Correspondence
463
Table 2. In-situ lymphoma: FLIS and MCLIS diagnostic criteria FLIS Morphology
Preserved
MCLIS Preserved/little or no spread to interfollicular area
IHC *Exclude partial involvement by overt FL or MCL
Bcl-2 (strong + in GC) CD10 (strong + in GC) Lower ki67/MIB-1
CD20+ CD5+ Cyclin-D1+
Clinical data
No evidence of coexistent overt lymphoma
No evidence of coexistent overt lymphoma
Management
Close follow-up is suggested
Close follow-up is suggested
IHC, Immunohistochemistry; FLIS, Follicular lymphoma in situ; MCLIS, Mantle cell lymphoma in situ; GC, Germinal centre; LN, Lymph node. CONFLICT OF INTEREST
The authors declare no conflicting interests. Larissa Sena Teixeira Mendes Andrew Wotherspoon Histopathology Department, The Royal Marsden Hospital, London, UK 1. Ganapathi KA, Pittaluga S, Odejide OO et al. Early lymphoid lesion: conceptual, diagnostic and clinical challenges. Haematologica 2014; 99; 1421–1432. 2. Henopp T, Quintanilla-Martinez L, Fend F, Adam P. Prevalence of follicular lymphoma in situ in consecutively analysed reactive lymph nodes. Histopathology 2011; 59; 139–142. 3. Adam P, Schiefer A, Prill S et al. Incidence of preclinical manifestations of mantle cell lymphoma and mantle cell lymphoma in situ in reactive lymphoid tissues. Mod. Pathol. 2012; 25; 1629–1636. 4. Jegalian AG, Eberle AC, Pack SD et al. Follicular lymphoma in situ: clinical implications and comparisons with partial involvement by follicular lymphoma. Blood 2011; 118; 2976– 2984. 5. Bonzheim I, Salaverna I, Haake A et al. A unique case of follicular lymphoma provides insights to the clonal evolution from follicular lymphoma in situ to manifest follicular lymphoma. Blood 2011; 118; 3442–3444. 6. Mamessier E, Song JY, Eberle FC et al. Early lesions of follicular lymphoma: a genetic perspective. Haematologica 2014; 99; 481–488.
Acantholytic squamous cell carcinoma of the lung showing significant signet ring cell component DOI: 10.1111/his.12762 © 2015 John Wiley & Sons Ltd Histopathology, 68, 461–468.
Sir: Acantholytic squamous cell carcinoma (SCC) is a rare variant of SCC and develops most commonly in sun-exposed areas of skin. Acantholytic SCC is also known as adenoid SCC, pseudovascular SCC, pseudovascular adenoid SCC and pseudoangiosarcomatous SCC, because the artefactual clefts that result from acantholysis resemble glandular lumens or vascular spaces in surgically resected specimens. Only a few cases of acantholytic SCC of the lung have been reported.1–3 Signet ring SCC is an extremely uncommon variant, and very few cases exclusively in the skin have been reported.4 Here we report the first case of acantholytic SCC with a focal signet ring cell component in the lung. A 64-year-old man who was a 35 pack-year ex-smoker, presented with a solitary pulmonary nodule on chest radiography during a regular medical examination. Chest computed tomography (CT) revealed a 2.8-cm mass in the left upper lobe. Wholebody positron emission tomography showed no hypermetabolic lesion except the left upper lobe mass. CT-guided fine-needle aspiration was performed and the cytological diagnosis was ‘suspicious of nonsmall-cell carcinoma’. The cytological features of this case were reported elsewhere (Cytopathology, in press). The patient underwent a left upper lobe lobectomy with mediastinal lymph node dissection. Macroscopically, a grey–tan solid mass measuring 2.9 9 2.4 cm was found at the periphery of the posterior segment (Figure 1A). Microscopically, the predominant tumour cells were discohesive and showed solid growth filling alveolar spaces lacking a specific pattern (Figure 1B). These tumour cells were round with bright eosinophilic cytoplasm and well-defined cytoplasmic borders. The tumour nuclei were round and pleomorphic and had vesicular chromatin with prominent nucleoli. Fewer than 1% of the tumour
464
Correspondence
A
D
B
E
C
F
Figure 1. A, A lobulating grey mass in the lung periphery. B, The majority of the tumour cells were discohesive and showed a solid growth pattern filling the alveolar spaces. C, Some of the tumour cells formed sheets (arrows) connected by intercellular bridges. D, Intracytoplasmic vacuoles of signet ring-like cells stained negative for Alcian blue. E, All tumour cells were diffusely positive for p40. F, All tumour cells were negative for thyroid transcription factor-1 (TTF-1).
