Histopathology 2015, 67, 404–409. DOI: 10.1111/his.12656

SHORT REPORT

Pseudoepitheliomatous hyperplasia mimicking invasive squamous cell carcinoma in extranodal natural killer/T-cell lymphoma: a report of 34 cases Yi-Hong Ling,1,2,† Chong-Mei Zhu,1,2,† Shi-Hong Wen,3 Rong-Zhen Luo,1,2 Peng Li,1,2 Yun Cao,1,2 Hui-Lan Rao,1,2 Su-Xia Lin1,2 & Mu-Yan Cai1,2 1

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China, 2Department of Pathology, Sun Yat-sen University Cancer Centre, Guangzhou, China, and 3Department of Anaesthesiology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China Date of submission 2 October 2014 Accepted for publication 19 January 2015 Published online Article Accepted 25 January 2015

Ling Y-H, Zhu C-M, Wen S-H, Luo R-Z, Li P, Cao Y, Rao H-L, Lin S-X & Cai M-Y (2015) Histopathology 67, 404–409. DOI: 10.1111/his.12656

Pseudoepitheliomatous hyperplasia mimicking invasive squamous cell carcinoma in extranodal natural killer/T-cell lymphoma: a report of 34 cases Aims: Pseudoepitheliomatous hyperplasia (PEH) is defined as a pattern of epidermal reaction. However, it has not yet been extensively documented in extranodal natural killer/T-cell lymphoma (ENKTL). The aim of our study was to analyse a series of ENKTLs concomitant with PEH mimicking squamous cell carcinoma (SCC). Methods and results: We analysed 34 cases of ENKTL with PEH. In our study, the incidence of PEH was 3.8% in ENKTLs diagnosed over a 13-year period. All 34 cases presented with PEH, appearing as tongue-like projections of squamous epithelium into the underlying submucosa/dermis with variable depths and jagged

borders. The keratinocytes sometimes showed a minor degree of cytological atypia, mostly in the stratum basale, and keratinocyte necrosis was absent. Atypical mitoses and a high nuclear/cytoplasmic ratio were absent. The submucosa and the squamous cell cords were also permeated by atypical lymphocytes. Conclusions: ENKTL can be associated with PEH, and the atypical lymphoid cell population can be highly subtle, and therefore may be easily mistaken for SCC, leading to inappropriate therapy. A correct diagnosis requires awareness and recognition of this pitfall by recognizing the associated conditions listed above, which distinguish PEH from SCC.

Keywords: extranodal natural killer/T-cell lymphoma, histopathology, pseudoepitheliomatous hyperplasia

Introduction Pseudoepitheliomatous hyperplasia (PEH) is a reactive epithelial proliferation, most commonly involving the

Address for correspondence: M-Y Cai or S-X Lin, Department of Pathology, Sun Yat-sen University Cancer Centre, No. 651, Dongfeng Road East, 510060 Guangzhou, China. e-mails: [email protected] or [email protected] † Y.H.L and C.-M.Z contributed equally to this work. © 2015 John Wiley & Sons Ltd.

mucous membranes or skin, and is typically observed in association with prolonged inflammation, chronic infection, and traumatic and/or neoplastic conditions.1–3 It is characterized by prominent irregular hyperplasia of the epithelium with tongue-like epithelial projections into the dermis, a finding otherwise named ‘pseudoinvasion’.3 Because of its resemblance to invasive well-differentiated squamous cell carcinoma (SCC), distinguishing between PEH and SCC is one of the most frequently encountered diagnostic

Pseudoepitheliomatous hyperplasia in ENKTL

dilemmas in histopathology, especially in superficial biopsies.4,5 Moreover, because the misinterpretation occurs frequently, the distinction is pivotal to avoid extensive and inappropriate therapy in clinical scenarios.6,7 Additionally, there is an increasing association of PEH with lymphomas such as extranodal natural killer (NK)/T-cell lymphoma (ENKTL), CD30-positive anaplastic large-cell lymphoma, and mycosis fungoides (MF).8–14 However, PEH is not well defined, and is widely recognized as a diagnostic pitfall in mainstream pathology textbooks, especially in instances of ENKTL.12–14 The nasal type of ENKTL is a clinical entity characterized by a unique immunophenotype and a strong association with Epstein–Barr virus (EBV).12–14 It is to be noted that the epidermis or squamous epithelial mucosa may show PEH mimicking SCC in some cases. To date, this particular feature has been poorly documented, and only scattered cases have been reported in ENKTL.12–14 In this study, we present 34 cases of ENKTL concomitant with PEH, and explore the clinicopathological findings that are helpful in distinguishing between PEH and SCC.

