Australasian Journal of Dermatology (2016) 57, e17–e19
doi: 10.1111/ajd.12279
BRIEF REPORTS
Nasal-type extranodal natural killer/T-cell lymphoma presenting as a solitary non-healing lower leg ulcer Tse-Yuan Liaw1,2 and Stephen Chu-Sung Hu3,4 1
Department of Dermatology, Cathay General Hospital, Taipei, 2School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, 3Department of Dermatology, Kaohsiung Medical University Hospital, and 4Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
ABSTRACT Nasal-type extranodal natural killer/T-cell lymphoma (ENTCL) is an aggressive form of non-Hodgkin’s lymphoma with a poor prognosis. Primary cutaneous lesions of ENTCL usually present as nodules or infiltrative plaques. The presentation of ENTCL as a solitary ulcer, in the absence of other cutaneous lesions and systemic symptoms and signs, is extremely rare and may be easily misdiagnosed. In this report, we describe an unusual case of ENTCL with a diagnostically challenging clinical presentation as a solitary non-healing leg ulcer in an elderly woman. Key words: extranodal natural killer/T-cell lymphoma, leg ulcer, radiation therapy.
Nasal-type extranodal natural killer/T-cell lymphoma (ENTCL) is a rare type of non-Hodgkin’s lymphoma associated with Epstein–Barr virus (EBV) infection.1 It is an aggressive lymphoma with a poor prognosis. It is infrequently seen in Western countries but is more prevalent in East Asia and Latin America.2 It most commonly arises from the nasal cavity or nasopharynx, and the skin is the second most common site of involvement.3 We here describe an unusual case of ENTCL presenting as a solitary leg ulcer.
CASE REPORT An 82-year-old woman presented in February 2012 with a painful ulcer that had appeared on her left lower leg for 1
Correspondence: Dr Stephen Chu-Sung Hu, Department of Dermatology, Kaohsiung Medical University Hospital, no. 100, Tzyou 1st Road, Kaohsiung 807, Taiwan. Email: [email protected] Tse-Yuan Liaw, MD. Stephen Chu-Sung Hu, M.Phil. Conflict of interest: none. Submitted 30 September 2014; accepted 19 October 2014. © 2014 The Australasian College of Dermatologists
month. Her past medical history included diabetes mellitus, hypertension, hyperlipidaemia, stroke, myocardial infarction and bladder cancer. The patient did not experience any episodes of fever or night sweating and there was no history of weight change. The ulcer failed to be ameliorated following systemic antibiotic treatment. On physical examination, a solitary 4.5 cm × 6 cm ulcer with exposed subcutaneous tissue and a necrotic, infiltrated border was seen on the patient’s left lower leg (Fig. 1). There were no other skin nodules, plaques or ulcers. No enlarged lymph nodes were palpable and there was no clinical evidence of hepatomegaly or splenomegaly. Laboratory data revealed a normal white blood cell count, and there were no anaemia, thrombocytopenia or atypical cells in the peripheral blood. Serum C-reactive protein and lactate dehydrogenase levels were normal. Liver function, renal function, urine and stool examinations were all normal. Epstein–Barr virus (EBV) DNA was detected in the peripheral blood by polymerase chain reaction. An incisional skin biopsy was performed, which revealed a diffuse infiltrate of medium-sized atypical lymphocytes extending from the dermis into the subcutaneous fat. The infiltrate was angiocentric and angiodestructive, and was associated with zones of necrosis (Fig. 2). The tumour cells had irregular hyperchromatic nuclei, and mitoses were frequent. Epidermotropism of the tumour cells was not seen. Immunohistochemical studies showed that the tumour cells were positive for CD2 and CD56 (Fig. 3a,b), but negative for CD3, CD4, CD8 and CD20. In addition, positive staining for EBV-encoded RNA (EBER) was found by in situ hybridisation (Fig. 3c). The skin biopsy tissue was also sent for microbial examination. Bacterial, fungal and mycobacterial cultures were all negative, and acid-fast stain and polymerase chain reaction for Mycobacterium tuberculosis were also negative.
