IV.	Malignant Lymphomas Mimicking Reactive Processes (continued) Marsha Kinney, James Cook and Steven Swerdlow

Case 7 Diagnosis: Extranodal NK/T-cell lymphoma, nasal type Case history: 39 year old male with pre-op diagnosis of "chronic laryngitis". Biopsy is of right subglottic area. After the case was signed out, additional history, which was actually known at our institution, was obtained by the original pathologist. About two years earlier the patient had right and left turbinate biopsies which demonstrated an extranodal NK/T-cell lymphoma, nasal type. The patient was treated following his recurrence. As of about 2 years later (8/06), he has a mildly positive PET scan in his turbinate that is of uncertain significance. The remainder of his scan was negative. No further follow-up. Histopathology : The small biopsies demonstrated an ulcerated dense diffuse somewhat polymorphous infiltrate. The ulcerated area showed neutrophils admixed with some lymphoid cells and plasma cells. Elsewhere there were numerous mostly small to intermediate-sized lymphoid cells, often with irregular nuclear contours admixed with somewhat variable numbers of plasma cells. The cells showed infiltration into the overlying epithelium. A Grocott stain was negative. Flow cytometric immunophenotypic studies: None performed. Paraffin section immunohistochemistry/in situ hybridization (ISH) : CD20 – Few scattered positive cells. CD3 – Moderate number of scattered positive strongly staining cells, numerous positive weakly staining cells. CD5 – Moderate number of scattered positive cells, probably similar to pattern of strongly staining CD3 positive cells (ie, many CD3+ cells are negative). CD4 – Moderate number of scattered strongly positive cells, plus staining of histiocytes, many lymphocytes are negative. CD8 – Few scattered positive cells. CD56 – Numerous positive cells in some areas. Granzyme B – Many positive cells. EBER ISH for EBV – Many positive cells. Genotypic & Cytogenetic studies: None performed. Diagnostic pathway: This biopsy, submitted with a pre-operative diagnosis of chronic laryngitis, was originally diagnosed as demonstrating a "dense lymphoid infiltrate associated with acute inflammation, ulcer and atypia of squamous mucosa, most consistent with reactive atypia." After the case was signed out, the surgeon called and informed the pathologist that the patient had a previous biopsy of lymphoma. At this point the pathologist became concerned and sent the case for consultation with the question "Does this represent recurrence of the patient's lymphoma?" The histopathology was reviewed as was the patient's prior biopsy which had been seen at our institution and diagnosed as an extranodal NK/T cell lymphoma, nasal type. The diagnosis was then confirmed using paraffin section immunohistochemistry and an in situ hybridization stain for Epstein-Barr virus. This case illustrates the following: Knowing a patient's clinical history can turn a potentially difficult case into one that is much easier to diagnose. Although in this case the location, particularly of the original biopsy suggested the diagnosis, remember that not all extranodal NK/T cell lymphomas of nasal type occur in the nose and, not all nasal lymphomas are NK/ T cell in origin. Extranodal and NK/T cell lymphomas of nasal type can be confused with inflammatory infiltrates due to the presence of admixed acute inflammatory cells in areas of ulceration or necrosis and admixed chronic inflammatory cells. The histopathologic features that should raise strong suspicion for a lymphoid neoplasm in this case include the dense infiltrate and at least somewhat enlarged lymphoid cells oftentimes with irregular nuclear contours. Biopsies of extranodal NK/T cell lymphomas of nasal type may not always demonstrate angiocentricity or areas of significant necrosis. Immunohistochemical stains and in situ hybridization for the Epstein-Barr virus are critical in confirming the diagnosis in a case such as this. Selection of appropriate stains requires knowing something about the differential diagnosis for lymphomas with this histopathologic appearance and at this site. One should not be shy about doing at least limited immunohistochemical stains as a quality assurance tool for yourself in evaluating lymphoid proliferations that raise any question of a malignant lymphoma. Standard genotypic studies looking for evidence of a B-cell or T cell clone would not be helpful in confirming the neoplastic nature of this infiltrate since this type of lymphoma