cells formed sheets connected by intercellular bridges, and had thick, glassy cytoplasm (Figure 1C). Some tumour cells had signet ring cell morphology due to intracytoplasmic vacuoles, which tested negative on Alcian blue and periodic acid-Schiff staining with or without diastase (Figure 1D). Immunohistochemically, all the tumour cells (including signet ring cells) stained positive for CK5/6, p63, p40 and EMA, but negative for thyroid transcription factor-1 (TTF-1), Napsin A, calretinin, Wilms’ tumour 1 (WT-1), D240, CD56 and synaptophysin (Figure 1E,F). The tumour also showed diffuse strong positivity for p16 immunostaining, a surrogate marker for high-risk human papillomavirus (HPV)-related carcinoma, but
HPV genotyping [GeneFinder HPV Liquid Bead MicroArray Genotype kit using L1 consensus polymerase chain reaction (PCR) and the Luminex xMAP system; Infopia, Anyang, South Korea] revealed no HPV DNA within the tumour. The tumour was EGFR and KRAS gene wild-type (PNA clampTM method; Panagene, Daejeon, South Korea). Cells with signet ring morphology are found more commonly in adenocarcinomas of gastric, pancreatic and breast origin, although their existence is also described in other malignant neoplasms, such as malignant melanoma, lymphoma, leiomyosarcoma, liposarcoma, basal cell carcinoma and cutaneous SCC. The exact mechanism of the formation of Histopathology, 68, 461–468.
Correspondence
optically clear spaces in SCC is unknown, but dilatations of the endoplasmic reticulum could be related to cytoplasmic vacuole formation.5 Thus, signet ring-like cells are not entirely a signature of glandular differentiation, so a special stain will be needed to identify specific intracytoplasmic substances such as mucin. Impaired cellular adhesion molecules have been associated with tumour cell acantholysis. Loss of E-cadherin and syndecan-1 expression has been reported in acantholytic SCC of the skin.6 In our case, E-cadherin expression was focally reduced in tumour cells, while syndecan-1 immunostaining was not performed. The prognosis of acantholytic SCC varies by involved organ and site. In the present case, the patient was disease free in 15 months. Here we describe a unique case of pulmonary SCC showing extensive tumour acantholysis and a signet ring cell component. Although rare, consideration of acantholytic or signet ring cell variant of SCC in the differential diagnosis of non-small-cell lung cancer may be helpful in surgical pathology practice. An accumulation of case reports is needed to elucidate the clinical and pathological features of this tumour variant. Heae Surng Park Sungsoo Lee1 Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, and 1 Department of Thoracic and Cardiovascular Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea 1. Nappi O, Swanson PE, Wick MR. Pseudovascular adenoid squamous cell carcinoma of the lung: clinicopathologic study of three cases and comparison with true pleuropulmonary angiosarcoma. Hum. Pathol. 1994; 25; 373–378. 2. Dodd LG. Fine-needle aspiration cytology of adenoid (acantholytic) squamous-cell carcinoma. Diagn. Cytopathol. 1995; 12; 168–172. 3. Smith AR, Raab SS, Landreneau RJ, Silverman JF. Fine-needle aspiration cytologic features of pseudovascular adenoid squamous-cell carcinoma of the lung. Diagn. Cytopathol. 1999; 21; 265–270. 4. El Demellawy D, Onuma K, Alowami S. Signet ring squamous cell carcinoma-the forgotten variant: case report and review of the literature. J. Cutan. Pathol. 2011; 38; 306–308. 5. McKinley E, Valles R, Bang R, Bocklage T. Signet-ring squamous cell carcinoma: a case report. J. Cutan. Pathol. 1998; 25; 176– 181. 6. Bayer-Garner IB, Smoller BR. The expression of syndecan-1 is preferentially reduced compared with that of e-cadherin in acantholytic squamous cell carcinoma. J. Cutan. Pathol. 2001; 28; 83–89.
Histopathology, 68, 461–468.