Abbreviations: EBER EBV ENTCL
EBV-encoded RNA Epstein–Barr virus extranodal natural killer/T-cell lymphoma
T‐Y Liaw et al.
e18
(a)
(b)
Figure 1 Deep-seated necrotic ulcer measuring 4.5 cm × 6 cm on the left lower leg.
On endoscopic examination her upper respiratory tract was normal. A chest X-ray, abdominal ultrasound, and whole body positron emission tomography/computed tomography showed no evidence of lymph node, bone marrow or visceral organ involvement. A diagnosis of extranodal natural killer/T-cell lymphoma (ENTCL) was made (Ann Arbor stage IE, T1bN0M0). The patient underwent regional radiation therapy with total dose of 5000 cGy divided into 25 fractions. The ulcerative wound on the left lower leg gradually healed after 6 months. However, local recurrence of lymphoma was found 1 year later, and multiple courses of radiotherapy have been administered up till the present time.
DISCUSSION Primary cutaneous lesions of ENTCL are usually nodules or infiltrative plaques located on the trunk and limbs. The highly destructive behaviour of the tumour can lead to extensive ulcers.4 However, the presentation of ENTCL as a solitary ulcer, in the absence of other cutaneous lesions and systemic symptoms and signs, is extremely rare. This unusual presentation may lead to misdiagnosis, including chronic diabetic ulcer, necrotising fasciitis, pyoderma gangrenosum, infections (deep fungal infection, mycobacterial infection), vasculitis (Wegener’s granulomatosis) and other cutaneous malignancies (squamous cell carcinoma). The delay in diagnosis may have a negative impact on the patient’s clinical outcome. © 2014 The Australasian College of Dermatologists
Figure 2 A skin biopsy showed (a) a diffuse infiltrate of neoplastic cells in the dermis and the subcutaneous fat tissue with prominent angiodestruction and zones of necrosis (×100). (b) High power view showed the angiocentric distribution of atypical, medium-sized lymphocytes with hyperchromatic and pleomorphic nuclei (×400).
EBV is detected in nearly all cases of ENTCL and is thought to be crucially involved in the pathogenesis of this malignancy.5,6 Therefore, the detection of EBV expression is required for the diagnosis. The gold standard for detecting EBV in neoplastic cells is by in situ hybridisation (EBER).7 In addition, a diagnosis of ENTCL also relies on the demonstration of CD56-positive atypical lymphocytes. In rare CD56-negative cases, the detection of EBV and expression of cytotoxic proteins (TIA-1, granzyme B, perforin) is required. In our case, the characteristic cell morphology, the presence of angiocentricity and angiodestruction, the positive expression of CD2 and CD56 and the detection of EBER by in situ hybridisation in atypical lymphocytes confirmed the diagnosis of ENTCL. Currently, there is no consensus regarding the optimal treatment of this disease. Generally, the treatment is largely determined by the extent of disease. Localised disease is commonly treated with radiation therapy with or without
ENTCL presenting as a solitary ulcer
(a)
e19
chemotherapy, while patients with advanced disease are usually treated with multiple-agent chemotherapy with or without haematopoietic stem cell transplantation.8–10 The prognosis is usually poor in spite of treatment, and most patients die within a few months. The median survival is less than 12 months for cases presenting in the skin. Poor prognostic factors include lymph node involvement, bone marrow or extra-cutaneous involvement and angiocentrism. Due to her age, her multiple underlying medical diseases, the early clinical stage with solitary skin lesion and the absence of systemic involvement, our patient was treated with regional radiotherapy without chemotherapy.
CONCLUSION
(b)
We describe a case of ENTCL with an unusual and diagnostically challenging presentation as a solitary non-healing ulcer on the leg. We propose that ENTCL should be considered in the differential diagnosis in patients presenting with solitary non-healing or poorly healing skin ulcers. A high index of suspicion and early diagnosis by skin biopsy may improve the outcome in this aggressive lymphoma.
ACKNOWLEDGEMENTS This work was supported by a grant from the Kaohsiung Medical University Hospital (KMUH100-0M28).
REFERENCES 1. 2.
(c) 3.
4.
5. 6.
7.
8. Figure 3 The immunohistochemical stains revealed (a) positive reactions with CD2 (×200) and (b) with CD56 (×200). (c) Epstein– Barr virus-encoded RNA was detected in atypical lymphocytes by in situ hybridisation (×200).
