department of Pathology, Vanderbilt University, Nashville, TN, United States
a r t i c l e
i n f o
Article history: Received 31 October 2012 Received in revised form 16 January 2013 Accepted 28 January 2013 Keywords: Intraepidermal epithelioma Squamous cell carcinoma Seborrheic keratosis Vimentin
a b s t r a c t The intraepidermal epithelioma (of Borst–Jadasson) constitutes a much discussed and debated entity. Currently, this diagnosis is rarely made in part, as ascribing clinical features to such lesions has, to date, proven difficult. In addition, intraepidermal proliferation of atypical cells with clonal features is more likely diagnosed as squamous cell carcinomas in situ, porocarcinomas or inflamed seborrheic keratoses. However, cutaneous tumors exhibiting microscopic and immunohistochemical features of clonally profligate malignant basaloid cells solely of epidermal origin do rarely exist. Their progression to dermal invasion appears even more uncommon. © 2013 Elsevier GmbH. All rights reserved.
Introduction
Clinical history
In 1904, Borst described a squamous cell carcinoma of the lip with nests of similar, and presumed malignant, cells in the adjacent epidermis [1]. Twenty-two years later, Jadasson reported what he believed was a basal cell carcinoma restricted to the epidermis and without dermal invasion [2]. Montgomery, in 1929 coined the term “intraepithelial epithelioma of Borst and Jadassohn”, believing it represented a malignant lesion [3]. In 1985, Steffen and Ackerman published an exhaustive treatise on the subject, opined that many of the lesions previously described represented irritated seborrheic keratoses and suggested that the term “intraepidermal epithelioma” be avoided [4]. Most recently, in a review of cutaneous squamous cell carcinoma, Cassarino et al. wrote “there appears to be a subset of cases which represent ‘true IEEs’ which should be referred to as IEE of Jadassohn” [5]. Little support exists for the term “intraepidermal epithelioma” (IEE) in part due to the difficulty in ascribing distinct clinical features to the lesion. Given the clonal appearance and atypia appreciated microscopically, these neoplasms are likely diagnosed and treated as squamous cell carcinomas in situ. Lesions exhibiting an invasive component have only rarely been reported.
In August 2005, a 73-year-old white female presented to her dermatologist complaining of a pruritic lesion on her left hip. Clinically diagnosed as an inflamed seborrheic keratosis, it was frozen with liquid nitrogen. The patient returned a year later, stating the lesion had recurred two months following her initial appointment. A shave biopsy was performed and diagnosed histopathologically as an irritated seborrheic keratosis. In October 2010, the patient presented again, stating the lesion had returned and occasionally bled following trauma from her clothing. Another shave biopsy was performed.
∗ Corresponding author at: 3900, The Vanderbilt Clinic, Nashville, TN 37232, United States. Tel.: +1 615 343 7270; fax: +1 615 343 952. E-mail address: [email protected] (A.S. Boyd). 0344-0338/$ – see front matter © 2013 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.prp.2013.01.011
Histopathological findings The initial biopsy demonstrated an acanthotic and hyperkeratotic epidermal tumor containing aggregates of basaloid cells proliferating in a clonal pattern (Fig. 1A). These basaloid cells exhibited crowding, nuclear atypia and, focally, clear cell features (Fig. 1B). Mitotic figures and apoptotic keratinocytes were also noted. Staining with pancytokeratin (AE1/AE3) illustrated the pattern of clonal proliferation with the basaloid cells exhibiting less uptake than the surrounding epidermis (Fig. 1C). A minichromosome maintenance protein 2 (MMP 2) stain was taken up preferentially by the basaloid cells (Fig. 1D). Rare aggregates of basaloid cells were vimentin and CD10 positive. Staining for carcinoembryonic antigen (CEA) was negative. The second biopsy exhibited an epidermis with similar features overlying dermal invasion by epithelioid cells (Fig. 2A). These epithelioid cells were large with bizarre nuclei, multiple nucleoli
A.S. Boyd, L.E. King Jr. / Pathology – Research and Practice 209 (2013) 260–263
261
Fig. 1. Histologic features of the lesion biopsied in 2005. (A) Low power view demonstrating hyperkeratosis, papillomatosis and an intraepidermal clonal proliferation of basaloid cells (hematoxylin and eosin 40×). (B) Intermediate power view of the clonal cells with focal clear cell features, atypia and mitotic figures (hematoxylin and eosin 200×). (C) Pancytokeratin (AE1/AE3) immunohistochemical staining exhibiting a biphasic pattern of antigen expression (80×). (D) Minichromosome maintenance protein 2 (MMP 2) immunohistochemical stain highlighting the proliferative index of the basaloid cells (80×).
