Ohgami, Robert S. MD, PhD; Arber, Daniel A. MD; Zehnder, James L. MD; Natkunam, Yasodha MD, PhD; Warnke, Roger A. MD
Department of Pathology, Stanford University Medical Center, Stanford, CA 94305
The authors have no funding or conflicts of interest to disclose.
Reprints: Robert S. Ohgami, MD, PhD, Department of Pathology, 300 Pasteur Drive, Stanford CA 94305 (e-mail: firstname.lastname@example.org).
In recent years, a new pathologic entity has emerged: indolent T-lymphoblastic proliferation (iT-LBP). iT-LBPs share immunophenotypic similarities with T-lymphoblastic lymphoma; however, T-lymphoblastic proliferations are clinically indolent, and unlike the malignant counterpart, these expansions of nonclonal terminal deoxynucleotidyl transferase (TdT)+ T cells do not require treatment. Here we review the clinical and pathologic features, which are required for an accurate diagnosis of an iT-LBP. We demonstrate specific criteria can be used to accurately diagnose iT-LBP, notably: (1) confluent groups of TdT+ T cells in a biopsy specimen, (2) relative preservation of surrounding normal lymphoid architecture, (3) TdT+ T cells without morphologic atypia, (4) absence of thymic epithelium, (5) nonclonal TdT+ T cells, (6) immunophenotype of developmentally normal immature thymic T cells, and (7) clinical evidence of indolence (follow-up >6 mo without progression).
In 1999, Velankar et al,1 identified a patient with a tumor of terminal deoxynucleotidyl transferase (TdT)+ T cells of the upper aerodigestive tract. Though consisting of immature TdT+ T cells in an extrathymic location, this lesion was clinically indolent, and required no treatment for >16 years. Given the benign nature of this T-cell expansion, this entity was titled: indolent T-lymphoblastic proliferation (iT-LBP). Since then nearly 10 detailed case reports of iT-LBP have been noted in the literature with increasing frequency in recent years.1–7
We recently reported on 3 cases of iT-LBP: 1 case spanning 5 years in a patient with a history of angioimmunoblastic T-cell lymphoma (AITL), another in association with acinic cell carcinoma, and another in a lymph node with findings of Castleman disease associated with a follicular dendritic cell tumor/sarcoma.2 Further work has additionally demonstrated that TdT+ T-lymphoblastic populations are also increased in many other cases from patients with concurrent Castleman disease and/or follicular dendritic cell tumors/sarcomas, as well as in patients with AITL.2,8
As pathologists encounter iT-LBP more frequently, its careful consideration must be made as alternative diagnoses such as thymoma or T-lympohoblastic lymphoma require quite disparate therapies. Here we review current literature and propose several criteria, which can be applied to reach an accurate diagnosis of an iT-LBP.
As iT-LBP can often be associated with other pathologic conditions, the clinical presentation is somewhat varied; however, all patients present with lymphadenopathy or a discrete tumor mass. Anatomic sites involved thus far include mandibular, cervical, supraclavicular, abdominal, retroperitoneal, and oropharyngeal locations.1–7,9
Of the cases described to date, 1 patient had a history of myasthenia gravis and 3 other cases have been seen in association with carcinomas: 2 cases with hepatocellular carcinoma and another with acinic cell carcinoma.2,4,6,7 iT-LBP have also been associated with Castleman disease and/or follicular dendritic cell tumors.2,8 As such, symptoms associated with those conditions may be secondarily present. In addition, indolent immature thymic populations have been preliminarily reported to be even more frequent in patients specifically with paraneoplastic autoimmune multiorgan syndrome in the context of follicular dendritic cell tumors.8 T-lymphoblastic populations have also been seen in cases of AITL and may persist in multiple lymph node sites even after clearance of AITL.2
In lymph nodes or other tissues, iT-LBP form a tumor mass, which can vary greatly in size from ≤1 to ≥9 cm in greatest diameter.1,3 The outer surface of these masses may be firm and fibrous or nonencapsulated; sectioning reveals pink-tan firm fleshy tissue. Yellow soft areas of necrosis have been described in cases associated with hepatocellular carcinoma.4,6
General preservation of overall tissue architecture is seen. In lymphoid tissues, these lymphoblasts localize predominantly to interfollicular/paracortical regions.1–3,5,7,9 In these regions, collections of small-medium lymphoid cells with immature blastic chromatin are seen; these cells lack significant atypia and nucleoli are inconspicuous (Fig. 1). Numerous mitoses are present with scattered histiocytes evenly interspersed throughout. In the cases associated with carcinomas, the lymphoblasts are interspersed or clustered between malignant epithelial cells; distinct lymphoepithelial lesions are not seen.2,4,6
The immunophenotype of these proliferations is that of immature thymocytes. All cases thus far, have shown expression of TdT and CD3 as well as coexpression of both CD4 and CD8 with variable but generally positive expression of CD10, CD99, and CD1a (Fig. 2).1–7 Other T-cell markers such as CD2, CD5, and CD7 are also typically positive but may be variable or decreased in expression levels compared with surrounding mature T cells. Cases identified to date lack CD34 expression, and B-cell markers (CD20, CD79a) are not detected. A detailed review of the immunophenotype of prior cases is noted in Table 1.
The Ki67 index is high in concordance with the morphologic presence of numerous mitoses (often 1 to 2 mitotic figures per high power field) and the proliferative indices vary from 40% up to 90%, as can be seen in normal thymic tissue. However, thymic epithelium is not seen as ruled out using pan-keratin or more specific epithelial marker immunostains.