Methods The inclusion criteria for this study were: (i) a diagnosis of ENKTL established by the pathologists according to the World Health Organization classification of tumours;15 and (ii) the presence of PEH of the epidermis overlying the lyphomatous infiltrate, mimicking a well-differentiated SCC. Thirty-four cases of ENKTL with PEH were collected from 2001 to 2014. After the biopsy tissue had been sent to the department of pathology, haematoxylin and eosin staining, immunohistochemical staining and in-situ hybridization for EBV-encoded RNA (EBER) were performed to yield a correct diagnosis (Data S1). The Institute Research Medical Ethics Committee of Sun Yat-sen University Cancer Centre granted approval for this study.

Results

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female ratio was 2.1:1. Most lesions were located in the midline region (67.6% in the nasal cavity, 14.7% in the nasopharynx, 11.7% in the oral cavity, and 2.9% in the cheek). Also, one case (2.9%) in the left back was evaluated (Table S1). PATHOLOGICAL FINDINGS

Histologically, PEH consisted of elongated thick downward projections of the epidermis, frequently with jagged borders and a sharply pointed base. These epithelial projections represented expansion of the follicular infundibulum with variable depth, often extending to the upper or middle mucosa. There was often hypergranulosis and orthokeratosis or parakeratosis. PEH could also feature concentric layers of visible keratinocytes with a focus of central keratinization, the socalled ‘keratin pearls’. The keratinocytes sometimes showed a minor degree of cytological atypia, mostly in the stratum basale, and keratinocyte necrosis was absent. Atypical mitoses and a high nuclear/cytoplasmic ratio were absent in all cases. PEH was strictly localized over the lymphomatous infiltrate, mimicking well-differentiated SCC with invasive borders, in all cases. The submucosa/dermis and the squamous cell cords were also permeated by atypical lymphocytes. The lymphocytes were composed of medium-sized cells or a mixture of small and large cells, often with irregularly folded nuclei that could appear elongated. The cytoplasm of lymphocytes was moderate in amount and often pale to clear. Mitotic figures were easily found in the lymphocytes. Additionally, all cases showed both prominent necrosis and angiocentricity/ angioinvasion/vascular destruction in lymphocytes (Figure 1). IMMUNOHISTOCHEMICAL STUDIES AND EBER

The hyperplastic epithelium was 100% positive for cytokeratin, and the lymphoid cells infiltrating under the epidermis always expressed leukocyte common antigen (100%), CD3 (94.1%), CD56 (100%), CD57 (100%), TIA1 (100%), granzyme B (100%), and perforin (82.4%), and occasionally expressed CD7 (36.3%) or CD30 (41.2%). On in-situ hybridization, 100% of cases showed the presence of EBV (Figure 1).

CLINICAL CHARACTERISTICS

Eight hundred and eighty-eight cases of ENKTL were diagnosed in our centre from 2001 to 2014. The incidence of ENKTL with PEH was 34 of 888 (3.8%) during this period. The age range was 20–75 years (mean, 42.3 years; median, 39 years). The male/ © 2015 John Wiley & Sons Ltd, Histopathology, 67, 404–409.

Discussion PEH is considered to be a pattern of epidermal reaction.1–3 The incidence rates of PEH reported in CD30positive lymphoproliferative disorders of the skin and