and varying amounts of vacuolated cytoplasm (Fig. 2B). Many also displayed homogenous, eosinophilic intracytoplasmic inclusions often impinging on nuclei. Mitotic figures, including atypical forms, were readily apparent along with focal areas of cell dyscohesion suggestive of evolving acantholysis. Formation of squamous pearls was not appreciated. The intradermal epithelioid cells were strongly cytokeratin 5/6 (Fig. 3A), Cam 5.2 and vimentin (Fig. 3B) positive and modestly pancytokeratin, cytokeratin 903, neuron specific enolase and CD10 positive. Each of these stains readily highlighted the intracytoplasmic inclusions. Mart-1, S-100, synaptophysin, Ber-EP4, cytokeratin 20, CEA, actin, epithelial membrane antigen and cytokeratin 7 stains were negative. Scanning electron microscopy was performed and revealed large paranuclear aggregates of filamentous material consistent with intermediate filaments (Fig. 4). Discussion
Fig. 2. Histologic features of the lesion biopsied in 2010. (A) Low power view demonstrating a similar clonal pattern of epidermal proliferation with dermal invasion of epithelioid cells (hematoxylin and eosin 20×). (B) High power view of the epithelioid cells exhibiting bizarre nuclei, mitotic figures, vacuolated cytoplasm and eosinophilic intracytoplasmic inclusions (hematoxylin and eosin 400×).
According to Steffen and Ackerman, cutaneous neoplasms exhibiting “atypical” cells of epithelial lineage include irritated seborrheic keratoses, solar keratoses, squamous cell carcinoma in situ (Bowen’s disease), mammary and extramammary Paget’s disease and epidermotropic carcinomas but not malignant hidroacanthoma simplex or eccrine porocarcinoma [4]. The lesion presented in this paper does not conform to any of these entities given its obvious atypia, clonal pattern of proliferation and immunohistochemical staining pattern. Moreover, its malignant nature is attested to by its invasive characteristics and proliferative index. Irritated or inflamed seborrheic keratoses may exhibit clonal proliferation similar to our lesion but would not be expected to demonstrate the pattern of pancytokeratin expression, this degree of basophilia or MMP 2 uptake nor this much cytologic atypia. It would be very unusual for solar or actinic keratoses to arise at this anatomic site. Moreover, these neoplasms are rarely acanthotic to this degree and do not demonstrate widespread clonal proliferative features or basaloid staining. The malignant cells of mammary and
262
A.S. Boyd, L.E. King Jr. / Pathology – Research and Practice 209 (2013) 260–263
Fig. 5. Vimentin stain of the epidermis above the area of dermal invasion (100×).
Fig. 3. Special staining features of the lesion biopsied in 2005. (A) Cytokeratin 5/6 (400×) and (B) vimentin (400×) are strongly expressed by the invading epithelioid cells. Note the strong staining of the intracytoplasmic inclusions.
extramammary Paget’s disease can be somewhat basaloid, usually secondary to mucin production but are rarely, if ever, well demarcated enough to impart a clonal appearance. These cells would also be expected to be strongly cytokeratin 7 and EMA positive. Metastatic deposits with epidermotropic features can demonstrate the clonal pattern observed in our patient’s lesion; however, there is usually a history of a malignancy and almost invariably the presence of additional tumor in the underlying dermis. Malignant hidroacanthoma simplex would be expected to exhibit evidence of ductal differentiation which would be highlighted with a CEA stain.
