Extranodal NK-T-cell lymphoma overview

# Overview
Extranodal NK cell lymphoma probably was first reported by McBride as a disease which rapidly destructs nose and face with progressing necrotic granuloma. The natural history of extranodal NK cell lymphoma was generally aggressive and lethal, this disease was initially termed as "rhinitis gangrenosa progressiva". Since the lesions usually was in midline and was aggressive and lethal, the term "lethal midline granuloma (LMG)" was used. First known case of natural-killer-cell lymphoma was diagnosed in a 19-years old boy. The diagnosis of natural-killer-cell lymphoma was confirmed by pathology as Wegener's Granulomatosis was ruled out.In contrast with B-cell lymphoma, the classification of such a rare neoplasm has been controversial, since the cytologic features have not been very useful. Further, by many entities, T-cell and natural killer cell (NK) neoplasms do not share any similar immuno-phenotype. Because of such matters, clinical features became handier for classification and somehow even more important than the precise cell of origin. since the majority of cytotoxic T-cell and NK cell lymphomas are located out of lymph nodes, the gene expressing cytotoxic molecules may predispose to apoptosis by tumor cells and by standard cells.Three major categories of extranodal T/NK cell tumors include: Extranodal NK/T-cell lymphoma, nasal type lymphoma, Extranodal NK/T-cell lymphoma, enteropathy type lymphoma, Extranodal NK/T-cell lymphoma, subcutaneous panniculitis-like, Extranodal NK-T-cell lymphoma may be classified according to WHO into 2 subtypes:, NK cell-derived neoplasms, namely, aggressive NK cell leukemia, Extranodal NK/T-cell lymphoma, nasal type, Based on the organ involvement, extranodal NK-T-cell lymphoma may be classified into: Extranodal NK-T-cell lymphoma, nasal type, Extranodal NK-T-cell lymphoma, extra nasal type.NK cells are CD3 and myloperoxidase negative on their surface. NK cells have germline configuration of T-cell receptor and immunoglobulin genes. NK cells originate from a bipotent NK/T-progenitor cell so they have a lot in common with T cells. NK cells express T-associate markers such as CD2, CD3e, CD7, CD8, CD16, CD56, CD57. Most tumors involve NK cells but also involve T cells as neoplastic cells, that is the main reason of classification as NK/T-cell lymphoma rather than NK-cell lymphoma. the immunophenotype of NK lymphoma cells is classically positive for CD2, CD56, and cytoplasmic CD3 epsilon. they are negative for surface CD3. Unlike normal NK cells, the tumor cells are usually negative for CD7 and CD16. they express cytotoxic granule associated proteins granzyme B, T-cell restricted intracellular antigen (TIA-1), and perforin. NK/T cell lymphoma expressing CD56 is rare but most commonly occurs int he head and neck region, skin, and soft tissue. genes involved in the pathogenesis of extranodal NK-T-cell lymphoma include.:HLA DQA1*0501, HLA DQB1*0201. these genes also are relevant with celiac disease.On gross pathology, angiocentric and angiodestructive pattern of growth with associated geographical necrosis and ulceration are characteristic findings of extranodal NK-T-cell lymphoma.Coagulative necrosis and apoptotic bodies are frequently encountered., Extranodal NK/T-cell lymphoma, nasal type occurs in nasal cavity and upper aerodigestive tract., Extranodal NK/T cell lymphoma, nasal type affects the nose and facial mid line exhibiting aggressive destruction., on microscopic histopathological analysis, medium sized tumor cells and polymorphic infiltrate of non-neoplastic inflammatory cells are characteristic findings of extranodal NK-T-cell lymphoma. the tumor cells are small to medium in size with occasional large and anaplastic forms. the lymphoma cells may be admixed with a polymorphic infiltrate of nonneoplastic inflammatory cells including small lymphocytes, plasma cells, histiocytes, and eosinophils.Extranodal NK/T-cell lymphoma is caused by transition mutation of p53. P53 overexpresion has assosiation with poor prognosis.Extranodal NK-T-cell lymphoma must be differentiated from other diseases such as NK cell lukemia, lymphomatoid granulomatosis, EBV-positive diffuse large B cell lymphoma, NOS, anaplastic large cell lymphoma, non specific inflammatory process, enteropathy associated T cell lymphoma, peripheral T cell lymphoma, hepatosplenic T cell lymphoma. Extranodal NK/T-cell lymphoma, nasal type must be diffrentiated from Wegner's granulomatosis, Polymorphic reticulosis, and Midline malignant lymphoma.NK cell lymphoma shows a poor prognosis because of rapid local progression and distant metastasis.The median age of onset is approximately 50 years and it is common in elderly. extranodal NK/T-cell lymphoma is a rare disease in children and often it is associated with mosquito-bite hypersensitivity or other EBV-associated disease.Natural Killer (NK) cell lymphoma is a rare disease. extranodal NK/T cell lymphoma, nasal