Introduction
Involvement of extranodal sites by lymphoma usually occurs in the presence of widespread disease elsewhere. Such secondary involvement occurs in both Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL). However, in approximately 30–40% of cases, primary involvement of an extranodal site occurs with lymph node involvement limited to the regional group of nodes — Stage 1-IIE. Both primary and secondary extranodal involvement is more common in NHL than HD. As primary extranodal HD is extremely rare, rigorous exclusion of disease elsewhere is essential before this diagnosis can be made. The incidence of extranodal involvement in NHL depends on a number of factors including the age of the patient, the presence of pre-existing immunodeficiency and the pathological subtype of lymphoma. For example, in children, lymphomas are more likely to arise extranodally, especially in the gastrointestinal tract, the major abdominal viscera and extranodal locations in the head and neck[1,2]. In the immunocompromised host, lymphomas also tend to occur at extranodal sites. In both these patient groups, the high incidence of extranodal involvement is a reflection of the fact that such lymphomas are usually of the more aggressive histological subtypes. As the frequency of NHL is increasing (both in the general population and in the immunocompromised), the incidence of extranodal disease is rising faster than that of nodal disease[3]. For example, primary lymphomas of the CNS and orbit are increasing in frequency at a rate of 10% and 6%, respectively, per annum.
Of the various pathological forms of NHL, mantle cell (a diffuse low-grade B cell lymphoma), lymphoblastic lymphomas (80% of which are T cell), Burkitt’s (small cell non-cleaved) and lymphomas arising in mucosal-associated lymphoid tissue (MALT lymphomas) demonstrate a propensity to arise in extranodal sites.
Classification
The classification of NHL has taxed pathologists and physicians alike. It is salutary to note that in the published literature there have been four attempts at classifying HD and over 40 attempts at classifying NHL in the last 50 years. Many of the difficulties that beset early taxonomists have been overcome with improved immunological and molecular methods of diagnosis. This culminated in the emergence of a new classification scheme, the Revised European-American Lymphoma classification (REAL), that depends heavily on a triad of morphology, immunophenotype and molecular methods for defining disease entities. The scheme forms the backbone of the forthcoming 2nd WHO Classification of Haematological Malignancies. For the purposes of this review, the REAL scheme will be adopted as the finalized WHO classification is presently unavailable. The REAL classification is an exhaustive statement about lymphoma and many rare conditions are included within it. Thus, an indication of the relative frequencies of each of the lymphoma types is given for an European/ North American population.
Prognostic factors
It has long been evident that prognosis varies between patients and between subtypes of lymphoma. In order to evaluate therapies better and indeed to choose the most appropriate treatment for a given patient, it was considered imperative that a uniform prognostic system be established. Thus, the International Prognostic Index (IPI) was developed following analysis of clinical features of over 3000 patients with ‘aggressive’ histology NHL. Five factors were statistically associated with significantly inferior overall survival:
age >60 years
elevated serum LDH
ECOG performance stages >1 (i.e. non-ambulatory),
advanced stage 3 or 4
presence of >1 extranodal site of disease. Thus the detection of extranodal disease is extremely important.
Hepatobiliary system and spleen
Liver
Liver involvement is present in up to 15% of adult patients with NHL (more frequently in children with NHL) and in about 5% of patients with HD, at the time of presentation. In HD, liver involvement almost invariably occurs in association with splenic disease. True primary hepatic lymphoma is extremely rare, up to 25% of affected patients are HBsAg-positive and there is also an increased incidence of chronic active hepatitis.
Pathologically, diffuse infiltration is the most common form of involvement as focal areas of infiltration are only present in 5–10% of patients with liver lymphoma. Therefore, cross-sectional imaging is insensitive in the detection of liver involvement. However, hepatomegaly strongly suggests the presence of diffuse infiltration (in contradistinction to the significance of splenomegaly). Despite initial enthusiasm, MRI has been shown to be relatively insensitive in the detection of diffuse disease[4–6]. The focal form of infiltration results in miliary nodules or large solitary or multiple masses resembling metastases on cross-sectional imaging. On ultrasound they are usually well-defined and hypoechoic; on CT they are hypodense before and after intravenous injection of contrast medium; on MR they are of higher signal intensity than the surrounding normal parenchyma on T2-weighted sequences[7].
NHL of the bile ducts and gall bladder is rare but occurs with relatively high frequency in patients with ARL.
