The Histologic Diagnosis of Intraepithelial Pagetoid Neoplasm JAMES

E. FITZPATRICK,

MD, LTC, MC

T

‘he histologic differential diagnosis of entities characterized by large, pale-staining cells scattered throughout the epidermis most comA monly includes Paget’s disease (mammary and extramammary), squamous cell carcinoma in-situ (Bowen’s disease), and melanoma in-situ. Paget’s disease is the cytologic and architectural prototype for this “pagetoid” pattern. Entities that less commonly demonstrate this histologic pagetoid pattern include sebaceous gland carcinoma, pagetoid dyskeratosis, epidermotropic metastatic carcinomas, pagetoid reticulosis, mycosis fungoides, trabecular cell carcinoma, clonal seborrheic keratosis, and hidroacanthoma simplex. In many cases these entities can be differentiated on clinical and histologic grounds using routine hematoxylin and eosin stains. Difficult cases can sometimes be differentiated using histochemical stains to demonstrate the presence or absence of cellular products such as melanin or sialomucin. However, these histochemical stains are often inconclusive or difficult to interpret in difficult cases. The advent of the immunoperoxidase technique has provided a diagnostic tool that is both more sensitive and specific than standard histochemical stains in differentiating this group of intraepithelial neoplasms. Immunohistochemistry has also resolved the nature and histogenesis of the Paget’s cell, a point of controversy since its description. This review will focus on the histologic, histochemical, and immunoperoxidase evaluation of difficult

From the Dermatology Service, Department of Medicine, Fitzsimons Army Medical Center, Aurora, Colorado. The opinions or assertions contained herein are the views of the authors and are not to be considered as reflecting the views of the Department of the Army or the Department of Defense. Address correspondence to:James E. Fitzpatrick, M.D., LTC, MC, Dermatology Service, Fifzsimons Army Medical Center, Aurora, CO 80045.

0 1991 by Elsevier Science Publishing

Co., Inc.

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intraepithelial tumors growth pattern.

that

demonstrate

a pagetoid

Paget’s Disease Paget’s disease may occur in either a mammary or extramammary location. Because recent studies have linked both forms of the disease to a common cell phenotype’** and the lesions are histologically identical, they will be discussed together. Clinically, Paget’s disease is characterized by sharply defined, erythematous to brown plaques that demonstrate variable scaling, oozing, and ulceration. Mammary Paget’s disease usually occurs in females but rare cases have been reported in males. The lesions are typically unilateral and involve the nipple, with variable extension to the areola or surrounding skin. Mammary Paget’s disease is associated with underlying ductal carcinoma that can be palpated in approximately one-half of all cases. Extramammary Paget’s disease most commonly occurs on skin characterized by a high density of apocrine glands. The most common reported site is the anogenital region, with occasional cases involving the axilla, external ear canal, and eyelid. The reported incidence of extramammary Paget’s disease associated with an underlying cutaneous adnexal adenocarcinoma is 24%.3 The nature and histogenesis of the Paget’s cell have been controversial until the advent of immunoperoxidase techniques. Most authorities favored an apocrine origin because of the association of this tumor with areas of high apocrine gland concentration or modified apocrine glands such as the breast. Histologically, the presence of sialomucin and glandular formation within some lesions provided further support for this hypothesis. Other authors have suggested that the Paget’s cell may arise from keratinocytes, melanocytes, pluripotential germinative epidermal cells, or eccrine gland sweat cells.’ Recent im-