type (NKTCL) and aggressive NK-cell leukemia (ANKCL) have a higher incidence in Asia, Central, and South America.NK T cell lymphoma, nasal type (NNKTL) consist 3000-10000 out of 100000 cases of non-Hodgkin lymphoma in Asia and South America and less than 1000 in 10000 patient in western countries.There is a strong association between with extranodal NK/T-cell lymphoma and EBV virus.There is a strong assosiation between Extranodal NK/T-cell lymphoma andFas(Po-1/CD95) mutations.According to the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for extranodal NK-T-cell lymphoma.If left untreated, patients with extranodal NK-T-cell lymphoma, nasal type may progress to develop proptosis and hard palate perforation. Common complications of extranodal NK-T-cell lymphoma include hepatosplenomegaly and pancytopenia. Depending on the extent of the tumor at the time of diagnosis, the prognosis may vary. Prognosis is generally regarded as poor.Extranodal NK/T cell lymphoma survival rate is not well predicted by Ann Arbor staging system. A new system was introduced based on B symptoms, Ann Arbor system, LDH level, and regional lymphadenopathy combined. Another parallel mechanism for extranodal NK/T cell lymphoma is based on tumor biologic and micro-environmental factors. High Ki-67 nuclear antigen is a marker for actively proliferation tumor cell which could be a related factor with mass bulk.
combination of these two findings on immunophenotyping of frozen section specimen cells and RT-PCR are confirmatory for Extranodal NK/T cell lymphoma:Detection of CD56 and EBER1 on tumor cells and EBV DNA (RT-PCR).Pathological examination of frozen section specimen may misled the NK/T cell diagnosis.Circulating cell free EBV DNA levels by RT-PCR is a diagnostic factor for EBV associated malignancies, Like extranodal NK/T cell lymphoma. Measuring both BamHI W DNA and LMP1 DNA is more useful as a prognosis predictor, these DNAs will decrease with treatment and increase with relapse. Recently, determination of negative immune checkpoints are considered as a drug target,in the case of extranodal NK/T cell lymphoma, PD-L1 will be expressed in the tumor, and patients with higher concentration of soluble PD-L1 showed worse prognosis.
The most common symptoms of extranodal NK-T-cell lymphoma include fever, weight loss, skin rash, night sweats, protrusion of eye, swelling of the face, discharge from the nose, nose bleeds, blockage of the nasal passages, chest pain, abdominal pain, bone pain, and painless swelling in the neck, axilla, groin, thorax, and abdomen. Extranodal NK/T cell lymphoma, nasal type, which is the most common sub type, is usually found as an ulcerative and necrotic granuloma in the nasal cavity, palate, and nasopharynx. Tumor can spread to surrounding tissue such as facial skin, paranasal sinus, and orbits, and cause exensive destruction of midline lesions. The most common symptoms at the time of diagnosis are nasal obstruction and bloody rhinorea.
Common physical examination findings of extranodal NK-T-cell lymphoma include fever, rash, ulcer, proptosis, midfacial destructive lesions, epistaxis, nasal obstruction due to mass, chest tenderness, abdomen tenderness, bone tenderness, peripheral lymphadenopathy, and central lymphadenopathy.
Laboratory tests for extranodal NK-T-cell lymphoma include complete blood count (CBC), blood chemistry studies, cytogenetic analysis, flow cytometry, immunohistochemistry, and immunophenotyping.
X-rays graphy of patients with extranodal NK/T cell lymphoma is not very usefull in order of diagnosis. Radiography show non-specific tumor changes.
CT scan may be helpful in the diagnosis of extranodal NK-T-cell lymphoma. Computerized tomography (CT) may be performed to detect metastasis and assess the local extent of extranodal NK-T-cell lymphoma.
MRI may be helpful in the diagnosis of extranodal NK-T-cell lymphoma.Magnetic resonance imaging (MRI) may be performed to better define local soft tissue and bony involvement of extranodal NK-T-cell lymphoma.
The predominant therapy for extranodal NK-T-cell lymphoma is radiation therapy. Adjudicative chemotherapy and stem cell transplant may be required.
Surgical intervention is not recommended for the management of extranodal NK/T cell lymphoma.
There are no established measures for the primary prevention of extranodal NK/T cell lymphoma.
Effective measures for the secondary prevention of extranodal NK-T-cell lymphoma include: LDH , MLH1, PDGFRA, VEGF, PD-L1, PD-1, Cyclin D1, p53, Ki-67.
High dose chemotherapy and autologous haematopoietic stem cell transplantation is used for varying types of lymphoma, however there is a lac of such experience in treating extranodal NK-T cell lymphoma. Further clinical trials are needed to prove that this therapy is handy and can be used as a method of therapy. Autologous transplantation appears to provide a great survival benefit only for those who attended a complete remission at the time of transplantation.