9.
10.
Willemze R, Jaffe ES, Burg G et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105: 3768–85. Liao JB, Chuang SS, Chen HC et al. Clinicopathologic analysis of cutaneous lymphoma in Taiwan: a high frequency of extranodal natural killer/T-cell lymphoma, nasal type, with an extremely poor prognosis. Arch. Pathol. Lab. Med. 2010; 134: 996–1002. Wang TT, Xu C, Liu SL et al. Clinicopathology, immunophenotype, T cell receptor gene rearrangement, Epstein–Barr virus status and p53 gene mutation of cutaneous extranodal NK/T-cell lymphoma, nasal-type. Chin. Med. J. (Engl.) 2013; 126: 1281–7. Chia HY, Tey HL, Tan KB et al. Nasal-type extranodal natural killer/T-cell lymphoma presenting with extensive leg ulcers. Clin. Exp. Dermatol. 2009; 34: e693–5. Suzuki R. Pathogenesis and treatment of extranodal natural killer/T-cell lymphoma. Semin. Hematol. 2014; 51: 42–51. Nitta Y, Iwatsuki K, Kimura H et al. Fatal natural killer cell lymphoma arising in a patient with a crop of Epstein–Barr virus-associated disorders. Eur. J. Dermatol. 2005; 15: 503–6. Neparidze N, Lacy J. Malignancies associated with Epstein– Barr virus: pathobiology, clinical features, and evolving treatments. Clin. Adv. Hematol. Oncol. 2014; 12: 358–71. Huang MJ, Jiang Y, Liu WP et al. Early or up-front radiotherapy improved survival of localized extranodal NK/T-cell lymphoma, nasal-type in the upper aerodigestive tract. Int. J. Radiat. Oncol. Biol. Phys. 2008; 70: 166–74. Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J. Clin. Oncol. 2008; 26: 4124– 30. Hosing C, Champlin RE. Stem-cell transplantation in T-cell non-Hodgkin’s lymphomas. Ann. Oncol. 2011; 22: 1471–7. © 2014 The Australasian College of Dermatologists
doi: 10.1111/ajd.12279
BRIEF REPORTS
Nasal-type extranodal natural killer/T-cell lymphoma presenting as a solitary non-healing lower leg ulcer Tse-Yuan Liaw1,2 and Stephen Chu-Sung Hu3,4 1
Department of Dermatology, Cathay General Hospital, Taipei, 2School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, 3Department of Dermatology, Kaohsiung Medical University Hospital, and 4Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
ABSTRACT Nasal-type extranodal natural killer/T-cell lymphoma (ENTCL) is an aggressive form of non-Hodgkin’s lymphoma with a poor prognosis. Primary cutaneous lesions of ENTCL usually present as nodules or infiltrative plaques. The presentation of ENTCL as a solitary ulcer, in the absence of other cutaneous lesions and systemic symptoms and signs, is extremely rare and may be easily misdiagnosed. In this report, we describe an unusual case of ENTCL with a diagnostically challenging clinical presentation as a solitary non-healing leg ulcer in an elderly woman. Key words: extranodal natural killer/T-cell lymphoma, leg ulcer, radiation therapy.
Nasal-type extranodal natural killer/T-cell lymphoma (ENTCL) is a rare type of non-Hodgkin’s lymphoma associated with Epstein–Barr virus (EBV) infection.1 It is an aggressive lymphoma with a poor prognosis. It is infrequently seen in Western countries but is more prevalent in East Asia and Latin America.2 It most commonly arises from the nasal cavity or nasopharynx, and the skin is the second most common site of involvement.3 We here describe an unusual case of ENTCL presenting as a solitary leg ulcer.