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munoperoxidase studies demonstrating positivity to carcinoembryonic antigen (CEA),2,4*5*6,7gross cystic disease fluid protein-15 (GCDFP-15),2,6 epithelial membrane antigen (EMA),2*7 and cytokeratins typical of glandular epithelia,*~2~4~8~9 combined with negative reactions to epidermal keratins8p9 clearly favor an apocrine origin. Examination of Paget’s disease stained with hematoxylin and eosin demonstrates an intraepithelial proliferation of large, round cells with atypical nuclei that are usually larger than the nuclei of adjacent keratinocytes. The cytoplasm is abundant, translucent to lightly eosinophilic, and devoid of intracellular bridges. Paget’s cells typically demonstrate a random distribution throughout the epidermis and often demonstrate extension into hair follicles and sweat gland ducts. An important histologic pattern is the tendency for Paget’s cells to proliferate in the spiny layer and compress underlying basal keratinocytes (Plates 6 and 7). In many cases of mammary Paget’s disease and some cases of extramammary Paget’s disease an underlying adenocarcinoma may often be demonstrated if the biopsy is deep enough and sufficient sections are available. Histologic variations include gland formation (Plate 6), presence of melanin, and presence of dyskeratotic cells. The latter two findings, while uncommon, may cause confusion with melanoma in-situ and squamous cell carcinoma in-situ, respectively. Paget’s cells often contain sialomucin that is composed of both neutral mucopolysaccharides and acid mucopolysaccharides. Extramammary Paget’s disease more commonly contains demonstrable sialomucin than mammary Paget’s disease; in one study up to 70% of mammary Paget’s disease did not demonstrate significant sialomutin.’ Neutral mucopolysaccharides are best demonstrated by the periodic acid-Schiff (PAS) method with diastase (Plate 8) while acid mucopolysaccharides are best demonstrated with colloidal iron (Plate 9). Alternate acid mucopolysaccharide stains include alcian blue or Mayer’s mucicarmine, which are generally not as sensitive. Immunoperoxidase techniques are more specific than histochemical techniques for differentiating Paget’s disease from other pagetoid lesions. The most commonly used immunohistochemistry stain is CEA, which is directed against a high molecular weight glycoprotein that can be found in normal eccrine and apocrine ductal epithelium. Extramammary Paget’s disease is usually decorated by CEA in 84%‘O- 100%2,6 of biopsies and appears to be an excellent marker (Plate 10). However, in mammary Paget’s disease, positive staining is demonstrated in only 35%* to 7O%‘of cases and thus does not appear to be a sensitive marker. Similar results are obtained with GCDFP-15, which decorates 56% of cases.2 The best immunoperoxidase marker for mammary Paget’s disease is achieved with EMA, which is positive in 90%‘- 1OO%2 of

Clinics in Dermatology 1991:9:255-259 biopsies (Plate 11). It should be noted that while the Paget’s cell is characteristically negative for keratin immunoreactivity,*O in some cases it may stain positive.2 This may reflect differences in technique or type of cytokeratins recognized by the primary antibody.

Squamous Cell Carcinoma In-Situ (Bowen’s Disease, Bowenoid Actinic Keratosis, Erythroplasia of Queyrat) Squamous cell carcinoma in-situ can be defined as fullthickness loss of normal architectural pattern and keratinocyte maturation associated with cytologic atypia. Unfortunately, different terms are used under different circumstances. Bowen’s disease occurs on non-sunexposed skin, bowenoid actinic keratosis occurs on sunexposed skin and usually arises from a preexisting actinic keratosis, and erythroplasia of Queyrat develops on the glans penis and adjacent mucosa. Clinically, all three lesions characteristically present as round to oval erythematous plaques with variable scale and papillomatosis. Superficial erosions are variably present, particularly on the glans penis. Pigmented squamous cell carcinoma in-situ may occur in up to 1.7% of all cases;” this variant may be clinically and histologically confused with melanoma. At low power, squamous cell carcinoma in-situ demonstrates variable acanthosis and papillomatosis and may demonstrate involvement of follicular infundibula. At higher power, the stratum corneum usually demonstrates marked confluent or patchy parakeratosis. Full-thickness loss of normal cell polarity and keratinocyte maturation is the pattern most commonly encountered; however, a pagetoid growth pattern may be present either focally or diffusely. Individual keratinocytes are cytologically atypical, often more so than the cells in either Paget’s disease or malignant melanoma in-situ. The cytoplasm may be either eosinophilic, suggesting keratinization, or appear pale, the latter cell type being almost indistinguishable from the cell of Paget’s disease (Plate 12). Dyskeratotic cells and multinucleated keratinocytes are frequently present and are important histologic features not typically found in Paget’s disease. Pigmented squamous cell carcinoma in-situ may be confused with malignant melanoma in-situ because both may demonstrate melanin within abnormal keratinocytes and in dermal melanophages. The atypical keratinocytes in squamous cell carcinoma in-situ often contain glycogen and stain positive with a PAS, This positivity is removed with diastase digestion because neutral mucopolysaccharides are not present. Acid mucopolysaccharide stains such as colloidal iron, Mayer’s mucicarmine, and alcian blue are invariably negative.

