Diagnosis and staging in gastrointestinal lymphoma

Best Practice & Research Clinical Gastroenterology 24 (2010) 3–12

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Best Practice & Research Clinical Gastroenterology

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Diagnosis and staging in gastrointestinal lymphoma Henk Boot, Gastroenterologist * Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Department of Medical Oncology and Gastroenterology, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands

Keywords: Gastrointestinal lymphoma MALT lymphoma EATL Diagnosis Staging Biopsy

The diagnosis gastrointestinal lymphoma can be made on endoscopic biopsies in the vast majority of cases. Definitive subtyping of the lymphoma according to the WHO classification with the use of additional immunological and molecular markers is the cornerstone for further decision making. Several lymphomas may occur multifocally or show both small cell and large cell components. Therefore, a second endoscopy with an extensive biopsy protocol (mapping) may be mandatory. Staging procedures are required for therapeutic decision making and should include CT-scan, laboratory studies and bone marrow examination as required in other lymphomas. Additional studies must be performed depending subtype and localisation of the lymphoma. In gastric lymphoma endosonography reveals prognostic information. In marginal zone lymphoma of MALT-type attention to other MALT-sites and autoimmune diseases is necessary. In enteropathy-associated T-cell lymphoma screening for coeliac disease and enteroscopy are required. In several lymphomas (diffuse large B-cell lymphoma and mantle cell lymphoma) a PET-scan is considered as standard of care. The value of staging procedures after treatment is less well defined. At least in gastric lymphomas, histology is the gold standard after treatment and during follow-up. Ó 2009 Published by Elsevier Ltd.

Introduction Determination of the extent of disease or staging in patients with malignancies provides prognostically valuable information and is often of critical importance for treatment planning. Clinical staging systems should also assists in evaluation of therapy, as in both descriptive studies and in

* Tel.: þ31 205122566; fax: þ31 205122572. E-mail address: [email protected] 1521-6918/$ – see front matter Ó 2009 Published by Elsevier Ltd. doi:10.1016/j.bpg.2009.12.003

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clinical trials the exchange of information cannot be performed without the use of a widely accepted staging system. However, classical lymphoma staging systems fall short in providing adequate prognostic treatment guidance. The landmark International Non-Hodgkin’s Lymphoma Prognostic Factors Project was a large multinational study that enabled the development of the International Prognostic Index (IPI)(Table 1) for patients with a diffuse large B-cell lymphoma (DLBCL) that consisted of Ann Arbor stage, patient characteristics and simple laboratory measurements [1]. The IPI has been validated in other types of lymphoma, also in the era of targeted therapies [2]. The classical Ann Arbor staging system and its modification adapted for extranodal disease as proposed by Musshoff in 1977, is a very simple and still most often used system in non-Hodgkin lymphomas, although it was originally designed for Hodgkin’s lymphoma in a period with very limited diagnostic possibilities (Table 2)[3]. There are large differences in the prevalence of lymphoma subtypes throughout the gastrointestinal tract. The specific lymphoma subtypes are described in the other chapters of this issue. Large epidemiological differences exist both geographically and between children and adults [4–8]. The most frequent lymphomas in adults in the western world are B-cell lymphomas: the mucosa-associated lymphoid tissue-lymphomas (MALT lymphoma) and DLBCL in the stomach and DLBCL in the small bowel. A notable exception is enteropathy-associated T-cell lymphoma (EATL) that may complicate coeliac disease. HIVrelated gastrointestinal lymphomas had an incidence of 3.86 per 100.000 during 1985–1989, but virtually disappeared since the introduction of highly active anti-retroviral therapy (HAART) with zero cases in 2000–2004 [7]. The incidence of gastric MALT lymphomas in a nation-wide epidemiological study in the Netherlands showed a rise until 1997 and an 8% annual decline thereafter [8]. The recognition of mucosa-associated lymphoid tissue (MALT) lymphomas originating in the stomach and at other extranodal sites [9] and the ensuing MALT lymphoma concept [10] has greatly influenced the ideas of both pathogenesis and treatment of these lymphomas [11,12]. The need to consider gastrointestinal lymphomas as distinct clinical entities from nodal lymphomas was recognised in the Lugano workshop convened to the pathology and staging of gastrointestinal lymphomas (Table 3) [13]. Moreover, the histological classification of non-Hodgkin lymphomas has evolved markedly since the 1970–1980s from simple morphology to the concept of disease entities with a characteristic morphological pattern, distinct immunological marker pattern, and discriminative chromosomal aberrations in concert with a typical clinical presentation, course and prognosis [14–16]. The gastrointestinal lymphomas encompass the majority of the extranodal lymphomas [4]. The definition of primary extranodal, including gastrointestinal, lymphomas remains somewhat controversial. An accepted definition is that the extranodal localisation is the presenting site and, after routine staging procedures, adapted for specific MALT-sites in case of MALT lymphomas, constitutes the predominant disease localisation at which the treatment must be directed [10,17,18]. Diagnosis At least in the stomach, duodenum and colon the diagnosis of gastrointestinal lymphoma can be made on endoscopic biopsies and a definitive subtyping of the lymphoma is possible with the use of