465
Epstein–Barr virus-positive T-cellassociated colitis mimicking inflammatory bowel disease: clinicopathological study of two cases DOI: 10.1111/his.12773 © 2015 John Wiley & Sons Ltd
Sir: Epstein–Barr virus (EBV) infects >90% of human beings, resulting in lifelong latency in memory B cells. Primary infection in childhood is often asymptomatic. Persistent active infection can occur in immunocompromised hosts, with morbidity and mortality. One example is chronic active EBV infection (CAEBV) affecting T cells or natural killer (NK) cells, characterized by fever, lymphadenopathy, a high number of blood EBV DNA copies, and histological and molecular evidence of EBV organ disease.1 It encompasses a disease spectrum that is most common in Asia, with polyclonal to monoclonal EBV-positive T or NK cell proliferation. The monoclonal disease overlaps with ‘EBV+ T-cell lymphoproliferative disorders (EBV+TCLPD) of childhood’ in the 2008 World Health Organization classification of lymphoma.2 We diagnosed CAEBV in two young Chinese boys presenting with chronic diarrhoea that mimicked chronic inflammatory bowel disease. Patient 1 (aged 12 years) presented with a 3-month history of diarrhoea, abdominal pain, and weight loss. Colonoscopy showed colitis with multiple ulcers. Blood, urine and stool cultures were negative. The patient had persistent fever, falling blood counts, active marrow haematopoiesis, hepatosplenomegaly with deranged liver function, and fresh blood per rectum. EBV-associated haemophagocytic syndrome was confirmed by positive serum EBV antibodies, and high numbers of whole blood and serum EBV DNA copies (2.07 9 105 and 2.43 9 104 copies/ml, respectively) as determined with quantitative real-time polymerase chain reaction (PCR). The patient developed profuse lower gastrointestinal (GI) bleeding necessitating subtotal colectomy. He was stable initially, but deteriorated suddenly, and died 9 months after admission. Examination of the colon showed multiple chronic and acute ischaemic ulcers with volcanic eruption of superficial glands (Figure 1A). Small-artery acute vasculitis with segmental fibrinoid necrosis was seen focally (Figure 1B). There were patchy infiltrates of mostly T cells (CD20-negative, CD3-positive, CD4-positive or CD8-positive, and CD56-negative) (Figure 1C). EBV-encoded RNA (EBER) in-situ hybridization (ISH) demonstrated
463
Table 2. In-situ lymphoma: FLIS and MCLIS diagnostic criteria FLIS Morphology
Preserved
MCLIS Preserved/little or no spread to interfollicular area
IHC *Exclude partial involvement by overt FL or MCL
Bcl-2 (strong + in GC) CD10 (strong + in GC) Lower ki67/MIB-1
CD20+ CD5+ Cyclin-D1+
Clinical data
No evidence of coexistent overt lymphoma
No evidence of coexistent overt lymphoma
Management
Close follow-up is suggested
Close follow-up is suggested
IHC, Immunohistochemistry; FLIS, Follicular lymphoma in situ; MCLIS, Mantle cell lymphoma in situ; GC, Germinal centre; LN, Lymph node. CONFLICT OF INTEREST
The authors declare no conflicting interests. Larissa Sena Teixeira Mendes Andrew Wotherspoon Histopathology Department, The Royal Marsden Hospital, London, UK 1. Ganapathi KA, Pittaluga S, Odejide OO et al. Early lymphoid lesion: conceptual, diagnostic and clinical challenges. Haematologica 2014; 99; 1421–1432. 2. Henopp T, Quintanilla-Martinez L, Fend F, Adam P. Prevalence of follicular lymphoma in situ in consecutively analysed reactive lymph nodes. Histopathology 2011; 59; 139–142. 3. Adam P, Schiefer A, Prill S et al. Incidence of preclinical manifestations of mantle cell lymphoma and mantle cell lymphoma in situ in reactive lymphoid tissues. Mod. Pathol. 2012; 25; 1629–1636. 4. Jegalian AG, Eberle AC, Pack SD et al. Follicular lymphoma in situ: clinical implications and comparisons with partial involvement by follicular lymphoma. Blood 2011; 118; 2976– 2984. 5. Bonzheim I, Salaverna I, Haake A et al. A unique case of follicular lymphoma provides insights to the clonal evolution from follicular lymphoma in situ to manifest follicular lymphoma. Blood 2011; 118; 3442–3444. 6. Mamessier E, Song JY, Eberle FC et al. Early lesions of follicular lymphoma: a genetic perspective. Haematologica 2014; 99; 481–488.