Spleen
The spleen is involved in 40% of patients with HD at the time of presentation, usually in the presence of nodal disease above and below the diaphragm (Stage III), but in a small proportion it is the sole focus of intraabdominal disease. In the majority of patients, the involvement is diffuse and particularly difficult to identify on cross-sectional imaging because splenomegaly does not necessarily indicate involvement; 33% of patients have splenomegaly without infiltration and, conversely, 33% of normal-sized spleens are found to contain tumour following splenectomy[8].
Focal splenic deposits occur in only about 10–25% of cases which, when they are greater than 1 cm in diameter, can be demonstrated on any form of cross-sectional imaging.
The sensitivity of ultrasound and CT for the detection of splenic involvement has proved to be extremely low (about 35%). MRI with supraparamagnetic ion oxide may improve the diagnostic accuracy but is seldom undertaken to assess the splenic status[9]. In the past, the poor sensitivity of imaging for the detection of splenic disease necessitated staging laparotomy with splenectomy. However, the development of effective combination chemotherapy with good salvage regimens has led to the abandonment of this practice almost universally.
Primary splenic NHL is rare, accounting for 1% of all patients who present with splenomegaly. Splenic involvement is also a particular feature of certain other pathological subtypes of NHL such as mantle cell lymphoma and splenic marginal zone lymphoma.
Gastrointestinal tract
The gastrointestinal tract is the initial site of lymphomatous involvement in up to 10% of all adult patients and up to 30% of children. It is therefore the most common site of primary extranodal NHL accounting for 30–45% of all extranodal presentations[7]. It is particularly common in children. As elsewhere, primary HD of the gastrointestinal tract is most unusual. Secondary involvement of the gastrointestinal tract is extremely common, usually from direct extension from involved mesenteric or retroperitoneal lymph nodes and consequently multiple sites of involvement do occur.
Primary lymphomas arise from lymphoid tissue of the lamina propria and the submucosa of the bowel wall, and occur most frequently below the age of 10 years and in the 6th decade. Primary gastrointestinal lymphoma is usually unifocal and accepted criteria for the diagnosis of primary disease include:
an absence of superficial or intrathoracic lymph node enlargement
no involvement of the liver or spleen
a normal white cell count
no more than local regional lymph node enlargement
A modified Ann Arbor classification can be applied:
Stage I indicating involvement of the hollow visceral wall alone (substaged according to bulk and extent of tumour)
Stage II indicating local extension, either to adjacent organs (IIE) or to draining lymph nodes (local first echelon or region).
Stomach
Involvement of the stomach accounts for about 50% of all gastrointestinal lymphoma being affected both in the primary and secondary forms.
Primary lymphoma accounts for about 2–5% of all gastric tumours[10]. It originates in the submucosa affecting the antrum more commonly than the body and the cardia. Radiologically, the appearances reflect the gross pathological findings; common appearances are multiple nodules, some with central ulceration, or a large, fungating lesion with or without ulceration. About a third of patients have diffuse infiltration with marked thickening of the wall and narrowing of the lumen, sometimes with extension into the duodenum indistinguishable from linitis plastica. Only about 10% are characterized by diffuse enlargement of the gastric folds, similar to the pattern seen in hypertrophic gastritis.
As the disease originates in the submucosa, the signs described above are best demonstrated on barium studies or endoscopically, but these investigations do not reflect the true extent of the disease. Computed tomography has proved particularly valuable in showing extensive gastric wall thickening and the extent of the extraluminal mass. A characteristic feature of gastric lymphoma is that there is rarely infiltration of adjacent organs, unlike in gastric carcinoma[11]. In the MALT lymphomas the gastric wall thickening may be minimal and CT is then of limited value in staging and assessment of response.
Small bowel
Lymphoma accounts for up to 50% of all primary tumours of the small bowel, occurring most frequently in the terminal ileum and becoming progressively less frequent proximally, such that duodenal lymphomas are rare[12]. The disease is multifocal in up to 50% of cases and because the disease originates in the lymphoid follicles, mural thickening with constriction of segments of bowel is typical. Patients commonly present with obstructive symptoms. The thickening of bowel is well demonstrated on CT. With progressive tumour spread through the submucosa and muscularis mucosa, long tube-like segments result. Aneurysmal dilatation of long segments of bowel also develop, presumably due to infiltration of the autonomic plexus. Such alternating areas of dilatation and constriction are a common manifestation of small bowel infiltration[12].