Table 1 International Prognostic Index – IPI [1]. Risk factors Ann Arbor stage III–IV >1 extranodal site High LDH Age > 60 years Performance status  2 (ECOG) Low risk Low intermediate risk High intermediate risk High risk

0–1 risk factors 2 risk factors 3 risk factors 4–5 risk factors

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Table 2 Ann Arbor staging system, modified according to Musshoff for extranodal lymphoma [3]. Stage I or stage IE

Single lymphatic organ or extranodal site

Stage II

Stage II1 Stage II2

Two or more lymphatic regions on the same site of the diaphragm or a single extranodal organ and lymph node involvement at the same site of diaphragm regional lymph nodes involved distant lymph nodes involved

Stage III Stage IV

Lymph nodes involved on both sides of diaphragm Disseminated disease with involvement of e.g. bone marrow, liver etc.

additional immunological markers. The endoscopic bioptic diagnosis will enable complete clinical staging and treatment planning. Even the small bowel is becoming within the reach of double- and even single-balloon enteroscopy and biopsy [19,20]. Although abnormal findings may be found in the small bowel with capsule endoscopy in patients with gastrointestinal lymphomas rather frequently, the impossibility to take biopsies is a serious drawback of this diagnostic procedure [21]. Although the diagnosis of gastric lymphoma can be established on biopsies in over 95% of the cases [22,23], the diminishing role of surgery in the treatment of especially gastric lymphoma requires the need for an adequate number of biopsies from both involved and macroscopically uninvolved mucosa to obtain a firm diagnosis of the type of lymphoma. This cannot be stressed sufficiently, as grading/ subtyping of the lymphoma on biopsies proved inaccurate in 25% of cases in the multicenter German–Austrian study, performed between 1993 and 1996 [23]. Histological criteria to grade lymphoma based on endoscopic biopsies with prognostic significance have been proposed previously [24]. The use of a large calibre biopsy forceps during a second mapping or ‘intragastric staging’ endoscopy is strongly recommended [22,25,26]. The symptoms and signs of gastrointestinal lymphomas are often not specific with dyspepsia, weight loss, abdominal pain, change of bowel habits and/or haemorrhage. In the stomach endoscopic features may mimic benign disease like gastritis, erosions, peptic ulcer, thickened folds or mass lesions like gastric cancer [23,27–30]. Secondary gastric localisation from another primary nodal or extranodal lymphoma also lacks a specific appearance [31]. There are only very few data available about magnified endoscopic images of gastric MALT- and other lymphomas at the time of the initial diagnosis and during follow-up with Helicobacter pylori eradication, radio- and or chemotherapy [32]. The diagnosis gastric lymphoma is often therefore not suspected clinically. A second endoscopy using a strict mapping protocol with 8–12 biopsies from involved sites and additional biopsies from uninvolved antrum, corpus and fundus, including biopsies to test for the presence of H. pylori is warranted [25,26]. The pathologist can provide not only the subtype of the lymphoma, but also add additional valuable prognostic information. The presence of t(11;18) in gastric MALT lymphomas e.g. is strongly associated with a more advanced stage of the disease and non-responsiveness to H. pylori eradication [33]. DLBCL is a heterogeneous disease that can be subdivided with help of RNA-microarrays in a germ centre B-cell and an activated B-cell type. This subdivision may be of prognostic relevance [34–36], but is mainly used for research purposes and not yet introduced into routine clinical practise. Also in mantle cell lymphoma prognostic factors have been identified, both a gene expression signature and a newly developed score (MIPI-score), particularly suited for mantle cell lymphoma patients. This may be of help to select patients that do not need immediate treatment [37–39]. In patients with refractory coeliac disease (RCD), type II with aberrant intra-epithelial T-cells can be seen as a precursor of EATL, that itself carries a poor prognosis [40–42]. As there is overwhelming evidence that chronic H. pylori infection causes the majority of gastric MALT lymphomas and ‘Helicobacter heilmannii’ an additional small minority, the presence of H. pylori has to be carefully documented or excluded by examination of gastric mucosa endoscopically not involved by the lymphoma during gastroscopy. The recommendation is to use histology (HE and modified Giemsa staining) and culture or molecular invasive tests [43–45]. The additional use of serology can increase the diagnostic yield, especially after the previous use of proton pump-inhibitors