Acantholytic squamous cell carcinoma of the lung showing significant signet ring cell component DOI: 10.1111/his.12762 © 2015 John Wiley & Sons Ltd Histopathology, 68, 461–468.
Sir: Acantholytic squamous cell carcinoma (SCC) is a rare variant of SCC and develops most commonly in sun-exposed areas of skin. Acantholytic SCC is also known as adenoid SCC, pseudovascular SCC, pseudovascular adenoid SCC and pseudoangiosarcomatous SCC, because the artefactual clefts that result from acantholysis resemble glandular lumens or vascular spaces in surgically resected specimens. Only a few cases of acantholytic SCC of the lung have been reported.1–3 Signet ring SCC is an extremely uncommon variant, and very few cases exclusively in the skin have been reported.4 Here we report the first case of acantholytic SCC with a focal signet ring cell component in the lung. A 64-year-old man who was a 35 pack-year ex-smoker, presented with a solitary pulmonary nodule on chest radiography during a regular medical examination. Chest computed tomography (CT) revealed a 2.8-cm mass in the left upper lobe. Wholebody positron emission tomography showed no hypermetabolic lesion except the left upper lobe mass. CT-guided fine-needle aspiration was performed and the cytological diagnosis was ‘suspicious of nonsmall-cell carcinoma’. The cytological features of this case were reported elsewhere (Cytopathology, in press). The patient underwent a left upper lobe lobectomy with mediastinal lymph node dissection. Macroscopically, a grey–tan solid mass measuring 2.9 9 2.4 cm was found at the periphery of the posterior segment (Figure 1A). Microscopically, the predominant tumour cells were discohesive and showed solid growth filling alveolar spaces lacking a specific pattern (Figure 1B). These tumour cells were round with bright eosinophilic cytoplasm and well-defined cytoplasmic borders. The tumour nuclei were round and pleomorphic and had vesicular chromatin with prominent nucleoli. Fewer than 1% of the tumour
464
Correspondence
A
D
B
E
C
F
Figure 1. A, A lobulating grey mass in the lung periphery. B, The majority of the tumour cells were discohesive and showed a solid growth pattern filling the alveolar spaces. C, Some of the tumour cells formed sheets (arrows) connected by intercellular bridges. D, Intracytoplasmic vacuoles of signet ring-like cells stained negative for Alcian blue. E, All tumour cells were diffusely positive for p40. F, All tumour cells were negative for thyroid transcription factor-1 (TTF-1).
cells formed sheets connected by intercellular bridges, and had thick, glassy cytoplasm (Figure 1C). Some tumour cells had signet ring cell morphology due to intracytoplasmic vacuoles, which tested negative on Alcian blue and periodic acid-Schiff staining with or without diastase (Figure 1D). Immunohistochemically, all the tumour cells (including signet ring cells) stained positive for CK5/6, p63, p40 and EMA, but negative for thyroid transcription factor-1 (TTF-1), Napsin A, calretinin, Wilms’ tumour 1 (WT-1), D240, CD56 and synaptophysin (Figure 1E,F). The tumour also showed diffuse strong positivity for p16 immunostaining, a surrogate marker for high-risk human papillomavirus (HPV)-related carcinoma, but
HPV genotyping [GeneFinder HPV Liquid Bead MicroArray Genotype kit using L1 consensus polymerase chain reaction (PCR) and the Luminex xMAP system; Infopia, Anyang, South Korea] revealed no HPV DNA within the tumour. The tumour was EGFR and KRAS gene wild-type (PNA clampTM method; Panagene, Daejeon, South Korea). Cells with signet ring morphology are found more commonly in adenocarcinomas of gastric, pancreatic and breast origin, although their existence is also described in other malignant neoplasms, such as malignant melanoma, lymphoma, leiomyosarcoma, liposarcoma, basal cell carcinoma and cutaneous SCC. The exact mechanism of the formation of Histopathology, 68, 461–468.