is usually of natural killer cell origin. Extranodal T/NK Cell Lymphomas: One of the major differences between the WHO lymphoma classification and many of those that preceded it is the specific identification of a significant number of distinctive extranodal lymphomas. Although not very common (at least in the U.S.), a major set of these are the extranodal T/NK lymphomas which include enteropathy-type T-cell lymphoma (ETCL), subcutaneous panniculitis-like T-cell lymphoma (SCPTCL), extranodal NK/T-cell lymphoma, nasal type and hepatosplenic T-cell lymphoma. [1, 2, 3] All of these lymphomas share many features including the fact that their diagnosis requires a combination of morphologic, immunophenotypic and anatomic information. All can have a variable cytologic appearance and all are composed of cytotoxic T or NK cells as identified by expression of the cytotoxic T cell associated granule TIA-1 with or without other cytotoxic T-cell associated proteins (granzyme, perforin). Even within one entity there can be major phenotypic differences, which, at least at this point in time, are generally not considered to be important. One exception to this is that, as currently defined, SCPTCL must be of alpha-beta T-cell type. Lymph node involvement is infrequent in many of these lymphomas and, except for the newly defined SCPTCL, they are considered to be very aggressive neoplasms. Extranodal NK/T-cell lymphoma, nasal type Making the diagnosis: The diagnosis of extranodal NK/T cell lymphoma, nasal type is made based on the anatomic site of the lymphoma (but remember not all occur in the nose and not all nasal lymphomas are NK/T cell lymphomas), the histopathology (which is not very specific) and immunophenotypic and other ancillary studies. Histopathology: Histologic sections demonstrate a diffuse proliferation of small, medium, large and/or anaplastic "atypical" lymphoid cells. [4, 5, 6] The neoplastic cells will have azurophilic granules on touch imprints stained with Romanovsky-type stains. Necrosis is very common but angiocentricity is reported in less than half to two thirds of cases. The necrosis present is believed to be due at least in part to factors such as chemokines or cytokines. [7, 8] A lack of angiodestruction and necrosis is reported to be associated with cases of "small cell type". [9] There may be many admixed acute and chronic inflammatory cells. These morphologic findings will lead to a differential diagnosis that, among other things, includes benign inflammatory processes and nasal lymphomas not of NK/T-cell type including other angiocentric lymphomas. Conversely, reactive proliferations can be confused with NK/T cell lymphomas. [10] Immunophenotype/EBV status: Most cases have the phenotype of true natural killer cells (but some are T-cell neoplasms). [4, 5, 6, 11] They demonstrate the following phenotype: surface CD3-, cytoplasmic CD3ε+, CD2+, CD5-, CD7± and most cases are CD4 and CD8 negative. Cytotoxic markers, such as TIA1 or granzyme B, are positive as is the NK-cell associated marker CD56. CD16 and CD57 are not expressed. Cases are almost invariably EBV positive as identified using EBER-1 in-situ hybridization. CD30 expression may be present.9 It should be remembered that, as with other lymphomas, not all cases have a typical phenotype. For example, in the study from the Massachusetts General Hospital, some cases were CD3 negative, one even CD45 negative and they documented CD56 expression in only half of the cases studied. [12] Others also find atypical phenotypes, such as cases with a lack of CD56 expression in paraffin sections. [11, 13] Rare cases lacking at least one of the cytotoxic markers have been reported, and some report EBV negative cases. [11, 14] The 2008 WHO chapter specifically requires that cytotoxic molecules and EBV present to make the diagnosis in a CD3e+ CD56- case. [15] CD3+, CD56-, EBV-, cytotoxic molecules negative cases are to be diagnosed as peripheral T-cell lymphoma, not otherwise specified. EBV- cases "should be accepted with some skepticism". [15] Clinical features: [12, 14, 15, 16, 17, 18] Extranodal NK/T-cell lymphomas of nasal type most typically occur as localized destructive nasal lesion. They may, however, involve other parts of the upper aerodigestive tract or sometimes other sites (hence the term "nasal type"). They are most common in the Orient but occur in the West. Their median survival is described as poor in the Orient (12.5 months in nasal/nasopharyngeal NK/T cell lymphomas in one series [16]; however, a