Clinics in Dermatology 2991;9:255- 259 The tumor cells of squamous cell carcinoma in-situ demonstrate keratin immunoreactivity (Plate 13) and are not decorated by CEA, EMA, GCDFP-15, S-100, and HMB-45.5J0

Melanoma In-Situ (Pagetoid Melanoma In-Situ) Melanoma in-situ is not commonly confused clinically with either Paget’s disease or squamous cell carcinoma in-situ. The distribution is different in that the most common locations are the back and legs, The primary lesion is a papule or plaque that is typically pigmented with varying shades of tan, brown, black, grey, white, and pink. Rare cases may be amelanotic and present as scaly, erythematous patches that may cause confusion with other lesions.12 Histologically, melanoma in-situ can also demonstrate a pagetoid growth pattern, as seen in the previously discussed entities. However, there is a pronounced tendency for junctional nesting and an absence of compression of basal keratinocytes by the tumor cells (Plate 14). In general, more cells are present in the bottom half of the epidermis than in the top half. Follicular extension is a common feature. At high power, the nuclei are atypical and are often smaller and more hyperchromatic than either Paget’s disease or squamous cell carcinoma in-situ; however, large vesicular nuclei may also be present. The cytoplasm is characteristically translucent and contains variable amounts of dusty melanin. Dendrites are usually absent, but when present these are a helpful distinguishing feature as neither Paget’s disease or squamous cell carcinoma in-situ show this finding. Melanoma in-situ cells may contain glycogen and stain positive by the PAS method. However, this positivity is removed by prior digestion with diastase because neutral mucopolysaccharides are not present. Similarly, acid mucopolysaccharide stains are negative. Fontana-Masson stain for melanin is typically positive and occasionally useful in documenting the presence of melanin; however, this it is not specific because the cells of both Paget’s disease and squamous cell carcinoma in-situ may contain transferred melanin. An interesting but uncommonly used technique is the presence of formaldehyde-induced fluorescence in 88% of unstained melanomas and the absence of this fluorescence in both Paget’s disease and squamous cell carcinoma in-situ.13 The immunohistochemical marker most commonly used to differentiate melanoma in-situ from other intraepithelial neoplasms is the S-100. Melanoma in-situ is usually decorated in 66%5-100%10 of cases (Plate 15), whereas squamous cell carcinoma in-situ is never positive. Paget’s disease is typically S-100 negative, but up to 26% of mammary Paget’s biopsies may demonstrate posi-

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tivity.2 This finding is not surprising because a similar percentage of ductal carcinomas of the breast are also positive.’ HMB-45 is an alternate monoclonal antibody that decorates melanomas, activated adult melanocytes, and fetal melanocytes, and it does not demonstrate positivity in other intraepithelial neoplasms.*4 Yet another alternative that is rarely used is vimentin, which decorates melanoma cells and mesenchymal tumors, but does not demonstrate positivity in Paget’s disease and squamous cell carcinoma in-situ.15

