J Cutan Pathol 2015: 42: 194–198 doi: 10.1111/cup.12421 John Wiley & Sons. Printed in Singapore
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Pseudocarcinomatous hyperplasia mimicking squamous cell carcinoma in a case of CD56-positive cytotoxic T-cell lymphoma We present the case of an 84-year-old patient with a cutaneous CD56 positive cytotoxic T-cell lymphoma associated with substantial pseudocarcinomatous hyperplasia mimicking squamous cell carcinoma (SCC). The patient presented with a 7-month history of several progressive, ulcerated plaques on his right forearm. An initial biopsy showed changes consistent with a diagnosis of SCC for which the patient underwent surgical treatment. Several months later, the patient developed recurrent ulcerated plaques on the right forearm of which several biopsies were performed. The biopsies repeatedly showed marked pseudocarcinomatous hyperplasia resembling SCC. Deeper punch biopsies, however, showed a dense superficial and deep infiltrate of markedly atypical lymphocytes. Immunohistochemical analysis revealed strong positive staining for CD3, CD8, CD56 with negative stains for CD30 and Epstein-Barr virus-encoded small non-polyadenylated RNAs (EBER). Staining for beta F1 and gamma-delta T-cell receptor (γδ TCR) were both negative. This constellation was most consistent with a diagnosis of cutaneous peripheral T-cell lymphoma, unspecified in association with marked pseudocarcinomatous hyperplasia. Our case adds cutaneous peripheral T-cell lymphoma, unspecified to the list of conditions associated with pseudocarcinomatous hyperplasia (PCH) and illustrates once again the potential pitfalls of distinguishing marked pseudocarcinomatous hyperplasia from SCC. Keywords: cutaneous T-cell lymphoma, pseudocarcinomatous hyperplasia, squamous cell carcinoma Ginsberg D, Hill H, Wilson B, Plaza JA, Schieke SM. Pseudocarcinomatous hyperplasia mimicking squamous cell carcinoma in a case of CD56-positive cytotoxic T-cell lymphoma. J Cutan Pathol 2015; 42: 194–198. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
194
David Ginsberg1 , Hilary Hill1 , Barbara Wilson1 , Jose A. Plaza2 and Stefan M. Schieke1 1
Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI, USA and 2 Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA
Stefan M. Schieke, MD, Department of Dermatology, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, USA Tel: +414 955 3132 Fax: +414 955 6221 e-mail: [email protected] Accepted for publication October 28, 2014
Pseudocarcinomatous CD56+ lymphoma Pseudocarcinomatous hyperplasia (PCH) is a reactive hyperplasia of the epidermis and adnexal epithelium, which can be associated with a number of different cutaneous pathologies. Clinically, PCH presents as plaques or nodules with varying degrees of crusting, scaling and ulceration. Over 40 cutaneous disorders are recognized to be associated with pseudocarcinomatous changes.1 Although PCH is most commonly associated with mycobacterial and deep fungal infections, the spectrum of associated disorders includes other infectious conditions such as viral, bacterial, protozoal, spirochetal processes, as well as neoplastic and chronic inflammatory disorders.1 The clinical and histopathological presentation of PCH often resembles squamous cell carcinoma (SCC)1 – 6 which sometimes can lead to diagnostic difficulty distinguishing the two entities. A limited number of cases showing the association of PCH and underlying cutaneous lymphoma have been reported previously. Interestingly, those cases almost exclusively fall into the category of primary cutaneous CD30-positive lymphoproliferative disorders such as anaplastic large cell lymphoma (ALCL) and lymphomatoid papulosis. Our case illustrates the clinical and histopathological similarity between SCC and marked pseudocarcinomatous changes in a case of underlying cutaneous CD56+ cytotoxic T-cell lymphoma best classified as peripheral T-cell lymphoma, unspecified/not otherwise specified (NOS). Primary cutaneous