# Historical Perspective
Extranodal NK cell lymphoma probably was first reported by McBride as a disease which rapidly destructs nose and face with progressing necrotic granuloma. The natural history of extranodal NK cell lymphoma was generally aggressive and lethal, this disease was initially termed as "rhinitis gangrenosa progressiva". Since the lesions usually was in midline and was aggressive and lethal, the term "lethal midline granuloma (LMG)" was used. First known case of natural-killer-cell lymphoma was diagnosed in a 19-years old boy. The diagnosis of natural-killer-cell lymphoma was confirmed by pathology as Wegener's Granulomatosis was ruled out.

# Classification
In contrast with B-cell lymphoma, the classification of such a rare neoplasm has been controversial, since the cytologic features have not been very useful. Further, by many entities, T-cell and natural killer cell (NK) neoplasms do not share any similar immuno-phenotype. Because of such matters, clinical features became handier for classification and somehow even more important than the precise cell of origin. since the majority of cytotoxic T-cell and NK cell lymphomas are located out of lymph nodes, the gene expressing cytotoxic molecules may predispose to apoptosis by tumor cells and by standard cells.Three major categories of extranodal T/NK cell tumors include: Extranodal NK/T-cell lymphoma, nasal type lymphoma, Extranodal NK/T-cell lymphoma, enteropathy type lymphoma, Extranodal NK/T-cell lymphoma, subcutaneous panniculitis-like, Extranodal NK-T-cell lymphoma may be classified according to WHO into 2 subtypes:, NK cell-derived neoplasms, namely, aggressive NK cell leukemia, Extranodal NK/T-cell lymphoma, nasal type, Based on the organ involvement, extranodal NK-T-cell lymphoma may be classified into: Extranodal NK-T-cell lymphoma, nasal type, Extranodal NK-T-cell lymphoma, extra nasal type

