Primary extranodal non-Hodgkin's lymphomas. Part 2: Head and ...

Annals of Oncology 10: 1023-1033. 1999.© 1999 Klimer Academic Publishers Primed in the Netherlands

Review

Primary extranodal non-Hodgkin's lymphomas.Part 2: Head and neck, central nervous system and other less common sites

E. Zucca, E. Roggero, F. Bertoni, A. Conconi & F. CavalliIsntuto Oncologico del/a Svizzera Italiana. Divisionedi Oncologia Medica, Ospedale San Giovanni Bellinzona, Switzerland

Key words: bone, brain, breast, CNS, extranodal non-Hodgkin's lymphomas, head and neck, liver, spleen, Waldeyer's ring

The first part of this Review, which included a generalintroduction and the discussion of gastro-intestinal,cutaneous and genito-urinary non-Hodgkin's lympho-mas, was published in a previous issue of this journal(Zucca E, Roggero E, Bertoni F, Cavalli F. Primaryextranodal non-Hodgkin's lymphomas. Part 1: Gastro-intestinal, cutaneous and genitourinary lymphomas.Annals of Oncology 1997; 8(8): 727-37). We do notdiscuss again here the general problems posed by theextranodal presentation of non-Hodgkin's lymphomas.However, it is important to remember that the funda-mental contribution of the R.E.A.L. Classification [4] inrecognising different lymphoma entities can be the basisto improve our knowledge in extranodal lymphomas aswell as in the nodal ones. However, at least thus far,treatment approaches are more influenced by the histo-logic type than the presenting site, thus emphasisinghow essential is a precise pathologic diagnosis.

The above mentioned Part 1 also contained the firstpart of the bibliography (References 1-101) and the firstsix tables.

D. Head and neck lymphoma

In the light of the current understanding of lymphomabiology [4], it is evident that considering all the lympho-mas arising in the head and neck region as a single groupis simply the heritage of a historical topographical dis-tinction, related to the fact that this anatomic region isthe second most common site of localised extranodalpresentation of non-Hodgkin's lymphoma. However it isnow clear that different lymphoma entities can arisewithin the head and neck area. The localisation oftumour presentation by site reveals tonsil to be the mostcommon, followed by nasopharynx, oral cavity, salivaryglands, paranasal sinuses and base of tongue. At the endof this section we will also discuss thyroid and orbitallymphomas, even though they are not usually consideredwith head and neck lymphomas.

The signs and symptoms of a non-Hodgkin's lym-

phoma may be similar to those of a head and necksquamous cancer, and only by biopsy can the distinctionbe made. Long-term results in patients presenting withextranodal lymphomas in the head and neck area varygreatly, depending not only on histology, but also onsites of presentation. In a series of 156 patients with headand neck lymphomas, the five-year survival according tosite was as follows: salivary gland (61%), oral cavity(57%), tonsil (49%), base of tongue (47%), nasopharynx(36%), and paranasal sinuses (12%) [102].

One problem related to most sites in the head andneck area is the precise definition of disease bulk. Re-cent advances in imaging, particularly CT and MRI,have greatly facilitated the definition of disease extent,even though documentation of precise margins remainsdifficult for some localisations (e.g., paranasal sinus)[12, 103].

Primary lymphomas of the Waldeyer's ring (tonsil, baseof tongue and nasopharynx)

As stated earlier, there is controversy as to whethertonsils and Waldeyer's ring in general should be con-sidered as nodal or extranodal sites. The tonsil resemblesMALT in its relation to the pharyngeal epithelium andits lack of afferent lymphatics, but its overall structure,lack of prominent marginal zone, predominant IgG asopposed to IgA secretion by its resident plasma cells aremore characteristic of peripheral lymph nodes [11].More than 70% of primary tonsillary NHLs are ofdiffuse large B-cell type. Lymphomas of MALT typeare uncommon in the tonsil; among low-grade tonsillaryNHLs; follicular lymphoma is quite common in contrastto the gut where it is very rare. Lymphoblastic (either ofB- or T-cell type) and Burkitt's lymphoma, commonlyaffecting palatine tonsil and paranasal sinuses, are almostexclusively found in paediatric patients [8, 11] (Table 7).About half of the Waldeyer's ring NHLs arise in thepalatine tonsil and about 20% of them are bilateral. Fullstaging procedures are mandatory, since about one ofthree patients presenting with tonsiliar lymphomas have

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Table 7. Histological subtypes (according to the R.E.A.L. Classifica-tion) in primary non-Hodgkin's lymphoma of the head and neckregion: Preferred sites of involvement.