peripheral T-cell lymphoma, NOS (PTCL, NOS) is a provisional category with rare and often aggressive variants of cutaneous T-cell lymphoma (CTCL). PTCL, NOS has been included into both the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification of cutaneous lymphomas and the WHO classification of non-Hodgkin lymphomas.7,8 This category serves as a collecting basin for unclassifiable cases and thus contains the least well studied subtypes of CTCL. Cases of PTCL, NOS represent an immunophenotypically and clinically heterogenous group with the unifying feature of a T-cell phenotype with expression of CD3, presence or absence of CD4 or CD8 and potentially a cytotoxic phenotype. Clinically, this type of lymphoma presents with solitary or disseminated nodules and tumors and a rapid progression to widespread disease. The lack of preceding patches and plaques is important to distinguish this type of lymphoma from mycosis fungoides. The prognosis is usually
poor with reported 5-year survival rates of 20% and less.9 Here we present an unusual and illustrative case of a patient presenting with marked PCH associated with underlying CD56+ cytotoxic T-cell lymphoma which would best be classified as PTCL, NOS. The high degree of epidermal hyperplasia led to an initial diagnosis of SCC which was treated with surgical excision. To our knowledge, the association of this type of CTCL and PCH has not been reported previously. Report of a patient An 84-year-old male patient presented to our hospital with several ulcerated plaques on the right forearm. Some of the lesions were localized at and close to the site of a previously diagnosed SCC for which the patient underwent complete excision about 4 months earlier. The patient first noted a rapidly progressive nodule on his right arm about 7–12 months before his surgery. A biopsy performed at an outside institution was found to be consistent with a diagnosis of SCC which was treated with complete excision and subsequent split thickness skin grafting. Several weeks after excision, the patient noticed recurring lesions on his right forearm within and near to the skin graft. He presented to our hospital for evaluation and management of the recurrent skin lesions about 4 months later (Fig. 1A,B). Review of systems was notable for a 20-pound weight loss over the past 2 months. A physical exam did reveal two eroded pink erythematous plaques on the dorsal and volar aspect of the right forearm. A complete skin exam did not reveal any other suspicious lesions. Biopsies taken at that point showed an invasive, well-differentiated, atypical squamous cell proliferation extending from the epidermis into the dermis, with marked pleomorphism, abundant eosinophilic cytoplasm and large vesicular nuclei. The process extended to the peripheral and deep tissue edges (Fig. 1C,D). Special stains (Periodic acid-Schiff, Gomori methenamine silver, acid fast bacillus) were negative for organisms. Owing to poor clinicopathological correlation, an additional deep punch biopsy was performed at a follow up visit 2 weeks later. The biopsy repeatedly showed an endophytic lesion with an invaginating well-differentiated squamous epithelium. The squamous cells showed a distinctive eosinophilic cytoplasm with cytologic atypia. However, in addition, a dense pan-dermal infiltrate of markedly atypical lymphocytes was
195
Ginsberg et al.
Fig. 1. Clinicopathologic presentation. Ulcerated plaques on the left forearm were noted at time of first presentation (A, B). Hematoxylin and eosin-stained sections of the cutaneous lesions are depicted (B, C). The biopsy shows nests of squamous epithelial cells, which arise from the epidermis and extend into the dermis. The cells show marked pleomorphism and have abundant eosinophilic cytoplasm and large vesicular nuclei.
Fig. 2. Histopathologic analysis of deeper tissue samples reveals a dense atypical lymphocytic infiltrate in hematoxylin and eosin-stained sections. The insert showed significant lymphocytic atypia.
