Extranodal Lymphomas

Pathology and Management

Franco Cavalli, Harald Stein, Emanuele Zucca, Franco Cavalli, Harald Stein, Emanuele Zucca

• Editore: CRC Press
• Anno: 2008
• ISBN:
  9781000611298
• Edizione: 1
• Argomento: Medicina
• Categoria: Teoría, práctica y referencia médicas

Lymphomas classically manifest themselves in the lymph nodes but can also present in other bodily tissues or systems; the organ where exactly they present may make a very great difference to the strategy that should be adopted for their management. This topic has only recently been consistently addressed as an issue on its own, apart from the rest

PART I

CONCEPTUAL BASIS

Challenging issues in the management of extranodal lymphomas Emanuele Zucca and Franco Cavalli

1

INTRODUCTION

The term extranodal lymphoma encompasses a vast assortment of morphologies, molecular alterations, and clinical presentations. Correct diagnosis and appropriate treatment of extranodal lymphoma are often complicated by the variety of lymphoma types and the relative rarity of many of these tumor types. Moreover, in comparison with nodal presentation, Band T-cell lymphoma diagnosed at extranodal sites may have quite different outcomes and may frequently require different therapeutic approaches due to specific organ-related problems. Indeed, the extranodal lymphomas represent a frequent challenge in routine lymphoma diagnosis, due to the diversity of morphologies, molecular abnormalities, and clinical pictures that can be present.

Until very recently, the literature on many of the specific types and sites of extranodal lymphomas was scant and often contradictory, lacking uniformity in histopathological classification. Many historical series were published before the recognition of mucosa-associated lymphoid tissue (MALT) as the origin of many extranodal lymphomas, and the older classification of non-Hodgkin’s lymphomas (NHL) did not take into account peculiar histogenetic features of primary extranodal lymphomas. The first attempt to eliminate this problem was made only in 1994 with the proposal of the REAL classification¹ and afterwards with the World Health Organization (WHO) classification,² which definitely recognized the presence of specific extranodal entities such as mycosis fungoides, enteropathy-associated T-cell lymphoma, nasal type natural killer (NK)/T-cell lymphomas, and the extranodal marginal zone B-cell lymphomas of MALT lymphoma.

This chapter provides an overview of the main challenging questions and controversial issues that one has to tackle when dealing with the management of extranodal lymphomas. Most of these issues are covered in detail in the rest of the book.

CONTROVERSY IN THE DEFINITION OF PRIMARY EXTRANODAL LYMPHOMAS

Approximately one-third of NHL arise from sites other than lymph nodes, spleen, or the bone marrow, and even from sites which normally contain no native lymphoid tissue.^3,4

The exact designation of extranodal lymphoma is controversial, particularly in the presence of both nodal and extranodal disease. The first definition has been proposed by Dawson for gastrointestinal lymphomas,⁵ and later refined by Lewin⁶ and Herrmann.⁷ The original Dawson criteria defined primary gastric lymphoma, a presentation with main disease manifestation in the stomach, with or without involvement of regional lymph nodes. Later these criteria were relaxed to allow for contiguous involvement of other organs (e.g. liver, spleen), and for distant nodal disease, providing that the extranodal lesion was the presenting site and, after routine staging procedures, constituted the predominant disease bulk, to which primary treatment must be directed.⁸

The designation of stage III and IV lymphomas as primary extranodal lymphomas is also debatable and many authors consider only stage I and II presentation as primary extranodal disease. However, since many extranodal lymphomas have the potential to disseminate, this approach may result in an incomplete picture. On the contrary, extranodal involvement in a disseminated disease may represent a secondary spread. Clearly, any chosen definition inevitably introduces a selection bias; a Dutch study from a population-based registry showed that the frequency of extranodal NHL fluctuated from 20% to 34%, depending on the adopted designation criteria.⁹

The Ann Arbor staging system is sometimes imperfect when dealing with extranodal presentation. As a consequence, the distinction between stage I and stage IV in the case of multifocal involvement of a single organ can be controversial, as well as the stage definition of bilateral involvement of ‘paired organs’.

The designation of extranodal vs extralymphatic site can also be questionable and may affect the classification of extranodal lymphomas, since lymphomas of tonsils and Waldeyer’s ring, thymus, spleen, appendix, and Peyer’s patches can be regarded as originating from lymphatic tissues and not considered as extranodal lesions. Nonetheless, most clinicians separate nodal from extranodal rather than lymphatic from extralymphatic disease, and the term extranodal lymphoma is generally adopted to indicate presentation outside lymph node areas.