Preferential site

Bcell

Follicle centre lymphoma

Lymphoplasmacytoid lymphoma

Mantle cell lymphoma

Marginal zone lymphoma (MALT-type)

Diffuse large cell lymphoma

Lymphoblastic lymphoma

Burkitt's lymphoma

Plasmablastic lymphoma of the oral cavity1"

Extramedullary plasmacytoma

TcellLymphoepitheliod lymphoma (Lennert'slymphoma) and other peripheral T-celllymphoma, unspecified

AngiocentricT/NK-cell (nasal andnasal-type) lymphoma (lethal midlinegranuloma)

Lymphoblastic lymphoma

Waldeyer's ring

Waldeyer's ring

Rare

Salivary glands andocular adnexa

Waldeyer's ring

Waldeyer's ring andparanasal sinuses

Waldeyer's ring and jaw

Rare, oral cavity and jaw

Nose

Waldeyer's ring

Nose, palate

Waldeyer's ring andparanasal sinuses

a Described as an AIDS-related lymphoma. usually EBV-associated, itdisplays morphologic features of diffuse large cell lymphoma, with astrikingly unusual phenotype showing the immunophenotypic featuresof plasma cells [106].

disseminated disease. An important aspect of the naturalhistory of Waldeyer's ring lymphoma is its relationshipto GI tract involvement, either concurrent with diagno-sis or at subsequent relapse [104]. Therefore, GI tractinvestigation belongs to the required staging procedurein cases with apparently localised tonsil presentations.The GI tract is clearly also the most common extranodalsite of disease progression [9],

Their treatment might be based on what we knowfrom the therapy of lymphomas of nodal origin sincenodal type histologies are predominant. However, indi-cations for local radiotherapy might be more stringentfor these lymphomas than for nodal lymphomas ingeneral [102]: a combined modality approach, using anantracycline-based chemotherapy regimen followed byradiation therapy (35-40 Gy) to the primary site andneck nodes is the most common approach. Overallsurvival at five years is approximately 60% to 75% [12].There is no indication for central nervous system (CNS)prophylaxis in stage I—II disease.

Salivary gland lymphoma and other lymphomas of theoral cavity

The vast majority of lymphomas in the oral cavity are ofintermediate- or high-grade malignancy, with follicular

lymphomas representing only 15%—20% of the cases[8, 105, 106]. However, in the salivary glands, about halfof the patients have low-grade B-cell lymphomas ofMALT type that seem to have arisen against a back-ground of chronic inflammation due to the myo-epithe-lial sialadenitis (MESA) often associated with Sjogren'ssyndrome. Whether some (and if so what percentage) ofthe high-grade lymphomas are also of MALT originremains to be determined [8, 107, 108].

The most frequently described localisations are thehard palate, the gingiva, the buccal mucosa, and thesalivary glands [105, 106]. Most of the knowledge ac-quired concerns lymphomas of salivary glands, the vastmajority of which are located in the parotid. Salivarygland lymphomas account for 5%—10% of all salivarygland tumours and somewhat less than 5% of lympho-mas at all sites [1, 23]. Several studies of large numbersof patients undergoing parotidectomy have reported al%-4% incidence of lymphoma.