noted (Fig. 2). Immunohistochemical analysis revealed positivity of the atypical cells for CD3, CD8, TIA-1, CD56 along with negative staining for CD30 (not shown) and Epstein-Barr virus-encoded small non-polyadenylated RNAs (EBER) (Fig. 3). Surprisingly, stains for beta-F1 as well as the γ chain of the gamma-delta T-cell receptor (γδ TCR) (GM1) were both negative (Fig. 3). It is important to note, however, that the GM1 stain was not performed until after the patient passed away and the case was worked up for publication. Up until then, the case was classified as a primary cutaneous γδ T-cell
196
lymphoma. The γδ T-cell phenotype was presumed based on the absent beta-F1 staining, a common practice before immunohistochemical detection of the gamma chain was available for paraffin-embedded tissue. A complete physical exam as part of a staging work up was unremarkable without signs of cervical, axillary, inguinal lymphadenopathy and hepatosplenomegaly. Complete blood cell count, basic metabolic panel, lactate dehydrogenase (LDH) and serum protein electrophoresis were within normal limits. A computer tomography (CT) scan of chest, abdomen and pelvis did not show signs of systemic involvement of his lymphoma. On the basis of clinical and available histopathological presentation, a diagnosis of cutaneous γδ T-cell lymphoma associated with marked PCH was made. The patient was classified as T2N0M0. At that point, the patient had developed worsening B-symptoms with continued weight loss, drenching night sweats in addition to fatigue and new skin lesions on his right forearm. The patient was admitted to the hospital and diagnosed with hemophagocytic syndrome. Owing to the overall poor prognosis of his condition, the patient and his family decided to initiate comfort care. He passed away about 2 months after his initial visit to our clinic.
Pseudocarcinomatous CD56+ lymphoma
Fig. 3. Immunoperoxidase staining of tumor tissue for CD3, CD8, BF1, GM1, TIA-1, CD56 and Epstein-Barr virus-encoded small non-polyadenylated RNAs (EBER) is illustrated.
Discussion To our knowledge, this is the first report describing marked PCH mimicking SCC in a case of cutaneous CD56+ cytotoxic T-cell lymphoma. Several reports in the literature describe the association of PCH with CTCL. Interestingly, PCH does not seem to be associated equally with all subtypes of CTCL. The majority of cases reporting the association of PCH with cutaneous lymphoma involve cases of CD30+ lymphoproliferative disorder. Among those, ALCL has most often been reported to be associated with marked PCH. The reported frequencies of association of PCH and ALCL vary considerably. The highest number of ALCL cases with accompanying PCH reported was 55% in a case series of 27 cases by Krishnan et al.10 More recent reports by Courville et al. and Zayour et al. showed lower frequencies, 28.5% and 14.3%, respectively.3,5 The variation may in part be due to the fact that primary cutaneous ALCL is a diagnosis based on clinicopathological correlation rather than histopathology alone and sometimes can be difficult to differentiate from lymphomatoid papulosis (LyP). To date, only a small number of cases of LyP associated with PCH have been reported.2,4 The association of PCH with other types of CTCL such as mycosis fungoides and Natural-killer (NK)/T cell lymphoma, nasal-type has been reported far less frequently.5,11 The preferential association of PCH with CD30+ lymphoproliferative disorder suggests
a specific relationship between the atypical infiltrate and epidermal proliferation.12 The underlying molecular link, however, has not been identified. While initial studies suggested the upregulation of epidermal growth factor (EGF), transforming growth factor (TGF)-α and EGF receptor, subsequent studies could not confirm those findings.2,5 A common characteristic of our case with some of the reported cases is the marked extent of PCH mimicking cutaneous SCC on histopathological exam. In one retrospective study of patients with PCH associated with either LyP or primary cutaneous ALCL, four of six patients were initially diagnosed with SCC. Of those four, three were treated for SCC with surgical excision of the lesion.4 Also clinically, the differentiation of PCH and SCC can be challenging and lesions of primary cutaneous ALCL mimicking keratoacanthoma have been reported.12 – 14 Our case highlights the challenge to correctly diagnose rare cases of cutaneous lymphoma. Initially, our patient was diagnosed with a cutaneous γδ T-cell lymphoma (CGDTCL), a rare and aggressive variant of CTCL.15 Clinical presentation and immunoprofile of our case with positive staining for CD3, CD8, CD56, TIA-1 and negative staining for BF-1, CD30 and EBER was considered to be most consistent with the diagnosis of cutaneous GDTCL. Although, the expression of the γδ heterodimer of the TCR was not directly shown in our case, the negative BF-1 stain and strong staining for CD3 along with a cytotoxic phenotype (TIA-1) and a negative
197
Ginsberg et al. EBER stain supported the diagnosis. Extranodal NK/T cell lymphoma, nasal-type was ruled out by negative staining for EBER and strongly positive staining for CD3. Anaplastic large cell lymphoma commonly associated with PCH was ruled based on the reported immunophenotype with negative staining for CD30. Interestingly, and surprisingly, further analysis of our case revealed a negative staining for the γ-chain of the γδ TCR with the currently available method for paraffin-embedded tissue. Given that both the BF-1 and GM-1 stain revealed several infiltrating, bystander T-cells, we do not believe that the negative staining represents a false negative but rather indicates a ‘TCR silent’ phenotype of this case. However, the negative staining could not be confirmed by flow analysis because of the lack of available tissue samples. Recently, a few cases of extranodal TCR silent lymphoma have been described. Of the 13 described cases, 6 presented initially with cutaneous lesions. All those cases showed a cytotoxic T-cell phenotype and showed negative staining for EBV.16 On our case, we concur with Garcia-Herrera et al. that the absence of positive BF-1 staining should not be mistaken for the presence of a γδ TCR phenotype.