Occasionally, the lymphomatous infiltration is predominantly submucosal, which results in multiple nodules or polyps of varying size scattered throughout the small bowel, but predominantly in the terminal ileum. It is this form of lymphoma that typically results in intussusception, usually in the ileocaecal region. This is the most common cause of intussusception in children older than 6 years. Barium studies typically show multiple polypoid filling defects, with or without central ulceration, and irregular thickening of the valvulae.
Secondary invasion of the small bowel is commonly seen when large mesenteric lymph node masses cause displacement encasement or compression of the bowel. Enteropathy-associated T-cell lymphoma and immunoproliferative small intestinal disease (alpha-chain disease) commonly present with clinical and imaging features of malabsorption. The latter is particularly likely to affect the whole small intestine, especially the duodenum and jejunum.
Colon and rectum
Primary colonic lymphomas are usually of the Burkitt’s or MALT subtypes, but account for under 0.1% of all colonic neoplasms, most arising in the caecum and rectum. Patients usually present with obstruction and rectal bleeding. The most common pattern of the disease is a diffuse or segmental distribution of small nodules 0.2 to 2.0 cm in diameter, typically with the mucosa intact. As the disease progresses, fissures, ulceration, structures and even fistulae can develop. A less common form of the disease is the solitary polypoid mass, often in the caecum, indistinguishable from carcinoma on imaging unless there is concomitant involvement of the terminal ileum, which is more suggestive of lymphoma.
In very advanced disease, there may be marked thickening of the colonic or rectal folds resulting in focal strictures or ulcerative masses with fistula formation. In the rectosigmoid, lymphomatous strictures are generally longer than carcinomatous ones and irregular excavation of the mass strongly suggests lymphoma.
Oesophagus
Involvement of the oesaphagus is extremely unusual and begins as a submucosal lesion, usually in the distal third of the oesophagus resulting in smooth luminal narrowing with intact overlying mucosa. Later, ulceration can develop. Secondary involvement by contiguous spread from adjacent nodal disease is more common but rarely results in dysphagia.
Pancreas
Primary pancreatic lymphoma accounts for only 1.3% of all pancreatic malignancies[13]. Intrinsic involvement of the pancreas usually results in a solitary mass lesion, indistinguishable from primary adenocarcinoma on ultrasound, CT or MRI[14]. Less commonly, diffuse uniform enlargement of the pancreas is seen. As elsewhere, involvement is far more common in NHL than in HD.
Secondary pancreatic involvement is seen in association with disease elsewhere and is most likely to result from direct infiltration from adjacent nodal masses.
Genitourinary tract
Although the genitourinary tract is uncommonly involved at the time of presentation (<5%), more than 50% of patients will have involvement of some part of the genitourinary tract in endstage disease. The testicle is the most commonly involved organ followed by the kidney and the perirenal space; only rarely are the bladder, prostate, uterus, vagina or ovaries involved[15]. True primary genitourinary lymphoma is rare as there is normally very little lymphoid tissue within the genitourinary tract.
Despite the sensitivity of CT in detecting lymphomatous renal masses, a large discrepancy exists between the frequency of involvement diagnosed ante mortem and post mortem, probably explained by the fact that renal involvement is a late phenomenon. Detection of renal involvement is usually of limited clinical importance as it rarely alters the stage of the disease, close to 90% of cases are in association with high-grade NHL, in more than 40% of patients the disease occurs at the time of recurrence only, and renal function is usually normal[16].
On imaging, the most common disease pattern is multiple masses, which result from haematogenous spread of lymphomatous cells (usually diffuse, large cell types but also non-cleaved cells of the Burkitt’s type) entering the kidney. On ultrasound these masses are hypoechoic with little posterior acoustic enhancement[17,18]. On CT, the masses may show a typical ‘density reversal pattern’ before and after contrast administration with the lesion being more dense than the surrounding parenchyma before contrast medium administration and less dense after. There may be associated soft tissue stranding in the perirenal space. A solitary renal mass is seen in only 5–15% of cases and may be indistinguishable from renal cell carcinoma[16]. An important feature of renal masses occurring in NHL is that in over 50% of cases there is no evidence of retroperitoneal lymph node enlargement detectable on CT.
Direct infiltration of the kidney by contiguous retroperitoneal nodal masses is the second most common type of renal involvement, accounting for about 25% of cases. There is often associated encasement of the renal vessels and also extension into the renal hilum and sinus. In a further 10%, soft tissue mass can be seen in the perirenal space, occasionally encasing the kidney without any evidence of invasion of the parenchyma.