However, the true incidence of primary lymphomasof the salivary glands is difficult to estimate because ofthe presence within the parotid gland of lymph nodesfrom which nodal lymphomas may arise, despite classi-fication as extranodal. This is often the case for follicularlymphomas and lymphocytic lymphoma (B-CLL) of theparotid gland and for lymphomas with high-grade his-tology [8]. The presence of nodal lymphoid tissue insidesalivary gland may also explain the conflicting cyto-genetic data regarding the presence in salivary glandlymphomas of the t(14;18)(q32;q21) translocation thatis characteristic of follicular lymphoma [8, 12, 109].

Survival statistics vary greatly from series to series,with a reported long-term survival of 50%-75% [12,108]. Overall, the survival rates quoted for most seriesare higher than for most other localisations of extrano-dal lymphoma.

There are few therapeutic rules concerning primarylocalisation in the palate and gingival; mutilating sur-gery should be avoided and a combination of chemo-therapy and radiotherapy should be applied, dependingon the histologic subtype [105]. The role of surgery insalivary gland lymphoma should be limited to exci-sional biopsy, while further therapy has to be tailoredto stage and especially histologic subtype (local radio-therapy alone for localised low-grade lymphomas orcombined modality approaches using doxorubicin-con-taining regimens and local radiation for aggressive his-tologies) [12].

Nasal angiocentric T/NK-cell lymphoma and otherlymphomas of the nasal and paranasal region

Primary lymphoma of the paranasal sinuses and of thenasal cavity comprises a controversial subset of malig-nant lymphomas, owing in part to the difficulty ofrecognising them, both clinically and pathologically.Their incidence is difficult to ascertain, given the prob-lems with recognition, the tendency to group theseuncommon lymphomas with those arising in adjacent


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structures and the variation in incidence among differentpopulations. These lymphomas appear to be exceedinglyrare in Western countries, where they usually show aB-cell phenotype, but relatively common among Asiansand Native Americans of Central and South America,suggesting a racial predisposition [110]. Indeed, in Asiancountries they represent the second largest group ofextranodal lymphomas after GI localisations, and mostof them have a T/NK-cell phenotype [110]. Most casespresent with a destructive nasal or midline facial lesion,erythema, and swelling and oedema can be prominent[110]. This category of lymphoma has been referred to inthe past as lethal midline granuloma and, more recently,as angiocentric T/NK-cell nasal lymphoma. Histologi-cally, the lymphoma characteristically shows a broadspectrum of cell size, and is associated with features ofangiocentric and angiodestructive growth and extensivenecrosis [4, 110, 111]. In early stages, there can be aprominent inflammatory background, often causing dif-ficulty in differentiating it from an inflammatory orinfectious process [110]. The most common immuno-phenotype is CD56+ (a natural killer cell antigen whichwould suggest a natural killer cell derivation), CD2+,surface CD3- but cytoplasmic CD3+ [110, 111]. T-cellreceptor antigen gene rearrangements are usually notdemonstrable [110, 112]. EBV sequences can be identi-fied in virtually all cases, strongly suggesting that EBVmay play an important role in the pathogenesis of thisdisease [111-115].

Although nasal T/NK-cell lymphoma thus appearsto be a distinctive type of neoplasm, lymphomas withsimilar characteristics have on rare occasions been iden-tified at other sites. In addition to the nasal cavity andthe nasal sinuses it has been described in other locationsin the upper aerodigestive tract, including the naso-pharynx, the oropharynx and the larynx [9, 110]. Rarecases of nasal-type T/NK-cell lymphoma may present inthe skin, soft tissues, in the gastrointestinal tract and int h e t e s t i s [ 1 1 0 , 1 1 1 ] .