The current classification system for cutaneous lymphomas8 does not allow for an exact categorization of the herein described lymphoma phenotype. Assuming a TCR silent phenotype, the best fit for our case of a CD56+ cytotoxic lymphoma in the current system is the category of PTCL, NOS. This case further highlights the provisional character of this category and underlines the need to carefully characterize the heterogenous spectrum of cases in this category. In summary, this case shows for the first time the association of PCH with a primary cutaneous CD56+ cytotoxic T-cell lymphoma. The marked epidermal hyperplasia was initially interpreted as SCC and only repeat biopsies allowed for the definitive diagnosis of a cutaneous lymphoma as the underlying process. This case illustrates the importance to look for potentially underlying dermal processes in the presence of epidermal hyperplasia and reminds the clinician on adequately sampling skin lesions to arrive at a definitive diagnosis in a timely fashion. Acknowledgement S.M.S. is supported by a Dermatology Foundation Medical Dermatology Career Development Award.
References 1. Zayour M, Lazova R. Pseudoepitheliomatous hyperplasia: a review. Am J Dermatopathol 2011; 33: 112. 2. Scarisbrick JJ, Calonje E, Orchard G, Child FJ, Russell-Jones R. Pseudocarcinomatous change in lymphomatoid papulosis and primary cutaneous CD30+ lymphoma: a clinicopathologic and immunohistochemical study of 6 patients. J Am Acad Dermatol 2001; 44: 239. 3. 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. 4. 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. 5. 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
198
6.
7.
8.
9.
10.
11.
epithelial growth factor expression. Br J Dermatol 1999; 140: 421. Kadin ME, Pinkus JL, Pinkus GS, et al. Primary cutaneous ALCL with phosphorylated/activated cytoplasmic ALK and novel phenotype: EMA/MUC1+, cutaneous lymphocyte antigen negative. Am J Surg Pathol 2008; 32: 1421. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105: 3768. Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program 2009; 131: 523. Bekkenk MW, Vermeer MH, Jansen PM, et al. Peripheral T-cell lymphoma unspecified presenting in the skin: analysis of prognostic factors in a group of 82 patients. Blood 2003; 102: 2213. Krishnan J, Tomaszewski M, Kao G. Primary cutaneous CD30-positive anaplastic large cell lymphoma. Report of 27 cases. J Cutan Pathol. 1993; 20: 193. Kou T, Lee S, Tsang N. Nasal NK/T cell lymphoma in Taiwan: a clinicopathologic study of 22 cases, with analysis of histologic subtypes, Epstein-Barr virus LMP-1 gene
12.
13.
14.
15.