Diffuse intrinsic infiltration of the kidney resulting in global enlargement is the least common manifestation of renal lymphomatous involvement. On ultrasound, the kidneys are diffusely enlarged, appearing diffusely hypoechoic. On CT, the appearance following intravenous injection of contrast medium is variable, but usually the normal parenchymal enhancement is replaced by homogeneous non-enhancing tissue.
Bladder and prostate
Bladder
The urinary bladder is a rare site of primary extranodal involvement, accounting for less than 1% of all bladder tumours[18]. It occurs more frequently in women than in men and there is often a history of recurrent cystitis. Small cell and MALT types are seen, both characteristically producing large multilobular submucosal masses with minimal or no mucosal ulceration. Transmural spread into adjacent pelvic organs can occur, as well demonstrated on cross-sectional imaging[19]. The prognosis is generally good.
Secondary lymphoma of the bladder is more common than primary disease and is found in 10–15% of patients with lymphoma at autopsy[15,19]. Such secondary involvement can affect the wall of the bladder intrinsically or result from contiguous spread from the adjacent involved nodes. Microscopic involvement is far more common than gross infiltration, but this too can be associated with haematuria. On CT the appearances are usually non-specific, indistinguishable from transitional cell carcinoma, producing either diffuse widespread thickening of the bladder wall or a large nodular mass.
Prostate
Primary prostatic lymphoma is also extremely rare, but in contradistinction to primary bladder NHL it carries a very poor prognosis. It is usually intermediate to highgrade and produces irritative obstructive symptoms. Histological examination usually shows diffuse infiltration with spread into the periprostatic tissues. Solitary nodules are uncommon. Most frequently, prostatic involvement is secondary to spread from the adjacent nodes.
Adrenal glands
Primary adrenal lymphoma is extremely rare, usually occurring in men over the age of 60. Secondary involvement of the adrenals is detected in about 6% of patients undergoing routine abdominal staging CT, usually in the presence of widespread retroperitoneal disease. Adrenal insufficiency is most unusual, even in the presence of bilateral disease. The appearance on cross-sectional imaging is indistinguishable from that of metastases. Bilateral adrenal hyperplasia in the absence of metastatic involvement has also been described[20].
Testis
Testicular lymphoma accounts for about 5% of primary testicular tumours overall: 25–50% of those in patients over 50 years and it is the most common primary tumour over the age of 60 years[21]. It is vanishingly rare in HD but is seen at presentation in approximately 1% of all patients with NHL, usually of intermediate to high-grade, diffuse large cell and Burkitt’s type. There is an association with lymphoma of Waldeyer’s ring, the skin and central nervous system. Patients usually present with a painless testicular swelling and in up to 25% of cases the involvement is bilateral.
Ultrasonically, the lesions usually have a non-specific appearance; with focal areas of decreased echogenicity. A more diffuse decrease in reflectivity of the testicle (without any focal abnormality) is also a well-recognized pattern. At present, MR does not appear to have advantage over ultrasound in the detection of testicular involvement[22].
Because of the association with disease elsewhere, staging must always include ultrasonic evaluation of the contralateral testis and whole body CT. Cranial CT or MRI and CSF examination should also be considered. Relapse can also occur in the contralateral testis.
Female genital tract
Isolated lymphomatous involvement of the female genital organs is rare, accounting for approximately 1% of extranodal NHL. Nearly 75% of women affected are post-menopausal and present with vaginal bleeding[23,24]. It affects the cervix more frequently than the uterus and vagina. Involvement of these gynaecological organs is best demonstrated by MRI where primary lymphoma of the cervix and/or vagina is characterized by a large soft tissue mass best seen as high signal intensity lesions on T2-weighting and clearly distinguished from the surrounding normal tissues[25]. Involvement of the uterine body usually produces diffuse enlargement, often with a lobular contour similar to a fibroid. Primary uterine lymphoma has a good prognosis and MRI can demonstrate complete resolution.
Primary ovarian lymphoma, by contrast, has a very poor prognosis as it often presents late and disease is frequently bilateral. It is less common than uterine lymphoma. In young women disease is usually of the high-grade lymphoblastic type, whereas in older women intermediate grade Burkitt’s-like tumours are seen with greater frequency[26]. Imaging appearances are identical to those of ovarian carcinoma[27].