The closest mimic of our patient’s tumor is that of Bowen’s disease which, in the case of her 2nd biopsy, had become invasive. Bowen’s disease typically demonstrates full thickness epidermal atypia and although they may display clonal proliferation it is rarely, if ever, to the degree noted in these biopsies. In addition, some degree of pagetoid spread by malignant keratinocytes is often noted, features not exhibited by our patient’s tumors. The immunohistochemical profile and staining pattern of our patient’s lesion was unusual, notably that invading tumor cells were both CD-10 and vimentin positive. Moreover, intraepidermal basaloid cells were vimentin negative except in nests above the areas of dermal invasion (Fig. 5). Co-expression of cytokeratin and vimentin has been reported in other tumors including renal, thyroid and lung adenocarcinoma and may reflect a reversion of the tumor to a more embryonic phenotype [6]. Ikegawa et al. reported 2 patients with a squamous cell carcinoma arising in burn scars which were both cytokeratin and vimentin positive [6]. Tumor cells exhibited acantholysis with highly atypical mitotic figures and horn pearls. Although prolonged fixation in formalin has been posited as capable of altering cytokeratin peptides such that they become cross reactive for vimentin [7], the authors suggested that the loss of the cells’ three dimensional histologic architecture may have been responsible. Iyer and Leong evaluated 30 cases of poorly differentiated cutaneous squamous cell carcinoma, noting that 12 were vimentin positive [8]. Two of these cases were acantholytic and exhibited perinuclear vimentin staining. They hypothesized that as vimentin is often expressed by metastatic carcinomas in serous cavities, the reduced cell to cell contact may be responsible for the acquisition of vimentin positivity and reflective of epithelial cells with a propensity to survive independently. It should be noted, however, that the immunohistochemical stains taken up by the intracytoplasmic inclusions may be artifactual in nature as dense aggregates of intermediate filaments can stain in a false positive fashion. It seems most likely that the vimentin and CD-10 positivity by the invading tumor cells is a function of their poor differentiation.
Funding sources None.
Conflict of interest Fig. 4. Scanning electron microscopy images of an intracytoplasmic inclusion. A high power (110,000×) image demonstrates intermediate filaments.
There are no conflicts of interest for the author and this information has not been previously presented.
A.S. Boyd, L.E. King Jr. / Pathology – Research and Practice 209 (2013) 260–263
Acknowledgments The electron microscopic images in this paper were kindly provided by James B. Atkinson, M.D., Professor, Department of Pathology, Vanderbilt University Medical Center. The authors wish to thank Denise Buntin, M.D. for her assistance with this patient and manuscript.
References [1] M. Borst, Ueber die moglichkeit ciner ausgedchenten intraepidermalen verbreitung des hatkrebses, Verh. Dtsch. Pathol. Ges. 7 (1904) 118–123.
263
[2] J. Jadassohn, Demonstration von selterneren hautepitheliomen, Bruns Beitr. Klin. Chir. 136 (1926) 345–358. [3] H. Montgomery, Superficial epitheliomatosis, Arch. Dermatol. 20 (1929) 338–357. [4] C. Steffen, A.B. Ackerman, Intraepidermal epithelioma of Borst–Jadassohn, Am. J. Dermatopathol. 7 (1985) 5–24. [5] D.S. Cassarino, D.P. DeRienzo, R.J. Barr, Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification. Part one, J. Cutan. Pathol. 33 (2006) 191–206. [6] S. Ikegawa, T. Saida, Y. Takizawa, Y. Tokuda, T. Ito, F. Fujioka, et al., Vimentinpositive squamous cell carcinoma arising in a burn scar, Arch. Dermatol. 125 (1989) 1672–1676. [7] M.R. Wick, V.N. Kaye, The role of diagnostic immunohistochemistry in dermatology, Semin. Dermatol. 5 (1986) 346–358. [8] P.V. Iyer, A.S.Y. Leong, Poorly differentiated squamous cell carcinomas of the skin can expression vimentin, J. Cutan. Pathol. 19 (1992) 34–39.