16.
association, and treatment modalities. Int J Surg Pathol 2004; 12: 375. Cespedes YP, Rockley PF, Flores F, Ruiz P, Kaiser MR, Elgart GW. Is there a positive relationship between CD30-positive lymphoproliferative disorders and epidermal proliferation? J Cutan Pathol 2000; 44: 239. Martin JM, Ricart JM, Monteagudo C, et al. Primary cutaneous CD30+ anaplastic large-cell lymphomas mimicking keratoacanthomas. Clin Exp Dermatol 2007; 32: 668. Lin JH, Lee Y. Primary cutaneous CD30+ anaplastic large cell lymphoma with keratoacanthoma-like pseudocarcinomatous hyperplasia and marked eosinophilia and neutrophilia. J Cutan Pathol 2004; 31: 458. Guitart J, Weisenburger DD, Subtil A, et al. Cutaneous [gamma][delta] T-cell lymphomas: a spectrum of presentations with overlap with other cytotoxic lymphomas. Am J Surg Pathol 2012; 36: 1656. Garcia-Herrera A, Song JY, Chuang SS, et al. Nonhepatosplenic γδ T-cell lymphomas represent a spectrum of aggressive cytotoxic T-cell lymphomas with a mainly extranodal presentation. Am J Surg Pathol 2011; 8: 1214.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Pseudocarcinomatous hyperplasia mimicking squamous cell carcinoma in a case of CD56-positive cytotoxic T-cell lymphoma We present the case of an 84-year-old patient with a cutaneous CD56 positive cytotoxic T-cell lymphoma associated with substantial pseudocarcinomatous hyperplasia mimicking squamous cell carcinoma (SCC). The patient presented with a 7-month history of several progressive, ulcerated plaques on his right forearm. An initial biopsy showed changes consistent with a diagnosis of SCC for which the patient underwent surgical treatment. Several months later, the patient developed recurrent ulcerated plaques on the right forearm of which several biopsies were performed. The biopsies repeatedly showed marked pseudocarcinomatous hyperplasia resembling SCC. Deeper punch biopsies, however, showed a dense superficial and deep infiltrate of markedly atypical lymphocytes. Immunohistochemical analysis revealed strong positive staining for CD3, CD8, CD56 with negative stains for CD30 and Epstein-Barr virus-encoded small non-polyadenylated RNAs (EBER). Staining for beta F1 and gamma-delta T-cell receptor (γδ TCR) were both negative. This constellation was most consistent with a diagnosis of cutaneous peripheral T-cell lymphoma, unspecified in association with marked pseudocarcinomatous hyperplasia. Our case adds cutaneous peripheral T-cell lymphoma, unspecified to the list of conditions associated with pseudocarcinomatous hyperplasia (PCH) and illustrates once again the potential pitfalls of distinguishing marked pseudocarcinomatous hyperplasia from SCC. Keywords: cutaneous T-cell lymphoma, pseudocarcinomatous hyperplasia, squamous cell carcinoma Ginsberg D, Hill H, Wilson B, Plaza JA, Schieke SM. Pseudocarcinomatous hyperplasia mimicking squamous cell carcinoma in a case of CD56-positive cytotoxic T-cell lymphoma. J Cutan Pathol 2015; 42: 194–198. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
194
David Ginsberg1 , Hilary Hill1 , Barbara Wilson1 , Jose A. Plaza2 and Stefan M. Schieke1 1
Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI, USA and 2 Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA
Stefan M. Schieke, MD, Department of Dermatology, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, USA Tel: +414 955 3132 Fax: +414 955 6221 e-mail: [email protected] Accepted for publication October 28, 2014
Pseudocarcinomatous CD56+ lymphoma Pseudocarcinomatous hyperplasia (PCH) is a reactive hyperplasia of the epidermis and adnexal epithelium, which can be associated with a number of different cutaneous pathologies. Clinically, PCH presents as plaques or nodules with varying degrees of crusting, scaling and ulceration. Over 40 cutaneous disorders are recognized to be associated with pseudocarcinomatous changes.1 Although PCH is most commonly associated with mycobacterial and deep fungal infections, the spectrum of associated disorders includes other infectious conditions such as viral, bacterial, protozoal, spirochetal processes, as well as neoplastic and chronic inflammatory disorders.1 The clinical and histopathological presentation of PCH often resembles squamous cell carcinoma (SCC)1 – 6 which sometimes can lead to diagnostic difficulty distinguishing the two entities. A limited number of cases showing the association