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Table 3 Lugano lymphoma classification system [13]. Stage I I1 I2 Stage II II1

II2

Tumour confined to the gastrointestinal tract, e.g. stomach Single primary site, or multiple non contiguous lesions Tumour infiltration limited to mucosa and/or submucosa Tumour infiltration into muscularis propria and/or subserosa and/or serosa Tumour extending into abdomen from primary GI site Nodal involvement Local perigastric nodes in gastric lymphoma mesenteric in small and large bowel lymphoma Distant mesenteric in gastric lymphoma para-aortic, para-caval, pelvic, inguinal

Stage IIE

Penetration of serosa with involvement of adjacent organs/tissues enumerate actual site of involvement, e.g. IIE(pancreas), IIE(abdominal wall) Where there is both nodal involvement and penetration into adjacent organs, stage should be denoted using both subscript end E, e.g. IIE1(pancreas)

Stage IV

Disseminated extranodal involvement, e.g. localisation in bone marrow, liver etc., or a gastric/bowel lesion with supradiaphragmatic nodal involvement

or antibiotics, as was shown in gastric MALT lymphoma patients [46]. The use of a 13C- or 14C-breath test to document H. pylori eradication does not circumvent the need for endoscopy and biopsies and is therefore not useful for the diagnosis of H. pylori infection or the confirmation of successful eradication in gastric MALT lymphoma patients. Staging – diagnostic work-up Although the extent of staging has been debated and has differed markedly between specialists reflecting both differences between gastroenterologists and haemato-oncologists and geocultural differences [47], the acceptance of the WHO-lymphoma classification and the recognised need for uniformity in staging and treatment response reporting should lead to an accepted number of general staging procedures [48,49]. Depending on the subtype of the lymphoma additional studies may be mandatory. Once the diagnosis lymphoma has been established history taking should include questions regarding possible aetiologies of the lymphoma as chronic infections are involved in the pathogenesis of marginal zone lymphomas of MALT-type [50] as e.g. H. pylori, C. jejuni, hepatitis C or autoimmune diseases of the thyroid and salivary glands. The presence of autoimmune diseases is not necessarily associated with localisation of a MALT lymphoma in the organ involved with the autoimmune disease. Gastric MALT lymphomas occur e.g. in Sjo¨gren’s disease and may also be associated with a chronic H. pylori infection [51]. An underlying coeliac disease in case of EATL must be investigated. HIV-infection related gastrointestinal lymphoma, although of decreasing prevalence in the era of HAART [7], must still be considered. The general physical examination is often non-contributory in gastric and intestinal lymphomas. Special emphasis should be paid however to the general condition of the patient (performance status), to the peripheral lymph nodes, including Waldeyer’s ring and the extent of liver and spleen and the presence of a palpable abdominal mass. Especially in MALT lymphomas, the thyroid, parotid glands and the conjunctiva should be investigated appropriately as MALT lymphomas can occur at these sites simultaneously with gastric MALT lymphomas. Baseline laboratory studies must include a complete blood count with differential count, serum chemistry including LDH and beta-2 microglobulin and protein electrophoresis to detect M-proteins. Additional serology should be done to document specific infections or autoimmune diseases when indicated by the specific type of lymphoma. A bone marrow aspirate with biopsy with a length of at least 2 cm is part of general lymphoma staging. Bone marrow involvement occurs frequently in several types of nodal and splenic marginal zone B-cell lymphomas (MZL), but is a rare event in gastric and other MALT-type MZL’s [52–54]. Both bone marrow and peripheral blood must be examined for monoclonal cells. Although gastric MZL,