Contents lists available at SciVerse ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.com/locate/prp
Teaching cases
Poorly differentiated squamous cell carcinoma arising from an intraepidermal epithelioma Alan S. Boyd a,b,∗ , Lloyd E. King Jr. a a b
Department of Medicine (Dermatology), Vanderbilt University, Nashville, TN, United States Department of Pathology, Vanderbilt University, Nashville, TN, United States
a r t i c l e
i n f o
Article history: Received 31 October 2012 Received in revised form 16 January 2013 Accepted 28 January 2013 Keywords: Intraepidermal epithelioma Squamous cell carcinoma Seborrheic keratosis Vimentin
a b s t r a c t The intraepidermal epithelioma (of Borst–Jadasson) constitutes a much discussed and debated entity. Currently, this diagnosis is rarely made in part, as ascribing clinical features to such lesions has, to date, proven difficult. In addition, intraepidermal proliferation of atypical cells with clonal features is more likely diagnosed as squamous cell carcinomas in situ, porocarcinomas or inflamed seborrheic keratoses. However, cutaneous tumors exhibiting microscopic and immunohistochemical features of clonally profligate malignant basaloid cells solely of epidermal origin do rarely exist. Their progression to dermal invasion appears even more uncommon. © 2013 Elsevier GmbH. All rights reserved.
Introduction
Clinical history
In 1904, Borst described a squamous cell carcinoma of the lip with nests of similar, and presumed malignant, cells in the adjacent epidermis [1]. Twenty-two years later, Jadasson reported what he believed was a basal cell carcinoma restricted to the epidermis and without dermal invasion [2]. Montgomery, in 1929 coined the term “intraepithelial epithelioma of Borst and Jadassohn”, believing it represented a malignant lesion [3]. In 1985, Steffen and Ackerman published an exhaustive treatise on the subject, opined that many of the lesions previously described represented irritated seborrheic keratoses and suggested that the term “intraepidermal epithelioma” be avoided [4]. Most recently, in a review of cutaneous squamous cell carcinoma, Cassarino et al. wrote “there appears to be a subset of cases which represent ‘true IEEs’ which should be referred to as IEE of Jadassohn” [5]. Little support exists for the term “intraepidermal epithelioma” (IEE) in part due to the difficulty in ascribing distinct clinical features to the lesion. Given the clonal appearance and atypia appreciated microscopically, these neoplasms are likely diagnosed and treated as squamous cell carcinomas in situ. Lesions exhibiting an invasive component have only rarely been reported.
In August 2005, a 73-year-old white female presented to her dermatologist complaining of a pruritic lesion on her left hip. Clinically diagnosed as an inflamed seborrheic keratosis, it was frozen with liquid nitrogen. The patient returned a year later, stating the lesion had recurred two months following her initial appointment. A shave biopsy was performed and diagnosed histopathologically as an irritated seborrheic keratosis. In October 2010, the patient presented again, stating the lesion had returned and occasionally bled following trauma from her clothing. Another shave biopsy was performed.
∗ Corresponding author at: 3900, The Vanderbilt Clinic, Nashville, TN 37232, United States. Tel.: +1 615 343 7270; fax: +1 615 343 952. E-mail address: [email protected] (A.S. Boyd). 0344-0338/$ – see front matter © 2013 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.prp.2013.01.011
Histopathological findings The initial biopsy demonstrated an acanthotic and hyperkeratotic epidermal tumor containing aggregates of basaloid cells proliferating in a clonal pattern (Fig. 1A). These basaloid cells exhibited crowding, nuclear atypia and, focally, clear cell features (Fig. 1B). Mitotic figures and apoptotic keratinocytes were also noted. Staining with pancytokeratin (AE1/AE3) illustrated the pattern of clonal proliferation with the basaloid cells exhibiting less uptake than the surrounding epidermis (Fig. 1C). A minichromosome maintenance protein 2 (MMP 2) stain was taken up preferentially by the basaloid cells (Fig. 1D). Rare aggregates of basaloid cells were vimentin and CD10 positive. Staining for carcinoembryonic antigen (CEA) was negative. The second biopsy exhibited an epidermis with similar features overlying dermal invasion by epithelioid cells (Fig. 2A). These epithelioid cells were large with bizarre nuclei, multiple nucleoli
A.S. Boyd, L.E. King Jr. / Pathology – Research and Practice 209 (2013) 260–263
261
Fig. 1. Histologic features of the lesion biopsied in 2005. (A) Low power view demonstrating hyperkeratosis, papillomatosis and an intraepidermal clonal proliferation of basaloid cells (hematoxylin and eosin 40×). (B) Intermediate power view of the clonal cells with focal clear cell features, atypia and mitotic figures (hematoxylin and eosin 200×). (C) Pancytokeratin (AE1/AE3) immunohistochemical staining exhibiting a biphasic pattern of antigen expression (80×). (D) Minichromosome maintenance protein 2 (MMP 2) immunohistochemical stain highlighting the proliferative index of the basaloid cells (80×).