of PCH and underlying cutaneous lymphoma have been reported previously. Interestingly, those cases almost exclusively fall into the category of primary cutaneous CD30-positive lymphoproliferative disorders such as anaplastic large cell lymphoma (ALCL) and lymphomatoid papulosis. Our case illustrates the clinical and histopathological similarity between SCC and marked pseudocarcinomatous changes in a case of underlying cutaneous CD56+ cytotoxic T-cell lymphoma best classified as peripheral T-cell lymphoma, unspecified/not otherwise specified (NOS). Primary cutaneous peripheral T-cell lymphoma, NOS (PTCL, NOS) is a provisional category with rare and often aggressive variants of cutaneous T-cell lymphoma (CTCL). PTCL, NOS has been included into both the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification of cutaneous lymphomas and the WHO classification of non-Hodgkin lymphomas.7,8 This category serves as a collecting basin for unclassifiable cases and thus contains the least well studied subtypes of CTCL. Cases of PTCL, NOS represent an immunophenotypically and clinically heterogenous group with the unifying feature of a T-cell phenotype with expression of CD3, presence or absence of CD4 or CD8 and potentially a cytotoxic phenotype. Clinically, this type of lymphoma presents with solitary or disseminated nodules and tumors and a rapid progression to widespread disease. The lack of preceding patches and plaques is important to distinguish this type of lymphoma from mycosis fungoides. The prognosis is usually
poor with reported 5-year survival rates of 20% and less.9 Here we present an unusual and illustrative case of a patient presenting with marked PCH associated with underlying CD56+ cytotoxic T-cell lymphoma which would best be classified as PTCL, NOS. The high degree of epidermal hyperplasia led to an initial diagnosis of SCC which was treated with surgical excision. To our knowledge, the association of this type of CTCL and PCH has not been reported previously. Report of a patient An 84-year-old male patient presented to our hospital with several ulcerated plaques on the right forearm. Some of the lesions were localized at and close to the site of a previously diagnosed SCC for which the patient underwent complete excision about 4 months earlier. The patient first noted a rapidly progressive nodule on his right arm about 7–12 months before his surgery. A biopsy performed at an outside institution was found to be consistent with a diagnosis of SCC which was treated with complete excision and subsequent split thickness skin grafting. Several weeks after excision, the patient noticed recurring lesions on his right forearm within and near to the skin graft. He presented to our hospital for evaluation and management of the recurrent skin lesions about 4 months later (Fig. 1A,B). Review of systems was notable for a 20-pound weight loss over the past 2 months. A physical exam did reveal two eroded pink erythematous plaques on the dorsal and volar aspect of the right forearm. A complete skin exam did not reveal any other suspicious lesions. Biopsies taken at that point showed an invasive, well-differentiated, atypical squamous cell proliferation extending from the epidermis into the dermis, with marked pleomorphism, abundant eosinophilic cytoplasm and large vesicular nuclei. The process extended to the peripheral and deep tissue edges (Fig. 1C,D). Special stains (Periodic acid-Schiff, Gomori methenamine silver, acid fast bacillus) were negative for organisms. Owing to poor clinicopathological correlation, an additional deep punch biopsy was performed at a follow up visit 2 weeks later. The biopsy repeatedly showed an endophytic lesion with an invaginating well-differentiated squamous epithelium. The squamous cells showed a distinctive eosinophilic cytoplasm with cytologic atypia. However, in addition, a dense pan-dermal infiltrate of markedly atypical lymphocytes was
195
Ginsberg et al.
Fig. 1. Clinicopathologic presentation. Ulcerated plaques on the left forearm were noted at time of first presentation (A, B). Hematoxylin and eosin-stained sections of the cutaneous lesions are depicted (B, C). The biopsy shows nests of squamous epithelial cells, which arise from the epidermis and extend into the dermis. The cells show marked pleomorphism and have abundant eosinophilic cytoplasm and large vesicular nuclei.