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Table 4 Paris Staging system for primary gastrointestinal lymphomasa,b [79]. Tx T0 T1 T1m T1sm T2 T3 T4 Nx N0 N1c N2 N3 Mx M0 M1 M2

Lymphoma extent not specified No evidence of lymphoma Lymphoma confined to the mucosa/submucosa Lymphoma confined to the mucosa Lymphoma confined to the submucosa Lymphoma infiltrates muscularis propria or subserosa Lymphoma penetrates serosa (visceral peritoneum) without invasion of adjacent structures Lymphoma invades adjacent structures or organs Involvement of lymph nodes not assessed No evidence of lymph node involvement Involvement of regional lymph nodes Involvement of intra-abdominal lymph nodes beyond the regional area Spread to extra-abdominal lymph nodes Dissemination not assessed no evidence of extranodal dissemination Non-continuous involvement of separate sites in gastrointestinal tract (e.g. stomach and rectum) Non-continuous involvement of other tissues (e.g. peritoneum, pleura) or organs (tonsils, parotid gland, ocular adnexa, lung, liver, spleen, kidney, breast etc.)

Bx B0 B1

Involvement of bone marrow not assessed No evidence of bone marrow involvement Lymphomatous infiltration of the bone marrow

TNM

Clinical staging: status of tumour, node, metastasis, bone marrow Histopathological staging: lymphoma confined to the mucosa/submucosa The histological examination will ordinarily include 6 or more lymph nodes

pTNMB pN

a Valid for lymphomas originating from the gastro-oesophageal junction to the anus (as defined by identical histomorphological structure). b In case of more than one visible lesion synchronously originating in the gastrointestinal tract, give the characteristics of the more advanced lesion. c Anatomical designation of lymph nodes as ‘regional’ according to site: (a) stomach: perigastric nodes and those located along the ramifications of the coeliac artery (that is left gastric artery, common hepatic artery, splenic artery) in accordance with compartments I and II of the Japanese Research Society for Gastric Cancer (1995); (b) duodenum: pancreaticoduodenal, pyloric, hepatic and superior mesenteric nodes; (c) jejunum/ileum: mesenteric nodes and, for the terminal ileum only, the ileocolic as well as the posterior caecal nodes; (d) colorectum: pericolic and perirectal nodes and those located along the ileocolic, right, middle and left colic, inferior mesenteric, superior rectal and internal iliac arteries.

MALT-type, is clinically a localised disease with an indolent clinical course in the majority of patients, circulating clonal cells can be demonstrated with sophisticated methods in a substantial percentage of patients [55,56]. In our own study a relationship with t(11;18) positive gastric MALT lymphomas was suggested [55], known to be associated with a more advanced stage of gastric MALT lymphoma [33,57]. The clinical relevance of such circulating cells is however not known. A spiral CT-scan with intravenous contrast of neck, chest, and abdominal cavity including the pelvis is necessary. The usefulness of three-dimensional, multidetector-row-CT has been demonstrated in gastric malignancies, especially gastric cancer. Especially when both transverse images, MPR (multiplanar reformation), combinations thereof and virtual gastroscopy are used, the diagnostic accuracy is high. The sensitivity exceeds 80% and specificity 90% [58–60]. Attention to technical detail with water as oral contrast and gastric distension during hypotonia is essential studying gastric malignancies [61]. In several lymphomas, especially DLBCL, follicular lymphoma and mantle cell lymphoma, staging has improved by the use of FDG-PET. Sensitivity exceeds 80% en specificity 90% which is superior to CT-scan [62–64]. Moreover, the interpretation of residual masses after chemotherapy is better with