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B

A

C

D

E

F

G

H

I

J

K

L

M

N

O

Figure 1. Histopathological features of extranodal natural killer/T-cell lymphoma (ENKTL) with pseudoepitheliomatous hyperplasia (PEH). A, The morphological findings of ENKTL with PEH. B, PEH in a case of small-cell-type ENKTL. C, Dense perivascular angiocentric proliferation of small to medium-sized pleomorphic lymphoid cells. D, Low-magnification view of ENKTL occupying the entire dermis, with ulcers observable. E, Epidermis showing striking PEH features characterized by prominent irregular hyperplasia of the epithelium with tongue-like epithelial projections into the dermis. Note the dermis and the squamous cell cords permeated by atypical lymphoid cells. F, The lymphoid cells are small to medium in size, surrounding the perivascular space with irregularly folded, angular or serpentine nuclear, fairly dense to granular chromatin. Nucleoli are inconspicuous, and atypical mitoses are usually observed. G, Squamous epithelial islands in close association with coagulative necrosis and nuclear debris, mixed with neoplastic cells. H, Details of neoplastic cells with a diffuse and angiodestructive growth pattern in ENKTL. I, ENKTL with PEH mimicking well-differentiated squamous cell carcinoma with invasive borders. Note the atypical lymphoid cells surrounding the squamous epithelial islands. J–N, Immunohistochemistry showing reactivity for CD3 (J), CD56 (K), TIA-1 (L), granzyme B (M), and perforin (N). O, Neoplastic cells are Epstein–Barr virus-encoded RNA-positive in ENKTL cases by in-situ hybridization.

MF are 28.5% and 2%, respectively.8 Our study analysed 34 cases of ENKTL with PEH. The incidence of PEH was 3.8% in the cases of ENKTL diagnosed in

our centre. ENKTL with PEH shows a wide age distribution (20–75 years), and an overall male predominance, with a male/female ratio of 2.1:1; almost all © 2015 John Wiley & Sons Ltd, Histopathology, 67, 404–409.

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Table 1. The characteristics differentiating extranodal natural killer/T-cell lymphoma with pseudoepitheliomatous hyperplasia (PEH) from squamous cell carcinoma (SCC) Features

PEH

SCC

Location

Usually in the midline, most commonly in the nasal cavity

No specific location

Association with other conditions

Common; often secondary to inflammation, chronic infection, and traumatic and/or neoplastic processes

Variable

Peripheral border of epithelium

Jagged with sharply pointed base; appearing as tongue-like projections of squamous epithelium into the underlying submucosa

Irregularly shaped and/or epithelial islands, often with surrounding dermal fibrosis

Keratin pearl formation

Occasional

Common

Cytological atypia

Minimal; usually located in the basal layer

Variable; nuclear crowding, high nuclear/ cytoplasmic ratio, and prominent nuclear pleomorphism

Mitotic activity

Rare; not atypical; usually in the basal layer

Common; atypical mitoses at any level of the epithelium

Accompanying prominent necrosis

Common

Variable

Angiocentricity/angioinvasion/ vascular destruction, and perineural invasion

Common

Variable

cases originated in the midline region (especially in the nasal cavity). All 34 cases presented with PEH, appearing as tongue-like projections of squamous epithelium into the submucosa with variable depth and jagged borders. As PEH masquerades as invasive SCC, and the atypical lymphoid populations may be inconspicuous, it is important to make a differential diagnosis of PEH from SCC, with which it is often confused.6,7 Histopathologically, several features may help to distinguish ENKTL with PEH from SCC. Generally, the cytological features, including nuclear crowding, prominent nuclear pleomorphism, numerous atypical mitotic figures, and dyskeratosis, favour the diagnosis of SCC, whereas the hyperplastic cells in PEH fail to show the cytological signs of malignancy, although they may show reactive atypia. Additionally, PEH usually presents with expanded follicular infundibulate and broad rete ridges.2,3 Furthermore, the associations with conditions involving infection, inflammatory processes, trauma and malignancy point more towards PEH.1–3 Hence, when PEH occurs secondarily to a neoplasm, the diagnosis is generally explicit, given that one recognizes such an association when dealing with a biopsy © 2015 John Wiley & Sons Ltd, Histopathology, 67, 404–409.