Correspondence
optically clear spaces in SCC is unknown, but dilatations of the endoplasmic reticulum could be related to cytoplasmic vacuole formation.5 Thus, signet ring-like cells are not entirely a signature of glandular differentiation, so a special stain will be needed to identify specific intracytoplasmic substances such as mucin. Impaired cellular adhesion molecules have been associated with tumour cell acantholysis. Loss of E-cadherin and syndecan-1 expression has been reported in acantholytic SCC of the skin.6 In our case, E-cadherin expression was focally reduced in tumour cells, while syndecan-1 immunostaining was not performed. The prognosis of acantholytic SCC varies by involved organ and site. In the present case, the patient was disease free in 15 months. Here we describe a unique case of pulmonary SCC showing extensive tumour acantholysis and a signet ring cell component. Although rare, consideration of acantholytic or signet ring cell variant of SCC in the differential diagnosis of non-small-cell lung cancer may be helpful in surgical pathology practice. An accumulation of case reports is needed to elucidate the clinical and pathological features of this tumour variant. Heae Surng Park Sungsoo Lee1 Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, and 1 Department of Thoracic and Cardiovascular Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea 1. Nappi O, Swanson PE, Wick MR. Pseudovascular adenoid squamous cell carcinoma of the lung: clinicopathologic study of three cases and comparison with true pleuropulmonary angiosarcoma. Hum. Pathol. 1994; 25; 373–378. 2. Dodd LG. Fine-needle aspiration cytology of adenoid (acantholytic) squamous-cell carcinoma. Diagn. Cytopathol. 1995; 12; 168–172. 3. Smith AR, Raab SS, Landreneau RJ, Silverman JF. Fine-needle aspiration cytologic features of pseudovascular adenoid squamous-cell carcinoma of the lung. Diagn. Cytopathol. 1999; 21; 265–270. 4. El Demellawy D, Onuma K, Alowami S. Signet ring squamous cell carcinoma-the forgotten variant: case report and review of the literature. J. Cutan. Pathol. 2011; 38; 306–308. 5. McKinley E, Valles R, Bang R, Bocklage T. Signet-ring squamous cell carcinoma: a case report. J. Cutan. Pathol. 1998; 25; 176– 181. 6. Bayer-Garner IB, Smoller BR. The expression of syndecan-1 is preferentially reduced compared with that of e-cadherin in acantholytic squamous cell carcinoma. J. Cutan. Pathol. 2001; 28; 83–89.
Histopathology, 68, 461–468.
465
Epstein–Barr virus-positive T-cellassociated colitis mimicking inflammatory bowel disease: clinicopathological study of two cases DOI: 10.1111/his.12773 © 2015 John Wiley & Sons Ltd
Sir: Epstein–Barr virus (EBV) infects >90% of human beings, resulting in lifelong latency in memory B cells. Primary infection in childhood is often asymptomatic. Persistent active infection can occur in immunocompromised hosts, with morbidity and mortality. One example is chronic active EBV infection (CAEBV) affecting T cells or natural killer (NK) cells, characterized by fever, lymphadenopathy, a high number of blood EBV DNA copies, and histological and molecular evidence of EBV organ disease.1 It encompasses a disease spectrum that is most common in Asia, with polyclonal to monoclonal EBV-positive T or NK cell proliferation. The monoclonal disease overlaps with ‘EBV+ T-cell lymphoproliferative disorders (EBV+TCLPD) of childhood’ in the 2008 World Health Organization classification of lymphoma.2 We diagnosed CAEBV in two young Chinese boys presenting with chronic diarrhoea that mimicked chronic inflammatory bowel disease. Patient 1 (aged 12 years) presented with a 3-month history of diarrhoea, abdominal pain, and weight loss. Colonoscopy showed colitis with multiple ulcers. Blood, urine and stool cultures were negative. The patient had persistent fever, falling blood counts, active marrow haematopoiesis, hepatosplenomegaly with deranged liver function, and fresh blood per rectum. EBV-associated haemophagocytic syndrome was confirmed by positive serum EBV antibodies, and high numbers of whole blood and serum EBV DNA copies (2.07 9 105 and 2.43 9 104 copies/ml, respectively) as determined with quantitative real-time polymerase chain reaction (PCR). The patient developed profuse lower gastrointestinal (GI) bleeding necessitating subtotal colectomy. He was stable initially, but deteriorated suddenly, and died 9 months after admission. Examination of the colon showed multiple chronic and acute ischaemic ulcers with volcanic eruption of superficial glands (Figure 1A). Small-artery acute vasculitis with segmental fibrinoid necrosis was seen focally (Figure 1B). There were patchy infiltrates of mostly T cells (CD20-negative, CD3-positive, CD4-positive or CD8-positive, and CD56-negative) (Figure 1C). EBV-encoded RNA (EBER) in-situ hybridization (ISH) demonstrated