All iT-LBP identified to date have nonclonal T-cell receptor (TCR) gene rearrangement studies (TCR γ and/or β).1–7 Karyotypic studies, where available have not identified definitive chromosomal abnormalities although the initial case described by Velankar et al1 was noted to have a possible chromosome 9 inversion.
TREATMENT AND PROGNOSIS
As the name indicates, treatment of iT-LBP is not required as these proliferations do not behave like aggressive lymphomas; however, if the proliferation is associated with a secondary disease such as carcinoma or follicular dendritic cell tumor, treatment for associated conditions may be necessary. In many instances, these iT-LBP have been treated with chemotherapy due to misdiagnosis as malignant lymphoma, but can persist as a stable tumor mass many years after treatment without continued progression or necessity for further treatment.2,7
The major differential diagnoses include T-lymphoblastic lymphoma, ectopic thymic tissue, and thymoma. Although ectopic thymic tissue and a thymoma can be ruled out by the presence or absence of thymic epithelium (thymic epithelial cells are present in thymic tissue and thymomas, as demonstrated by keratin markers, but not in iT-LBP) the separation from T-lymphoblastic lymphoma is more challenging.
Malignant T-lymphoblastic lymphoma when involving a nodal site generally effaces the entire node, or if only demonstrating partial involvement, will infiltrate relatively nondiscriminately throughout the entire node obliterating residual follicles. In contrast, iT-LBP show dense infiltrates of small-medium–sized cells, which localize to regions where T cells are normally found, interfollicular/paracortical regions (Fig. 1; Table 2).
In addition, the lymphoblasts in malignant T-lymphoblastic lymphoma may show distinctive morphologic nuclear irregularities, whereas the cells of iT-LBP are small-medium in size without distinctive atypia. Immunophenotypically up to 51% of cases of T-lymphoblastic lymphoma may show aberrant antigen expression whereas the immunophenotype of iT-LBP mirror those of normal immature cortical thymocytes.10 In addition, the majority of malignant T-lymphoblastic lymphomas have clonal rearrangements of TCR, whereas all cases of iT-LBP reported to date have nonclonal TCR studies.11 Finally, although T-lymphoblastic lymphoma universally requires therapy and rapidly progresses, there is no evidence of disease progression when patients with iT-LBP are left untreated and followed for extended periods of time (>6 mo; Table 2).
Increased populations of nonclonal T-lymphoblasts in extrathymic locations have been described in isolation as well as in association with carcinomas, with Castleman disease and/or follicular dendritic cell tumors, as well as in patients with histories of AITL. In some cases these populations form dense aggregates and tumors, raising suspicion for a malignant process. However, careful morphologic examination of the tissue and immunophenotypic and molecular studies along with close clinical follow-up can provide the necessary information for an accurate diagnosis of iT-LBP.
Although iT-LBP in some respects mimics normal thymic lymphoid tissue, it lacks thymic epithelium. Speculation as to the origin of these immature T cells has been made and some have proposed that these cells are either constitutively released from the mediastinal thymus, or that these cells are developing and proliferating in these extrathymic locations from a precursor stem cell contained within the lymph node. Further work will be required to determine the nature of these proliferations and reason for their continued expansion.
1. Velankar MM, Nathwani BN, Schlutz MJ, et al. Indolent T-lymphoblastic proliferation: report of a case with a 16-year course without cytotoxic therapy. Am J Surg Pathol. 1999;23:977–981
2. Ohgami RS, Zhao S, Ohgami JK, et al. TdT+ T-lymphoblastic populations are increased in Castleman disease, in Castleman disease in association with follicular dendritic cell tumors, and in angioimmunoblastic T-cell lymphoma. Am J Surg Pathol. 2012;36:1619–1628
3. Kim WY, Kim H, Jeon YK, et al. Follicular dendritic cell sarcoma with immature T-cell proliferation. Hum Pathol. 2010;41:129–133
4. Eun S, Jeon YK, Jang JJ. Hepatocellular carcinoma with immature T-cell (T-lymphoblastic) proliferation. J Korean Med Sci. 2010;25:309–312
5. Qian YW, Weissmann D, Goodell L, et al. Indolent T-lymphoblastic proliferation in Castleman lymphadenopathy. Leuk Lymphoma. 2009;50:306–308
6. Wang ZM, Xiao WB, Zheng SS, et al. Hepatocellular carcinoma with indolent T-lymphoblastic proliferation. Leuk Lymphoma. 2006;47:2424–2426
7. Strauchen JA. Indolent T-lymphoblastic proliferation: report of a case with an 11-year history and association with myasthenia gravis. Am J Surg Pathol. 2001;25:411–415
8. Walters MP, Macon WR, Kurtin PJ, et al. Follicular dendritic cell sarcoma frequently contains intratumoral TdT-positive T cells that are associated with paraneoplastic autoimmune multiorgan syndrome (PAMS), 100th USCAP Annual Meeting
9. Hartert M, Strobel P, Dahm M, et al. A follicular dendritic cell sarcoma of the mediastinum with immature T cells and association with myasthenia gravis. Am J Surg Pathol. 2010;34:742–745
10. Marks DI, Paietta EM, Moorman AV, et al. T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993). Blood. 2009;114:5136–5145
11. Pilozzi E, Muller-Hermelink HK, Falini B, et al. Gene rearrangements in T-cell lymphoblastic lymphoma. J Pathol. 1999;188:267–270
© 2013 Lippincott Williams & Wilkins, Inc.