specimen that is adequate in terms of representing both lesions, as exemplified by the well-recognized association of granular cell tumours with exuberant PEH.16,17 Also, PEH occurring in the context of ENKTL poses unique challenges, and some focal points should be noted to differentiate it from SCC. First, ENKTL is always found in the midline, whereas there is no specific location for SCC. Second, it is not difficult to recognize the dense proliferation of neoplastic cells in prototypical ENKTL. Nevertheless, in cases where the number of lymphocytes can be very scant and overshadowed by the epidermal proliferation, the angiodestructive growth pattern of lymphoid cells and the accompanying coagulative necrosis are two additional important histopathological clues. When these have been found, intensive clinical information should be sought and more ancillary tests may be requested. Third, to the best of our knowledge, ENKTL arises as a consequence of the malignant transformation of NK and/or T cells expressing the neural cell adhesion molecule (CD56) and cytotoxic molecules such as TIA-1, granzyme B, and perforin.18,19 Additionally, ENKTL is associated with EBV infection.18–20 Thus, immunohistochemical staining and EBER are helpful in making the diagnosis

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of ENKTL with PEH when it is not easy to distinguish it from SCC solely on the basis of histopathology. As yet, the exact mechanisms of PEH are still uncertain. Previous studies have indicated that cytokines produced by T cells, including interferon-c (IFN-c), transforming growth factor-a, and epidermal growth factor receptor and its ligand epidermal growth factor, may induce squamous differentiation in the epidermal keratinocytes, thus leading to PEH.21–23 It has also been suggested that IFN-c could be associated with cell invasion in ENKTL.24 It is assumed that IFN-c produced by lymphoma cells might promote squamous differentiation and subsequently induce PEH.14 Nevertheless, much remains to be done to elucidate the pathogenesis of PEH in ENKTL. In summary, ENKTL can be associated with PEH, and the atypical lymphoid cell population can be very subtle, and may therefore be easily mistaken for invasive SCC, leading to inappropriate therapy. To reach a correct diagnosis, awareness and recognition of this pitfall by recognizing the above associated conditions distinguishing PEH from SCC (Table 1) is crucial.

Acknowledgements This study was supported by grants from the Nature Science Foundation of China (No. 81302139) and the Programme for Excellent Young Talents in Sun Yatsen University Cancer Centre (No. 520101210101).

Author contributions Y. H. Ling, C. M. Zhu and S. H. Wen performed the research. S. X. Lin and M. Y. Cai designed the research study. R. Z. Luo and H. L. Rao contributed essential reagents and tools. P. Li and Y. Cao analysed the data. Y. H. Ling and M. Y. Cai edited the manuscript. All of the authors approved the final version of the manuscript.

Conflict of interest The authors state that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

References 1. Fu X, Jiang D, Chen W, Sun Bs T, Sheng Z. Pseudoepitheliomatous hyperplasia formation after skin injury. Wound Repair Regen. 2007; 15; 39–46. 2. Zayour M, Lazova R. Pseudoepitheliomatous hyperplasia: a review. Am. J. Dermatopathol. 2011; 33; 112–122.