Miscellaneous Pagetoid Conditions While the previously discussed entities commonly demonstrate a pagetoid growth pattern, other entities may occasionally enter the differential diagnosis. Sebaceous gland carcinoma of the eyelid may present as chronic blepharoconjunctivitis, papillary conjunctivitis, or meibomianitis and even produce cornea1 opacities due to pagetoid growth of tumor cells.r6 Histologically, this neoplasm is easily diagnosed if areas of invasion are present because this tumor demonstrates basaloid aggregates of atypical epithelial cells with variable amounts of cytoplasmic lipid vacuoles that may impinge on and deform the nucleus (Plate 16). Occasionally the biopsy is small and only pagetoid areas may be present. Pagetoid areas demonstrate atypical cells with a random intraepithelial growth pattern and cytoplasmic lipid vacuoles that may be confused with sialomucin. Negative staining for neutral and acid mucopolysaccharides are helpful in excluding sialomucin. The most sensitive and specific histologic feature useful in distinguishing this from other intraepithelial neoplasms is the identification of areas of typical sebaceous gland carcinoma. This can usually be accomplished by serial sectioning or repeat biopsy. Commercially available specific sebaceous gland antibodies are not available, but sebaceous cells are decorated by EMA, which may produce confusion with Paget’s disease. However, sebaceous gland carcinomas are not decorated by CEA or GCDFP-15. Epidermotropic carcinomas can also extend locally from other types of malignancies including gastrointestinal and urethral cancers. Histologically and histochemitally these may be difficult to separate from Paget’s disease. The diagnosis can often be suspected by history and location but definitive diagnosis can only be made by finding the primary malignancy. Pagetoid dyskeratosis is an incidental finding that may be found as a histologic curiosity in apparently normal skin or overlying another primary skin lesion.” This entity is thought to be due to focal abnormal keratinization of benign keratinocytes. Histologically, pagetoid dyskeratosis demonstrates a focal pagetoid growth pattern of

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keratinocytes with cytologically benign nuclei that are often pyknotic and surrounded by a clear halo. Occasionally, the nuclei may be large and resemble the Paget’s cell (Plate 17). The cytoplasm is typically pale but may contain eosinophilic or keratohyaline granules. Pagetoid dyskeratosis can be usually distinguished from intraepithelial neoplasms by the focal nature, pyknotic nuclei, absence of cytological atypia, and tendency to involve the suprabasal portion of the epidermis. All special histochemical and immunohistochemical stains are negative with the exception of strong positive staining with keratin antibodies. Pagetoid reticulosis (Woringer-Kolopp disease), mycosis fungoides, trabecular cell carcinoma, and histiocytosis X also may demonstrate epidermotropism of tumor cells, but they are easily excluded because they do not typically produce large, pale cells resembling the Paget’s cell. Clonal seborrheic keratosis and hidroacanthoma simplex (intraepidermal eccrine poroma) may demonstrate an intraepithelial growth pattern but the cells are arranged in large clones rather than demonstrating the more random single-cell pattern.

Histologic Approach to Biopsies Demonstrating a Pagetoid Pattern Most biopsy specimens demonstrating a pagetoid pattern can be differentiated by history and routine H&E stains. Histologic features that are almost diagnostic of Paget’s disease include compression of basal keratinocytes by tumor cells and gland formation. Atypical pagetoid cells that involve all layers of the epidermis and presence of dyskeratotic cells and multinucleated keratinocytes favor squamous cell carcinoma in-situ. Junctional nesting, melanin, and dendritjc cells strongly suggest melanoma insitu. Ambiguous cases that cannot be diagnosed with H&E should next be examined with special stains. The most useful stains are the PAS stain with and without diastase digestion and an acid mucopolysaccharide stain. In most histology laboratories the colloidal iron is the most sensitive stain; however, either Mayer’s mucicarmine or alcian blue can also be used. The histochemical and immunoperoxidase markers most useful in distinguishing this groups of neoplasms are summarized in Table 1. Immunoperoxidase technique is the most specific and sensitive diagnostic method, but the relatively high cost prohibits its use in routine cases. Additional disadvantages include the fact that local availability may be limited for some dermatologists and some histology laboratories produce inconsistent results because of technical difficulties associated with the procedure. The most commonly used and available antibodies include CEA for Paget’s

Table 1. lmmunohistochemistry Stain l’AS/diastase (neutral MI’S) Colloidal iron (acid MPS) Fontana-Masson (melanin) Antibody CEA GCDFP-15 EMA Keratin s-100 HMB-45 Vimentin l

Occasionally

of Paxetoid Lesions see In-situ

Melanoma In-situ

variable variable variable

negative negative variable

negative negative Dositive

variable variable positive variable negative* negative negative

negative negative negative positive negative negative negative

negative negative negative negative positive positive positive

Paget’s Disease

1

positive in mammary Paget’s disease.

disease, keratin for squamous cell carcinoma, and S-100 for melanoma. Unusual or borderline cases may require staining with EMA, GCDFP-15, HMB-45, or vimentin antibodies. It should be emphasized that even immunoperoxidase technique may produce weak or negative results and rare cases may require clinicopathologic correlation, electron microscopy, or repeat biopsies before the correct diagnosis can be rendered.