and varying amounts of vacuolated cytoplasm (Fig. 2B). Many also displayed homogenous, eosinophilic intracytoplasmic inclusions often impinging on nuclei. Mitotic figures, including atypical forms, were readily apparent along with focal areas of cell dyscohesion suggestive of evolving acantholysis. Formation of squamous pearls was not appreciated. The intradermal epithelioid cells were strongly cytokeratin 5/6 (Fig. 3A), Cam 5.2 and vimentin (Fig. 3B) positive and modestly pancytokeratin, cytokeratin 903, neuron specific enolase and CD10 positive. Each of these stains readily highlighted the intracytoplasmic inclusions. Mart-1, S-100, synaptophysin, Ber-EP4, cytokeratin 20, CEA, actin, epithelial membrane antigen and cytokeratin 7 stains were negative. Scanning electron microscopy was performed and revealed large paranuclear aggregates of filamentous material consistent with intermediate filaments (Fig. 4). Discussion
Fig. 2. Histologic features of the lesion biopsied in 2010. (A) Low power view demonstrating a similar clonal pattern of epidermal proliferation with dermal invasion of epithelioid cells (hematoxylin and eosin 20×). (B) High power view of the epithelioid cells exhibiting bizarre nuclei, mitotic figures, vacuolated cytoplasm and eosinophilic intracytoplasmic inclusions (hematoxylin and eosin 400×).
According to Steffen and Ackerman, cutaneous neoplasms exhibiting “atypical” cells of epithelial lineage include irritated seborrheic keratoses, solar keratoses, squamous cell carcinoma in situ (Bowen’s disease), mammary and extramammary Paget’s disease and epidermotropic carcinomas but not malignant hidroacanthoma simplex or eccrine porocarcinoma [4]. The lesion presented in this paper does not conform to any of these entities given its obvious atypia, clonal pattern of proliferation and immunohistochemical staining pattern. Moreover, its malignant nature is attested to by its invasive characteristics and proliferative index. Irritated or inflamed seborrheic keratoses may exhibit clonal proliferation similar to our lesion but would not be expected to demonstrate the pattern of pancytokeratin expression, this degree of basophilia or MMP 2 uptake nor this much cytologic atypia. It would be very unusual for solar or actinic keratoses to arise at this anatomic site. Moreover, these neoplasms are rarely acanthotic to this degree and do not demonstrate widespread clonal proliferative features or basaloid staining. The malignant cells of mammary and
262
A.S. Boyd, L.E. King Jr. / Pathology – Research and Practice 209 (2013) 260–263
Fig. 5. Vimentin stain of the epidermis above the area of dermal invasion (100×).
Fig. 3. Special staining features of the lesion biopsied in 2005. (A) Cytokeratin 5/6 (400×) and (B) vimentin (400×) are strongly expressed by the invading epithelioid cells. Note the strong staining of the intracytoplasmic inclusions.
extramammary Paget’s disease can be somewhat basaloid, usually secondary to mucin production but are rarely, if ever, well demarcated enough to impart a clonal appearance. These cells would also be expected to be strongly cytokeratin 7 and EMA positive. Metastatic deposits with epidermotropic features can demonstrate the clonal pattern observed in our patient’s lesion; however, there is usually a history of a malignancy and almost invariably the presence of additional tumor in the underlying dermis. Malignant hidroacanthoma simplex would be expected to exhibit evidence of ductal differentiation which would be highlighted with a CEA stain.