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Table 5 Histological grading system for post-treatment biopsy evaluation of gastric MALT Lymphoma [84]. Score

Lymphoid infiltrate

LEL

Stromal changes

CR (complete histological remission)

Absent or scattered plasma cells and small lymphoid cells in the LP Aggregates of lymphoid cells or lymphoid nodules in the LP/MM and/or SM Dense, diffuse, or nodular extending around glands in the LP Dense, diffuse, or nodular

Absent

Normal or empty LP and/or fibrosis

Absent

Empty LP and/or fibrosis

Focal LEL or absent

Focal empty LP and/or fibrosis

Present, may be absent

No change

pMRD (probable minimal residual disease) rRD (responding residual disease) NC (no change)

MM, muscularis mucosae. LP, lamina propria. SM, submucosa. LEL, lymphoepithelial laesions.

FDG-PET than with CT-scan [62–64]. Although the use of FDG-PET after one to four cycles of chemotherapy reveals prognostic information, no data are at present available that prognosis improves by adapting treatment on these findings [65]. These studies were mainly performed in patients with nodal lymphomas, but there are no reasons to assume that extranodal, e.g. gastrointestinal lymphomas with comparable histology will behave differently. Visual inspection of FDG-PET scan is considered adequate, but with the first diagnostic staging scan ‘false positive’ findings should be excluded, especially colonic polyps and even colon cancer must be ruled out when e.g. a PET positive lesion in the colon is suspected. In marginal zone lymphomas, the lesions are often FDG-PET negative, especially when endoscopy shows only minor abnormalities and a FDG-PET scan is therefore not required as routine staging procedure [66,67]. Additional staging procedures are required in specific lymphomas. In the marginal zone cell lymphoma of the stomach, also called MALT lymphoma, the endoscopic appearance suggests the diagnosis lymphoma in only a minority of patients [28]. Therefore a second oesophagogastroduodenoscopy using an extensive biopsy protocol of multiple sites of duodenum and stomach, both with normal and abnormal appearance, is warranted, in general 20–30 biopsies are taken during such a mapping endoscopy [25,26]. The reasons for such a biopsy protocol are twofold: firstly MALT-type gastric lymphoma is often a multifocal disease and secondly transformation into a DLBCL may occur. The multifocal character of the disease can be demonstrated with both conventional histology and more extensively when investigated with PCR [68–70], thereby facilitating endoscopic bioptic followup knowing the distribution of the disease. Secondly, a number of MALT-type lymphomas may transform into a DLBCL or harbour a significant large cell component, that should be taken into account in treatment decisions. The finding of such a previous unrecognised large cell component in repeated biopsy specimens was 10% in our own series [22] and was already known from gastric resection specimens in 25% of cases [23]. The grading/subtyping of gastric MALT lymphoma and DLBCL is well possible on endoscopic biopsies and has prognostic and therapeutic relevance [24]. Multiorgan involvement could be demonstrated in 25% of patients with gastric MALT lymphoma with the use of an extensive staging program including colonoscopy with biopsy and MRI of salivary and lacrimal glands with extra gastrointestinal localisation in six of 15 patients [54]. The higher propensity of extragastric MALT lymphomas to present with disseminated disease, including secondary gastric localisation of especially pulmonary MALT lymphomas was also recognised in this study as well as by others [54,71,72]. Locoregional staging of gastric neoplasms is best performed with endoscopic ultrasound. In early series with the resection specimen as the gold standard, EUS was better then CT-scan for both T- and N-stage [73,74]. Although spiral CT-scan with possibilities of reconstruction in several planes will enable measurement of response to chemotherapy if a specialised protocol with gastric distension with combined water and air is used [58–61], it lacks sufficient detail to ascertain invasion in mucosa, submucosa, muscularis propria and beyond. EUS is mandatory to provide these data as there is definite relationship between tumour stage, both T- and N-stage and the likelihood that a histological remission can be obtained with H. pylori eradication in gastric MALT lymphomas [69,75]. However, the accuracy of EUS may be less when performed outside ‘gastric lymphoma centres’ [76]. The value of EUS