# Pathophysiology
NK cells are CD3 and myloperoxidase negative on their surface. NK cells have germline configuration of T-cell receptor and immunoglobulin genes. NK cells originate from a bipotent NK/T-progenitor cell so they have a lot in common with T cells. NK cells express T-associate markers such as CD2, CD3e, CD7, CD8, CD16, CD56, CD57. Most tumors involve NK cells but also involve T cells as neoplastic cells, that is the main reason of classification as NK/T-cell lymphoma rather than NK-cell lymphoma. the immunophenotype of NK lymphoma cells is classically positive for CD2, CD56, and cytoplasmic CD3 epsilon. they are negative for surface CD3. Unlike normal NK cells, the tumor cells are usually negative for CD7 and CD16. they express cytotoxic granule associated proteins granzyme B, T-cell restricted intracellular antigen (TIA-1), and perforin. NK/T cell lymphoma expressing CD56 is rare but most commonly occurs int he head and neck region, skin, and soft tissue. genes involved in the pathogenesis of extranodal NK-T-cell lymphoma include.:HLA DQA1*0501, HLA DQB1*0201. these genes also are relevant with celiac disease.On gross pathology, angiocentric and angiodestructive pattern of growth with associated geographical necrosis and ulceration are characteristic findings of extranodal NK-T-cell lymphoma.Coagulative necrosis and apoptotic bodies are frequently encountered., Extranodal NK/T-cell lymphoma, nasal type occurs in nasal cavity and upper aerodigestive tract., Extranodal NK/T cell lymphoma, nasal type affects the nose and facial mid line exhibiting aggressive destruction., on microscopic histopathological analysis, medium sized tumor cells and polymorphic infiltrate of non-neoplastic inflammatory cells are characteristic findings of extranodal NK-T-cell lymphoma. the tumor cells are small to medium in size with occasional large and anaplastic forms. the lymphoma cells may be admixed with a polymorphic infiltrate of nonneoplastic inflammatory cells including small lymphocytes, plasma cells, histiocytes, and eosinophils.

# Causes
Extranodal NK/T-cell lymphoma is caused by transition mutation of p53. P53 overexpresion has assosiation with poor prognosis.

# Differential Diagnosis
Extranodal NK-T-cell lymphoma must be differentiated from other diseases such as NK cell lukemia, lymphomatoid granulomatosis, EBV-positive diffuse large B cell lymphoma, NOS, anaplastic large cell lymphoma, non specific inflammatory process, enteropathy associated T cell lymphoma, peripheral T cell lymphoma, hepatosplenic T cell lymphoma. Extranodal NK/T-cell lymphoma, nasal type must be diffrentiated from Wegner's granulomatosis, Polymorphic reticulosis, and Midline malignant lymphoma

# Epidemiology and Demographics
NK cell lymphoma shows a poor prognosis because of rapid local progression and distant metastasis.The median age of onset is approximately 50 years and it is common in elderly. extranodal NK/T-cell lymphoma is a rare disease in children and often it is associated with mosquito-bite hypersensitivity or other EBV-associated disease.Natural Killer (NK) cell lymphoma is a rare disease. extranodal NK/T cell lymphoma, nasal type (NKTCL) and aggressive NK-cell leukemia (ANKCL) have a higher incidence in Asia, Central, and South America.NK T cell lymphoma, nasal type (NNKTL) consist 3000-10000 out of 100000 cases of non-Hodgkin lymphoma in Asia and South America and less than 1000 in 10000 patient in western countries.

# Risk Factors
There is a strong association between with extranodal NK/T-cell lymphoma and EBV virus.There is a strong assosiation between Extranodal NK/T-cell lymphoma andFas(Po-1/CD95) mutations.

# Screening
According to the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for extranodal NK-T-cell lymphoma.

# Natural History, Prognosis, and Complications
If left untreated, patients with extranodal NK-T-cell lymphoma, nasal type may progress to develop proptosis and hard palate perforation. Common complications of extranodal NK-T-cell lymphoma include hepatosplenomegaly and pancytopenia. Depending on the extent of the tumor at the time of diagnosis, the prognosis may vary. Prognosis is generally regarded as poor.