Fig. 2. Histopathologic analysis of deeper tissue samples reveals a dense atypical lymphocytic infiltrate in hematoxylin and eosin-stained sections. The insert showed significant lymphocytic atypia.
noted (Fig. 2). Immunohistochemical analysis revealed positivity of the atypical cells for CD3, CD8, TIA-1, CD56 along with negative staining for CD30 (not shown) and Epstein-Barr virus-encoded small non-polyadenylated RNAs (EBER) (Fig. 3). Surprisingly, stains for beta-F1 as well as the γ chain of the gamma-delta T-cell receptor (γδ TCR) (GM1) were both negative (Fig. 3). It is important to note, however, that the GM1 stain was not performed until after the patient passed away and the case was worked up for publication. Up until then, the case was classified as a primary cutaneous γδ T-cell
196
lymphoma. The γδ T-cell phenotype was presumed based on the absent beta-F1 staining, a common practice before immunohistochemical detection of the gamma chain was available for paraffin-embedded tissue. A complete physical exam as part of a staging work up was unremarkable without signs of cervical, axillary, inguinal lymphadenopathy and hepatosplenomegaly. Complete blood cell count, basic metabolic panel, lactate dehydrogenase (LDH) and serum protein electrophoresis were within normal limits. A computer tomography (CT) scan of chest, abdomen and pelvis did not show signs of systemic involvement of his lymphoma. On the basis of clinical and available histopathological presentation, a diagnosis of cutaneous γδ T-cell lymphoma associated with marked PCH was made. The patient was classified as T2N0M0. At that point, the patient had developed worsening B-symptoms with continued weight loss, drenching night sweats in addition to fatigue and new skin lesions on his right forearm. The patient was admitted to the hospital and diagnosed with hemophagocytic syndrome. Owing to the overall poor prognosis of his condition, the patient and his family decided to initiate comfort care. He passed away about 2 months after his initial visit to our clinic.
Pseudocarcinomatous CD56+ lymphoma
Fig. 3. Immunoperoxidase staining of tumor tissue for CD3, CD8, BF1, GM1, TIA-1, CD56 and Epstein-Barr virus-encoded small non-polyadenylated RNAs (EBER) is illustrated.
Discussion To our knowledge, this is the first report describing marked PCH mimicking SCC in a case of cutaneous CD56+ cytotoxic T-cell lymphoma. Several reports in the literature describe the association of PCH with CTCL. Interestingly, PCH does not seem to be associated equally with all subtypes of CTCL. The majority of cases reporting the association of PCH with cutaneous lymphoma involve cases of CD30+ lymphoproliferative disorder. Among those, ALCL has most often been reported to be associated with marked PCH. The reported frequencies of association of PCH and ALCL vary considerably. The highest number of ALCL cases with accompanying PCH reported was 55% in a case series of 27 cases by Krishnan et al.10 More recent reports by Courville et al. and Zayour et al. showed lower frequencies, 28.5% and 14.3%, respectively.3,5 The variation may in part be due to the fact that primary cutaneous ALCL is a diagnosis based on clinicopathological correlation rather than histopathology alone and sometimes can be difficult to differentiate from lymphomatoid papulosis (LyP). To date, only a small number of cases of LyP associated with PCH have been reported.2,4 The association of PCH with other types of CTCL such as mycosis fungoides and Natural-killer (NK)/T cell lymphoma, nasal-type has been reported far less frequently.5,11 The preferential association of PCH with CD30+ lymphoproliferative disorder suggests
a specific relationship between the atypical infiltrate and epidermal proliferation.12 The underlying molecular link, however, has not been identified. While initial studies suggested the upregulation of epidermal growth factor (EGF), transforming growth factor (TGF)-α and EGF receptor, subsequent studies could not confirm those findings.2,5 A common characteristic of our case with some of the reported cases is the marked extent of PCH mimicking cutaneous SCC on histopathological exam. In one retrospective study of patients with PCH associated with either LyP or primary cutaneous ALCL, four of six patients were initially diagnosed with SCC. Of those four, three were treated for SCC with surgical excision of the lesion.4 Also clinically, the differentiation of PCH and SCC can be challenging and lesions of primary cutaneous ALCL mimicking keratoacanthoma have been reported.12 – 14 Our case highlights the challenge to correctly diagnose rare cases of cutaneous lymphoma. Initially, our patient was diagnosed with a cutaneous γδ T-cell lymphoma (CGDTCL), a rare and aggressive variant of CTCL.15 Clinical presentation and immunoprofile of our case with positive staining for CD3, CD8, CD56, TIA-1 and negative staining for BF-1, CD30 and EBER was considered to be most consistent with the diagnosis of cutaneous GDTCL. Although, the expression of the γδ heterodimer of the TCR was not directly shown in our case, the negative BF-1 stain and strong staining for CD3 along with a cytotoxic phenotype (TIA-1) and a negative