3. El-Khoury J, Kibbi AG, Abbas O. Mucocutaneous pseudoepitheliomatous hyperplasia: a review. Am. J. Dermatopathol. 2012; 34; 165–175. 4. Grunwald MH, Lee JY, Ackerman AB. Pseudocarcinomatous hyperplasia. Am. J. Dermatopathol. 1988; 10; 95–103. 5. Zarovnaya E, Black C. Distinguishing pseudoepitheliomatous hyperplasia from squamous cell carcinoma in mucosal biopsy specimens from the head and neck. Arch. Pathol. Lab. Med. 2005; 129; 1032–1036. 6. Kamino H, Tam ST, Alvarez L. Malignant melanoma with pseudocarcinomatous hyperplasia—an entity that can simulate squamous cell carcinoma. A light-microscopic and immunohistochemical study of four cases. Am. J. Dermatopathol. 1990; 12; 446–451. 7. Reis-Filho JS, Gasparetto EL, Schmitt FC, Fillus-Neto J. Pseudoepitheliomatous hyperplasia in cutaneous malignant melanoma: a rare and misleading feature. J. Cutan. Pathol. 2001; 28; 496–497. 8. Courville P, Wechsler J, Thomine E et al. Pseudoepitheliomatous hyperplasia in cutaneous T-cell lymphoma. A clinical, histopathological and immunohistochemical study with particular interest in epithelial growth factor expression. The French Study Group on Cutaneous Lymphoma. Br. J. Dermatol. 1999; 140; 421–426. 9. Zayour M, Gilmore E, Heald P, Rose M, Poligone B, Lazova R. A distinct entity in the spectrum of the CD30 + cutaneous lymphoproliferative diseases: oligolesional nodules with pseudoepitheliomatous hyperplasia followed by spontaneous resolution. Am. J. Dermatopathol. 2009; 31; 37–43. 10. Biswas A, Gey van Pittius D, Stephens M, Smith AG. Recurrent primary cutaneous lymphoma with florid pseudoepitheliomatous hyperplasia masquerading as squamous cell carcinoma. Histopathology 2008; 52; 755–758. 11. Price NM, Fuks ZY, Hoffman TE. Hyperkeratotic and verrucous features of mycosis fungoides. Arch. Dermatol. 1977; 113; 57– 60. 12. Kuo TT, Shih LY, Tsang NM. Nasal NK/T cell lymphoma in Taiwan: a clinicopathologic study of 22 cases, with analysis of histologic subtypes, Epstein-Barr virus LMP-1 gene association, and treatment modalities. Int. J. Surg. Pathol. 2004; 12; 375– 387. 13. Valiathan M, Rao RV, Rao L, Jaffe ES, Pillai S. Nasal NK/T cell lymphoma mimicking a squamous cell carcinoma: a case report. Indian J. Pathol. Microbiol. 2005; 48; 257–259. 14. Nonomura Y, Otsuka A, Endo Y et al. Extranodal NK/T-cell lymphoma, nasal type, presenting pseudoepitheliomatous hyperplasia mimicking squamous cell carcinoma. Eur. J. Dermatol. 2012; 22; 688–689. 15. Swerdlow SH, Campo E, Harris NL et al. eds. World Health Organization classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC Press, 2008. 16. Torrijos-Aguilar A, Alegre-de Miquel V, Pitarch-Bort G, Mercader-Garcia P, Fortea-Baixauli JM. Cutaneous granular cell tumor: a clinical and pathologic analysis of 34 cases. Actas Dermosifiliogr 2009; 100; 126–132. 17. Desimone RA, Ginter PS, Chen YT. Granular cell tumor of the breast eliciting exuberant pseudoepitheliomatous hyperplasia. Int. J. Surg. Pathol. 2014; 22; m156–m157. 18. Nava VE, Jaffe ES. The pathology of NK-cell lymphomas and leukemias. Adv. Anat. Pathol. 2005; 12; 27–34. 19. Kohrt H, Advani R. Extranodal natural killer/T-cell lymphoma: current concepts in biology and treatment. Leuk. Lymphoma 2009; 50; 1773–1784. © 2015 John Wiley & Sons Ltd, Histopathology, 67, 404–409.

Pseudoepitheliomatous hyperplasia in ENKTL

20. Li X, Babayi A, Sang W et al. Clinicopathologic, immunophenotypic, and EBER in situ hybridization study of extranodal natural killer/T-cell lymphoma, nasal type in multi-ethnic groups. Clin. Lab. 2014; 60; 419–425. 21. Mott RT, Rosenberg A, Livingston S, Morgan MB. Melanoma associated with pseudoepitheliomatous hyperplasia: a case series and investigation into the role of epidermal growth factor receptor. J. Cutan. Pathol. 2002; 29; 490–497. 22. Barkan GA, Paulino AF. Are epidermal growth factor and transforming growth factor responsible for pseudoepitheliomatous hyperplasia associated with granular cell tumors? Ann. Diagn. Pathol. 2003; 7; 73–77. 23. Akilov OE, Donovan MJ, Stepinac T et al. T helper type 1 cytokines and keratinocyte growth factor play a critical role in pseudoepitheliomatous hyperplasia initiation during cutaneous leishmaniasis. Arch. Dermatol. Res. 2007; 299; 315–325.

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24. Moriai S, Takahara M, Ogino T et al. Production of interferon{gamma}-inducible protein-10 and its role as an autocrine invasion factor in nasal natural killer/T-cell lymphoma cells. Clin. Cancer Res. 2009; 15; 6771–6779.

Supporting Information Additional Supporting Information may be found in the online version of this article: Data S1. Supplementary methods. Table S1. The clinical characteristics of pseudoepitheliomatous hyperplasia in extranodal NK/T-cell lymphoma.