Acknowledgment The author would like to acknowledgeJohn DeSpain, M.D. the case material for Figures 2, 3, 5, 6, 7, and 8.

for providing

References 1. Nagle RB, Lucas DO, McDaniel KM, et al. Paget’s Cells: New evidence linking mammary and extramammary Paget cells to a common cell phenotype. Am J Clin Path01 1985;83:431-38. 2. Guarner J, Cohen C, DeRose PB. Histogenesis of extramammary and mammary Paget cells: An immunohistochemica1 study. Am J Dermatopathol 1989;11:313-18. 3. Chanda JJ. Extramammary Paget’s disease: Prognosis and relationship to internal malignancy. J Am Acad Dermatol 1985;13:1009-14, 1985. 4. Hamm H, Vroom TM, Czarnetski BM. Extramammary Paget’s cells: Further evidence of sweat gland derivation. J Am Acad Dermatol 1986;15:1275-81. 5. Guldhammer B, Norgarrd T. The differential diagnosis of intraepidermal malignant lesions using immunohistochemistry. Am J Dermatopathol 1986;8:295 - 301. 6. Mazougian G, Pinkus GS, Haagensen

DE, Jr. Extramam-

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PAGETOID NEOPLASMS

Bowen’s disease and review of 420 Bowen’s disease lesions. J Dermatol Surg Oncol 1988;14:765-69.

mary Paget’s disease-Evidence for an apocrine origin: An immunoperoxidase study of gross cystic disease fluid protein-15, carcinoembryonic antigen, and keratin proteins. Am J Surg Path01 1984;8:43-50.

12. Goldberg DJ. Amelanotic melanoma presenting as Bowen’s disease. J Dermatol Surg Oncol 1983;9:902-04.

7. Wood WS, Hegedus C. Mammary Paget’s disease and intraductal carcinoma. Histologic, histochemical, and immunocytochemical composition. Am J Dermatopathol 1988; 10:183-88.

13. Dalal BI, Slinger RF. Formaldehyde-induced fluorescence in melanomas and other lesions. Diagnostic significance and mechanism of fluorescence. Arch Path01 Lab Med 1985;109:551-54.

8. Kariniemi AL, Ramaekers F, Lehto I’, Vitanen I. Paget cells express cytokeratins typical of glandular epithelia. Br J Dermatol 1985;112:179-83.

14. Smoller BR, McNutt NS, Hsu A. HMB-45 recognizes stimulated melanocytes. J Cutan Path01 1989;16:49-53.

9. Moll I, Moll R. Cells of extramammary Paget’s disease express cytokeratins different from those of epidermal cells. J Invest Dermatol 1985;84:3-8. 10. Rosen L, Amazon K, Frank B. Bowen’s disease, Paget’s disease, and malignant melanoma in-situ. South Med J 1986;79:410-13. 11. Ragi G, Turner MS, Klein LE, St011 HL, Jr. Pigmented

15. Doherty MJ, Russo GG, Jolly HW. Immunoenzyme techniques in dermatopathology. J Am Acad Dermatol 1989;20:827-37. 16. Khalil MK, Lorenzetti DWC. Sebaceous gland carcinoma of the lid. Can J Ophthalmol 1980;15:117-20. 17. Tschen JA, McGavran MH, Kettler AH. Pagetoid dyskeratosis: A selective keratinocyte response. J Am Acad Dermato1 1988;19:891-94.

The histologic diagnosis of intraepithelial Pagetoid neoplasms.

The Histologic Diagnosis of Intraepithelial Pagetoid Neoplasm JAMES E. FITZPATRICK, MD, LTC, MC T ‘he histologic differential diagnosis of entitie...
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