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Table 6 Staging requirements in gastrointestinal lymphomas adapted to subtype and localisation. All lymphomas: Physical examination, CT-scan from (neck) chest and abdomen General laboratory studies including: haemoglobin, leucocytes with differential count and immunophenotyping of peripheral blood, thrombocytes, LDH, immunoelectropheresis, b2-microglobulin, renal function and liver enzymes Bone marrow examination Pathology DLBCL – PET-scan, IPI score MZL, MALT-type – Examination other MALT-sites, attention to autoimmune diseases Mantle cell lymphoma – PET-scan, MIPI-score Follicular lymphoma – PET-scan to be considered EATL – single/double balloon endoscopy and screening for coeliac disease Localisation Gastric localisatio - EUS in all types of lymphoma Small bowel – depending on histology; single/double balloon endoscopy to be considered Colorectum – depending on histology, at least complete colonoscopy

during follow-up is much more limited compared to initial staging as normalisation of the gastric wall thickness and characteristics lags behind the occurrence of histological remission [77,78]. The use of EUS is more extensively discussed elsewhere in this issue. The predictive value of EUS-findings to foretell the histological response to H. pylori eradication in gastric MALT lymphomas was at the basis of the development of the Paris staging system for primary gastrointestinal lymphomas as proposed by the EGILS (European Gastro-Intestinal Lymphoma Study Group) [79] (Table 4). However, this system has not yet been evaluated in prospective series. The Paris staging system combined the TNM-system and the classical Ann Arbor lymphoma staging with the adaptation according Musshoff [3] with the infiltration depth of the gastric wall as assessed by endosonography. Nor the subdivision as suggested by Radaskiewicz [80], nor the Lugano staging system [13] were considered adequate to guide treatment decisions in gastric MALT lymphomas. As may be expected, the accuracy of both EUS and CT-scanning is insufficient after chemotherapy both in gastric lymphoma and in gastric cancer to replace the pathological evaluation with gastric biopsy in lymphoma or the resection specimen in gastric cancer [78,81]. The endoscopic bioptic follow-up should also pay strong attention to other preneoplastic lesions in the stomach related to chronic infection with H. pylori. There is an elevated gastric cancer risk as suggested in several case reports and small series, but also in a recent epidemiological study [8,82,83]. It is advisable to use the response evaluation as proposed by Copie–Bergmann during the follow-up of gastric MALT lymphomas after H. pylori eradication (Table 5) [84]. The persistence or even recurrence of minor pathological residual/recurrent gastric MALT lymphoma without symptoms or significant endoscopic abnormalities should be managed with close follow-up only as chemotherapy/or radiotherapy can often be considered ‘overtreatment’, due to the indolent clinical course of the disease [85]. Localised non-gastric MALT lymphomas, e.g. in the lung or salivary glands, often have an indolent clinical course and histology is not used during follow-up to confirm a remission [86]. In summary, clinical symptoms and signs, as well as endoscopic images are often not specific for gastrointestinal lymphoma. The diagnosis in most gastrointestinal lymphomas can be made on endoscopic biopsies. Therapeutic decision making must rely on a firm pathological subtyping of the lymphoma. Therefore, a repeated endoscopic procedure using an extensive biopsy protocol is mandatory in every patient. Staging procedures should encompass general lymphoma rules, but depending on the specific lymphoma and its localisation, additional investigations are often required (Table 6). Locoregional staging in gastric lymphoma requires the use of endosonography. The multifocal localisation and dissemination pattern in marginal zone lymphomas of MALT-type are different from other lymphomas. The documentation of remission in gastric lymphoma, especially MALT lymphoma, resides on histology. EUS and CT-scan have insufficient accuracy for this purpose.

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