197
Ginsberg et al. EBER stain supported the diagnosis. Extranodal NK/T cell lymphoma, nasal-type was ruled out by negative staining for EBER and strongly positive staining for CD3. Anaplastic large cell lymphoma commonly associated with PCH was ruled based on the reported immunophenotype with negative staining for CD30. Interestingly, and surprisingly, further analysis of our case revealed a negative staining for the γ-chain of the γδ TCR with the currently available method for paraffin-embedded tissue. Given that both the BF-1 and GM-1 stain revealed several infiltrating, bystander T-cells, we do not believe that the negative staining represents a false negative but rather indicates a ‘TCR silent’ phenotype of this case. However, the negative staining could not be confirmed by flow analysis because of the lack of available tissue samples. Recently, a few cases of extranodal TCR silent lymphoma have been described. Of the 13 described cases, 6 presented initially with cutaneous lesions. All those cases showed a cytotoxic T-cell phenotype and showed negative staining for EBV.16 On our case, we concur with Garcia-Herrera et al. that the absence of positive BF-1 staining should not be mistaken for the presence of a γδ TCR phenotype.
The current classification system for cutaneous lymphomas8 does not allow for an exact categorization of the herein described lymphoma phenotype. Assuming a TCR silent phenotype, the best fit for our case of a CD56+ cytotoxic lymphoma in the current system is the category of PTCL, NOS. This case further highlights the provisional character of this category and underlines the need to carefully characterize the heterogenous spectrum of cases in this category. In summary, this case shows for the first time the association of PCH with a primary cutaneous CD56+ cytotoxic T-cell lymphoma. The marked epidermal hyperplasia was initially interpreted as SCC and only repeat biopsies allowed for the definitive diagnosis of a cutaneous lymphoma as the underlying process. This case illustrates the importance to look for potentially underlying dermal processes in the presence of epidermal hyperplasia and reminds the clinician on adequately sampling skin lesions to arrive at a definitive diagnosis in a timely fashion. Acknowledgement S.M.S. is supported by a Dermatology Foundation Medical Dermatology Career Development Award.
References 1. Zayour M, Lazova R. Pseudoepitheliomatous hyperplasia: a review. Am J Dermatopathol 2011; 33: 112. 2. Scarisbrick JJ, Calonje E, Orchard G, Child FJ, Russell-Jones R. Pseudocarcinomatous change in lymphomatoid papulosis and primary cutaneous CD30+ lymphoma: a clinicopathologic and immunohistochemical study of 6 patients. J Am Acad Dermatol 2001; 44: 239. 3. 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. 4. 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. 5. 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
198
6.
7.
8.
9.
10.
11.
epithelial growth factor expression. Br J Dermatol 1999; 140: 421. Kadin ME, Pinkus JL, Pinkus GS, et al. Primary cutaneous ALCL with phosphorylated/activated cytoplasmic ALK and novel phenotype: EMA/MUC1+, cutaneous lymphocyte antigen negative. Am J Surg Pathol 2008; 32: 1421. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105: 3768. Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program 2009; 131: 523. Bekkenk MW, Vermeer MH, Jansen PM, et al. Peripheral T-cell lymphoma unspecified presenting in the skin: analysis of prognostic factors in a group of 82 patients. Blood 2003; 102: 2213. Krishnan J, Tomaszewski M, Kao G. Primary cutaneous CD30-positive anaplastic large cell lymphoma. Report of 27 cases. J Cutan Pathol. 1993; 20: 193. Kou T, Lee S, Tsang N. Nasal NK/T cell lymphoma in Taiwan: a clinicopathologic study of 22 cases, with analysis of histologic subtypes, Epstein-Barr virus LMP-1 gene
12.
13.
14.
15.
16.
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