study from the Massachusetts General Hospital reported an outcome similar to sinonasal diffuse large B-cell lymphomas. [12] Nasal NK/T lymphomas can be associated with a hemophagocytic (macrophage activation) syndrome, which is an important cause of mortality in these patients. They can also involve lymph nodes and disseminate widely to other extranodal sites. Extra-upper aerodigestive tract cases are reported to have a worse prognosis. [19] These authors suggest that this is a better way of recognizing a more aggressive group of cases rather than dividing cases into nasal versus extra-nasal locations. The International Prognostic Index is also prognostically useful in these cases as is "local tumor invasiveness". [13, 20] In most studies, cell size is not of independent prognostic significance. [9] References: Chan JK. Peripheral T-cell and NK-cell neoplasms: an integrated approach to diagnosis. Modern Pathology 12: 177-199, 1999. Jaffe ES, Krenacs L, Kumar S, et al. Extranodal peripheral T-cell and NK-cell neoplasms. American Journal of Clinical Pathology 111: S46-55, 1999. Kinney MC. The role of morphologic features, phenotype, genotype, and anatomic site in defining extranodal T-cell or NK-cell neoplasms. American Journal of Clinical Pathology 111: S104-118, 1999. Chan JKC, Jaffe ES, Ralfkiaer E, Extranodal NK/T-cell lymphoma, nasal type. in World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Jaffe ES, Harris NL, Stein H, et al., [Eds.] IARC: Lyon. 2001, 204-207. Jaffe ES, Krenacs L, Raffeld M. Classification of cytotoxic T-cell and natural killer cell lymphomas. Semin Hematol 40: 175-184, 2003. Nava VE, Jaffe ES. The pathology of NK-cell lymphomas and leukemias. Adv Anat Pathol 12: 27-34, 2005. Ng CS, Lo ST, Chan JK, et al. CD56+ putative natural killer cell lymphomas: production of cytolytic effectors and related proteins mediating tumor cell apoptosis? Hum Pathol 28: 1276-1282, 1997. Teruya-Feldstein J, Jaffe ES, Burd PR, et al. The role of Mig, the monokine induced by interferon-gamma, and IP-10, the interferon-gamma-inducible protein-10, in tissue necrosis and vascular damage associated with Epstein-Barr virus-positive lymphoproliferative disease. Blood 90: 4099-4105, 1997. Kuo TT, Shih LY, Tsang NM. Nasal NK/T cell lymphoma in Taiwan: a clinicopathologic study of 22 cases, with analysis of histologic subtypes, Epstein-Barr virus LMP-1 gene association, and treatment modalities. Int J Surg Pathol 12: 375-387, 2004. Taddesse-Heath L, Feldman JI, Fahle GA, et al. Florid CD4+, CD56+ T-cell infiltrate associated with Herpes simplex infection simulating nasal NK-/T-cell lymphoma. Mod Pathol 16: 166-172, 2003. Kitamura A, Yamashita Y, Hasegawa Y, et al. Primary lymphoma arising in the nasal cavity among Japanese. Histopathology 47: 523-532, 2005. Cuadra-Garcia I, Proulx GM, Wu CL, et al. Sinonasal lymphoma: a clinicopathologic analysis of 58 cases from the Massachusetts General Hospital. Am J Surg Pathol 23: 1356-1369, 1999. Ng SB, Lai KW, Murugaya S, et al. Nasal-type extranodal natural killer/T-cell lymphomas: a clinicopathologic and genotypic study of 42 cases in Singapore. Mod Pathol 17: 1097-1107, 2004. Lee MY, Tsou MH, Tan TD, et al. Clinicopathological analysis of T-cell lymphoma in Taiwan according to WHO classification: high incidence of enteropathy-type intestinal T-cell lymphoma. Eur J Haematol 75: 221-226, 2005. Chan JKC, Quintanilla-Martinez L, Ferry JA, et al., Extranodal NK/T-cell lymphoma, nasal type. in WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Swerdlow SH, Campo E, Harris NL, et al., [Eds.] IARC: Lyon. 2008, 285-288. Cheung MM, Chan JK, Lau WH, et al. Primary non-Hodgkin's lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients. J Clin Oncol 16: 70-77, 1998. Cheung MM, Chan JK, Lau WH, et al. Early stage nasal NK/T-cell lymphoma: clinical outcome, prognostic factors, and the effect of treatment modality. Int J Radiat Oncol Biol Phys 54: 182-190, 2002. Tham IW, Lee KM, Peng Yap S, et al. Outcome of patients with nasal natural killer (NK)/T-cell lymphoma treated with radiotherapy, with or without chemotherapy. Head Neck, 2005. Lee J, Park YH, Kim WS, et al. Extranodal nasal type NK/T-cell lymphoma: elucidating clinical prognostic factors for risk-based stratification of therapy. Eur J Cancer 41: 1402-1408, 2005. Kim TM, Park YH, Lee SY, et al. Local tumor invasiveness is more predictive of survival than International Prognostic Index in stage I(E)/II(E) extranodal NK/T-cell lymphoma, nasal type. Blood 106: 3785-3790, 2005.