# Diagnosis
Extranodal NK/T cell lymphoma survival rate is not well predicted by Ann Arbor staging system. A new system was introduced based on B symptoms, Ann Arbor system, LDH level, and regional lymphadenopathy combined. Another parallel mechanism for extranodal NK/T cell lymphoma is based on tumor biologic and micro-environmental factors. High Ki-67 nuclear antigen is a marker for actively proliferation tumor cell which could be a related factor with mass bulk.
combination of these two findings on immunophenotyping of frozen section specimen cells and RT-PCR are confirmatory for Extranodal NK/T cell lymphoma:Detection of CD56 and EBER1 on tumor cells and EBV DNA (RT-PCR).Pathological examination of frozen section specimen may misled the NK/T cell diagnosis.Circulating cell free EBV DNA levels by RT-PCR is a diagnostic factor for EBV associated malignancies, Like extranodal NK/T cell lymphoma. Measuring both BamHI W DNA and LMP1 DNA is more useful as a prognosis predictor, these DNAs will decrease with treatment and increase with relapse. Recently, determination of negative immune checkpoints are considered as a drug target,in the case of extranodal NK/T cell lymphoma, PD-L1 will be expressed in the tumor, and patients with higher concentration of soluble PD-L1 showed worse prognosis.
The most common symptoms of extranodal NK-T-cell lymphoma include fever, weight loss, skin rash, night sweats, protrusion of eye, swelling of the face, discharge from the nose, nose bleeds, blockage of the nasal passages, chest pain, abdominal pain, bone pain, and painless swelling in the neck, axilla, groin, thorax, and abdomen. Extranodal NK/T cell lymphoma, nasal type, which is the most common sub type, is usually found as an ulcerative and necrotic granuloma in the nasal cavity, palate, and nasopharynx. Tumor can spread to surrounding tissue such as facial skin, paranasal sinus, and orbits, and cause exensive destruction of midline lesions. The most common symptoms at the time of diagnosis are nasal obstruction and bloody rhinorea.
Common physical examination findings of extranodal NK-T-cell lymphoma include fever, rash, ulcer, proptosis, midfacial destructive lesions, epistaxis, nasal obstruction due to mass, chest tenderness, abdomen tenderness, bone tenderness, peripheral lymphadenopathy, and central lymphadenopathy.
Laboratory tests for extranodal NK-T-cell lymphoma include complete blood count (CBC), blood chemistry studies, cytogenetic analysis, flow cytometry, immunohistochemistry, and immunophenotyping.
X-rays graphy of patients with extranodal NK/T cell lymphoma is not very usefull in order of diagnosis. Radiography show non-specific tumor changes.
CT scan may be helpful in the diagnosis of extranodal NK-T-cell lymphoma. Computerized tomography (CT) may be performed to detect metastasis and assess the local extent of extranodal NK-T-cell lymphoma.
MRI may be helpful in the diagnosis of extranodal NK-T-cell lymphoma.Magnetic resonance imaging (MRI) may be performed to better define local soft tissue and bony involvement of extranodal NK-T-cell lymphoma.

# Treatment
The predominant therapy for extranodal NK-T-cell lymphoma is radiation therapy. Adjudicative chemotherapy and stem cell transplant may be required.
Surgical intervention is not recommended for the management of extranodal NK/T cell lymphoma.
There are no established measures for the primary prevention of extranodal NK/T cell lymphoma.
Effective measures for the secondary prevention of extranodal NK-T-cell lymphoma include: LDH , MLH1, PDGFRA, VEGF, PD-L1, PD-1, Cyclin D1, p53, Ki-67.
High dose chemotherapy and autologous haematopoietic stem cell transplantation is used for varying types of lymphoma, however there is a lac of such experience in treating extranodal NK-T cell lymphoma. Further clinical trials are needed to prove that this therapy is handy and can be used as a method of therapy. Autologous transplantation appears to provide a great survival benefit only for those who attended a complete remission at the time of transplantation.