VARIABILITY IN THE REPORTED INCIDENCE OF PRIMARY EXTRANODAL LYMPHOMAS

The NHL incidence in Western countries has increased substantially in the last 40 years.¹⁰ This increase appears to be higher in extranodal rather than nodal disease.^{11, 12, 13} This may in part be due to improved diagnostic procedures (particularly in brain and gastrointestinal lymphomas) and changes in classification, but much of the change is real and the reasons for it have been the subject of much debate. The acquired immunodeficiency syndrome (AIDS) epidemics in the 1980s does not explain completely this rise¹² and the etiology of extranodal lymphomas appears to be multifactorial and includes immune suppression, infections, both viral and bacterial, and exposure to pesticides and other environmental agents.¹⁰ The differences in the extranodal lymphoma incidence patterns by histological subtype are notable and suggest etiological heterogeneity.¹⁴ However, despite the considerable progress made in the understanding of MALT lymphoma and its relationship to bacterial infections,^{15, 16, 17, 18} the precise cause of most lymphoid neoplasms remains to be elucidated.

The proportion of NHL presenting at extranodal sites accounts for from one-quarter to more than one-half of new lymphoma cases, with important geographic variations (e.g. USA and Canada 27%, Denmark 37%, Holland 41%, Italy 48%, Hong Kong 29%, Thailand 58%).^{3,12,19, 20, 21, 22, 23, 24} The reasons for these discrepancies include variable reporting criteria, with diverse definitions of primary extranodal disease, variable inclusion of mycosis fungoides and other T-cell lymphomas, variable inclusion of Waldeyer’s ring lymphomas, different types of data source (referral cancer centers vs population-based tumor registry series). Nevertheless, true geographic differences are also present: for example, the higher incidence of Epstein–Barr virus (EBV) and human T-lymphotropic virus 1 (HTLV1)-associated T-cell lymphomas and the lower incidence of follicular and small lymphocytic lymphoma in Asia is most likely affecting the frequency of extranodal presentations.

DIFFERENT CLINICOPATHOLOGICAL FEATURES AT DIFFERENT SITES

Signs and symptoms at presentation depend largely on the lymphoma localization and usually do not differ significantly from those of other malignancies affecting that specific organ. Gastric lymphomas present typically with symptoms of peptic disease, bowel lymphomas with diarrhea or obstruction, bone lymphoma usually with fractures and pain, or central nervous system (CNS) lymphomas with the symptoms associated to an intracranial mass. Especially in the absence of nodal involvement, primary extranodal lymphoma is often not suspected and most often is clinically indistinguishable from a carcinoma arising in the same site. Histological diagnosis with immunophenotypic and histochemical analysis is therefore particularly important.

The histological spectrum of extranodal lymphomas on the whole differs from that of nodal lymphomas. A population-based US study showed that about one-third of diffuse large B-cell lymphomas (the most common histologic subtype in most countries) can primarily present at extranodal sites, while more than three-quarters of peripheral T-cell lymphomas (almost all involving the skin) and less than 10% of follicular lymphoma cases are extranodal. Nearly half of the extranodal cases were of diffuse large cell histology.¹²

Extranodal lymphomas can arise in almost every organ.^3,4 However, most of the extranodal presentations appears to be clustered in a few sites: skin, stomach, brain, small intestine, and – when included in the reports – the Waldeyer’s ring, being about one-third of all the extranodal lymphomas found in the gastrointestinal tract.^{8,12,25, 26, 27}

With respect to histological classification, aggressive subtypes are predominant in NHL of CNS, testis, bone, and liver, whereas, in the gastrointestinal tract, a large spectrum of histological disease entities can be seen, comprising diffuse large B-cell lymphoma, MALT lymphoma (including the immunoproliferative small intestinal disease), Burkitt’s lymphoma, enteropathy-associated T-cell lymphoma, mantle cell lymphoma, and follicular lymphoma.

Certain extranodal sites appear to have characteristic patterns of either B- or T-cell disease (e.g. nearly all primary lymphoma of the bone ...

Indice dei contenuti

• Cover
• Title Page
• Copyright Page
• Table of Contents
• Contributors
• Preface
• PART I: CONCEPTUAL BASIS
• PART II: PATHOBIOLOGY AND CLINICOPATHOLOGICAL CORRELATIONS
• PART III: MAIN ENTITIES/LOCATIONS
• Index