The closest mimic of our patient’s tumor is that of Bowen’s disease which, in the case of her 2nd biopsy, had become invasive. Bowen’s disease typically demonstrates full thickness epidermal atypia and although they may display clonal proliferation it is rarely, if ever, to the degree noted in these biopsies. In addition, some degree of pagetoid spread by malignant keratinocytes is often noted, features not exhibited by our patient’s tumors. The immunohistochemical profile and staining pattern of our patient’s lesion was unusual, notably that invading tumor cells were both CD-10 and vimentin positive. Moreover, intraepidermal basaloid cells were vimentin negative except in nests above the areas of dermal invasion (Fig. 5). Co-expression of cytokeratin and vimentin has been reported in other tumors including renal, thyroid and lung adenocarcinoma and may reflect a reversion of the tumor to a more embryonic phenotype [6]. Ikegawa et al. reported 2 patients with a squamous cell carcinoma arising in burn scars which were both cytokeratin and vimentin positive [6]. Tumor cells exhibited acantholysis with highly atypical mitotic figures and horn pearls. Although prolonged fixation in formalin has been posited as capable of altering cytokeratin peptides such that they become cross reactive for vimentin [7], the authors suggested that the loss of the cells’ three dimensional histologic architecture may have been responsible. Iyer and Leong evaluated 30 cases of poorly differentiated cutaneous squamous cell carcinoma, noting that 12 were vimentin positive [8]. Two of these cases were acantholytic and exhibited perinuclear vimentin staining. They hypothesized that as vimentin is often expressed by metastatic carcinomas in serous cavities, the reduced cell to cell contact may be responsible for the acquisition of vimentin positivity and reflective of epithelial cells with a propensity to survive independently. It should be noted, however, that the immunohistochemical stains taken up by the intracytoplasmic inclusions may be artifactual in nature as dense aggregates of intermediate filaments can stain in a false positive fashion. It seems most likely that the vimentin and CD-10 positivity by the invading tumor cells is a function of their poor differentiation.
Funding sources None.
Conflict of interest Fig. 4. Scanning electron microscopy images of an intracytoplasmic inclusion. A high power (110,000×) image demonstrates intermediate filaments.
There are no conflicts of interest for the author and this information has not been previously presented.
A.S. Boyd, L.E. King Jr. / Pathology – Research and Practice 209 (2013) 260–263
Acknowledgments The electron microscopic images in this paper were kindly provided by James B. Atkinson, M.D., Professor, Department of Pathology, Vanderbilt University Medical Center. The authors wish to thank Denise Buntin, M.D. for her assistance with this patient and manuscript.
References [1] M. Borst, Ueber die moglichkeit ciner ausgedchenten intraepidermalen verbreitung des hatkrebses, Verh. Dtsch. Pathol. Ges. 7 (1904) 118–123.
263
[2] J. Jadassohn, Demonstration von selterneren hautepitheliomen, Bruns Beitr. Klin. Chir. 136 (1926) 345–358. [3] H. Montgomery, Superficial epitheliomatosis, Arch. Dermatol. 20 (1929) 338–357. [4] C. Steffen, A.B. Ackerman, Intraepidermal epithelioma of Borst–Jadassohn, Am. J. Dermatopathol. 7 (1985) 5–24. [5] D.S. Cassarino, D.P. DeRienzo, R.J. Barr, Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification. Part one, J. Cutan. Pathol. 33 (2006) 191–206. [6] S. Ikegawa, T. Saida, Y. Takizawa, Y. Tokuda, T. Ito, F. Fujioka, et al., Vimentinpositive squamous cell carcinoma arising in a burn scar, Arch. Dermatol. 125 (1989) 1672–1676. [7] M.R. Wick, V.N. Kaye, The role of diagnostic immunohistochemistry in dermatology, Semin. Dermatol. 5 (1986) 346–358. [8] P.V. Iyer, A.S.Y. Leong, Poorly differentiated squamous cell carcinomas of the skin can expression vimentin, J. Cutan. Pathol. 19 (1992) 34–39.