CASE REPORT An 82-year-old woman presented in February 2012 with a painful ulcer that had appeared on her left lower leg for 1
Correspondence: Dr Stephen Chu-Sung Hu, Department of Dermatology, Kaohsiung Medical University Hospital, no. 100, Tzyou 1st Road, Kaohsiung 807, Taiwan. Email: [email protected] Tse-Yuan Liaw, MD. Stephen Chu-Sung Hu, M.Phil. Conflict of interest: none. Submitted 30 September 2014; accepted 19 October 2014. © 2014 The Australasian College of Dermatologists
month. Her past medical history included diabetes mellitus, hypertension, hyperlipidaemia, stroke, myocardial infarction and bladder cancer. The patient did not experience any episodes of fever or night sweating and there was no history of weight change. The ulcer failed to be ameliorated following systemic antibiotic treatment. On physical examination, a solitary 4.5 cm × 6 cm ulcer with exposed subcutaneous tissue and a necrotic, infiltrated border was seen on the patient’s left lower leg (Fig. 1). There were no other skin nodules, plaques or ulcers. No enlarged lymph nodes were palpable and there was no clinical evidence of hepatomegaly or splenomegaly. Laboratory data revealed a normal white blood cell count, and there were no anaemia, thrombocytopenia or atypical cells in the peripheral blood. Serum C-reactive protein and lactate dehydrogenase levels were normal. Liver function, renal function, urine and stool examinations were all normal. Epstein–Barr virus (EBV) DNA was detected in the peripheral blood by polymerase chain reaction. An incisional skin biopsy was performed, which revealed a diffuse infiltrate of medium-sized atypical lymphocytes extending from the dermis into the subcutaneous fat. The infiltrate was angiocentric and angiodestructive, and was associated with zones of necrosis (Fig. 2). The tumour cells had irregular hyperchromatic nuclei, and mitoses were frequent. Epidermotropism of the tumour cells was not seen. Immunohistochemical studies showed that the tumour cells were positive for CD2 and CD56 (Fig. 3a,b), but negative for CD3, CD4, CD8 and CD20. In addition, positive staining for EBV-encoded RNA (EBER) was found by in situ hybridisation (Fig. 3c). The skin biopsy tissue was also sent for microbial examination. Bacterial, fungal and mycobacterial cultures were all negative, and acid-fast stain and polymerase chain reaction for Mycobacterium tuberculosis were also negative.
Abbreviations: EBER EBV ENTCL
EBV-encoded RNA Epstein–Barr virus extranodal natural killer/T-cell lymphoma
T‐Y Liaw et al.
e18
(a)
(b)
Figure 1 Deep-seated necrotic ulcer measuring 4.5 cm × 6 cm on the left lower leg.
On endoscopic examination her upper respiratory tract was normal. A chest X-ray, abdominal ultrasound, and whole body positron emission tomography/computed tomography showed no evidence of lymph node, bone marrow or visceral organ involvement. A diagnosis of extranodal natural killer/T-cell lymphoma (ENTCL) was made (Ann Arbor stage IE, T1bN0M0). The patient underwent regional radiation therapy with total dose of 5000 cGy divided into 25 fractions. The ulcerative wound on the left lower leg gradually healed after 6 months. However, local recurrence of lymphoma was found 1 year later, and multiple courses of radiotherapy have been administered up till the present time.
DISCUSSION Primary cutaneous lesions of ENTCL are usually nodules or infiltrative plaques located on the trunk and limbs. The highly destructive behaviour of the tumour can lead to extensive ulcers.4 However, the presentation of ENTCL as a solitary ulcer, in the absence of other cutaneous lesions and systemic symptoms and signs, is extremely rare. This unusual presentation may lead to misdiagnosis, including chronic diabetic ulcer, necrotising fasciitis, pyoderma gangrenosum, infections (deep fungal infection, mycobacterial infection), vasculitis (Wegener’s granulomatosis) and other cutaneous malignancies (squamous cell carcinoma). The delay in diagnosis may have a negative impact on the patient’s clinical outcome. © 2014 The Australasian College of Dermatologists
Figure 2 A skin biopsy showed (a) a diffuse infiltrate of neoplastic cells in the dermis and the subcutaneous fat tissue with prominent angiodestruction and zones of necrosis (×100). (b) High power view showed the angiocentric distribution of atypical, medium-sized lymphocytes with hyperchromatic and pleomorphic nuclei (×400).
EBV is detected in nearly all cases of ENTCL and is thought to be crucially involved in the pathogenesis of this malignancy.5,6 Therefore, the detection of EBV expression is required for the diagnosis. The gold standard for detecting EBV in neoplastic cells is by in situ hybridisation (EBER).7 In addition, a diagnosis of ENTCL also relies on the demonstration of CD56-positive atypical lymphocytes. In rare CD56-negative cases, the detection of EBV and expression of cytotoxic proteins (TIA-1, granzyme B, perforin) is required. In our case, the characteristic cell morphology, the presence of angiocentricity and angiodestruction, the positive expression of CD2 and CD56 and the detection of EBER by in situ hybridisation in atypical lymphocytes confirmed the diagnosis of ENTCL. Currently, there is no consensus regarding the optimal treatment of this disease. Generally, the treatment is largely determined by the extent of disease. Localised disease is commonly treated with radiation therapy with or without
ENTCL presenting as a solitary ulcer
(a)
e19
chemotherapy, while patients with advanced disease are usually treated with multiple-agent chemotherapy with or without haematopoietic stem cell transplantation.8–10 The prognosis is usually poor in spite of treatment, and most patients die within a few months. The median survival is less than 12 months for cases presenting in the skin. Poor prognostic factors include lymph node involvement, bone marrow or extra-cutaneous involvement and angiocentrism. Due to her age, her multiple underlying medical diseases, the early clinical stage with solitary skin lesion and the absence of systemic involvement, our patient was treated with regional radiotherapy without chemotherapy.
CONCLUSION
(b)
We describe a case of ENTCL with an unusual and diagnostically challenging presentation as a solitary non-healing ulcer on the leg. We propose that ENTCL should be considered in the differential diagnosis in patients presenting with solitary non-healing or poorly healing skin ulcers. A high index of suspicion and early diagnosis by skin biopsy may improve the outcome in this aggressive lymphoma.
ACKNOWLEDGEMENTS This work was supported by a grant from the Kaohsiung Medical University Hospital (KMUH100-0M28).
REFERENCES 1. 2.
(c) 3.
4.
5. 6.
7.
8. Figure 3 The immunohistochemical stains revealed (a) positive reactions with CD2 (×200) and (b) with CD56 (×200). (c) Epstein– Barr virus-encoded RNA was detected in atypical lymphocytes by in situ hybridisation (×200).
9.
10.
Willemze R, Jaffe ES, Burg G et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105: 3768–85. Liao JB, Chuang SS, Chen HC et al. Clinicopathologic analysis of cutaneous lymphoma in Taiwan: a high frequency of extranodal natural killer/T-cell lymphoma, nasal type, with an extremely poor prognosis. Arch. Pathol. Lab. Med. 2010; 134: 996–1002. Wang TT, Xu C, Liu SL et al. Clinicopathology, immunophenotype, T cell receptor gene rearrangement, Epstein–Barr virus status and p53 gene mutation of cutaneous extranodal NK/T-cell lymphoma, nasal-type. Chin. Med. J. (Engl.) 2013; 126: 1281–7. Chia HY, Tey HL, Tan KB et al. Nasal-type extranodal natural killer/T-cell lymphoma presenting with extensive leg ulcers. Clin. Exp. Dermatol. 2009; 34: e693–5. Suzuki R. Pathogenesis and treatment of extranodal natural killer/T-cell lymphoma. Semin. Hematol. 2014; 51: 42–51. Nitta Y, Iwatsuki K, Kimura H et al. Fatal natural killer cell lymphoma arising in a patient with a crop of Epstein–Barr virus-associated disorders. Eur. J. Dermatol. 2005; 15: 503–6. Neparidze N, Lacy J. Malignancies associated with Epstein– Barr virus: pathobiology, clinical features, and evolving treatments. Clin. Adv. Hematol. Oncol. 2014; 12: 358–71. Huang MJ, Jiang Y, Liu WP et al. Early or up-front radiotherapy improved survival of localized extranodal NK/T-cell lymphoma, nasal-type in the upper aerodigestive tract. Int. J. Radiat. Oncol. Biol. Phys. 2008; 70: 166–74. Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J. Clin. Oncol. 2008; 26: 4124– 30. Hosing C, Champlin RE. Stem-cell transplantation in T-cell non-Hodgkin’s lymphomas. Ann. Oncol. 2011; 22: 1471–7. © 2014 The Australasian College of Dermatologists