In Western countries, as stated before, the majority ofcases arising in the nasal region are intermediate orhigh-grade B-cell lymphomas [116, 117]. It has beennoted that the B-cell phenotype is predominant in theparanasal sinus localisation, whilst T-cell immunophe-notypic expression is typical of the nasal lymphoma[118]. Recent reports have emphasised the tendency ofparanasal lymphomas to present with bulky localiseddisease, to relapse in non-contiguous nodal and extra-nodal sites after radiation therapy, and to frequentlyspread to the central nervous system [9, 23, 102, 104,110, 117]. The local bulkiness of the disease at the time ofdiagnosis in nasal and paranasal sinus lymphomas maybe related to their origin in and growth into clinicallysilent sites such as the sinuses, the parapharyngeal spaceor the infratemporal fossa. In addition, because lymphnode involvement is uncommon, most patients presentonly after locally advanced disease has caused pain,nasal obstruction, or facial distortion. Thus, the TNMstaging system, which describes accurately the extent of

local disease, may be used in addition to the Ann Arborstaging system [9, 23, 102-104, 117, 119].

In the past, treatment results in patients with para-nasal sinus lymphoma have been dismal, with a five-yearsurvival of only 12%—15% [102]. Among patients treatedwith radiation therapy alone the systemic recurrence rateis relevant (approximately half of the cases, generallywithin the first year after irradiation) despite excellentlocal control [110]. No clear predilection for gastro-intestinal relapses has been described, and the para-meningeal anatomic location of the paranasal sinuslymphomas explains the high risk for leptomeningealrelapse reported in some series [117]. Recently, therefore,a combined approach including systemic anthracycline-containing chemotherapy and involved field irradiationhas become the standard treatment for B-cell lympho-mas presenting in the nasal cavity or paranasal sinuses[117, 119, 120].

Treatment of T/NK-cell nasal lymphoma in theliterature has been inconsistent, with some groupsusing localised radiotherapy alone, and others multi-agent chemotherapy with or without additional radia-tion therapy. Prognosis is usually poor once dissemina-tion occurs. Reports on long-term results are very sparseand inconclusive; about one-half of the patients succumbto the disease [110, 111]. The hemophagocytic syndrome(hepatosplenomegaly, liver function abnormalities,thrombocytopenia, and erythrophagocytosis) is a com-mon clinical complication which adversely affects sur-vival in nasal T/NK-cell lymphoma [118], and EBVprobably plays a role in its pathogenesis [110].

Primary lymphoma of the ocular adnexa (orbitallymphoma)

The term of primary lymphoma of the ocular adnexarefers to the lymphoma arising in the extraocular orbitalspace, involving either the anterior compartment of theorbital cavity (the eyelids, the lachrymal gland and theconjunctiva) or the posterior (retrobulbar) compart-ment.

Orbital lymphoma is considerably more commonthan intraocular lymphoma (lymphoma of the eye),accounting for about l%-2% of all lymphomas [9, 12,23]. The two types of presentation should be clearlydistinguished because of their different natural histories:the intraocular lymphoma is a subset of primary CNSlymphoma. Traditional histopathological classificationhas proven complex; presently, however, it seems thatmost low-grade cases can be considered to be of MALTorigin [8, 121]. Only a minority of orbital lymphomas areintermediate- or high-grade, while most of them have alow-grade histology. This may be reflected in the 60%-75% 10-year survival rates reported for most series [23,122-124].

Treatment should be designed to cure, and extensivesurgery must be avoided. Radiation therapy has beenthe common form of treatment for primary orbitallymphoma and high local control rates can be achieved


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with moderate-dose irradiation (25-35 Gy) [12, 91, 124].At this dosage, visual complications are limited, butdoses above 35 Gy result in an increased risk of compli-cations. A correct imaging approach, including ultra-sound, CT MRI and/or CTscan, to the orbital region isessential in the planning of the target volume [12, 103].About 1/3 to 1/4 of the patients will progress in eitherthe controlateral orbit or with systemic disease afterlocal radiotherapy. It appears that retrobulbar involve-ment carries a higher risk of disease failure than anteriorcompartment disease [124]. So far there is little datato indicate that combined modality therapy should beapplied, although this should be considered in the fewpatients showing an aggressive histology subtype [9, 91,124]. In most instances, however, primary orbital lym-phoma should still be handled with low-dose radio-therapy only, even if single-agent chemotherapy seemsto be a valid alternative [122, 123].

Thyroid lymphoma

Primary thyroid lymphoma is uncommon, accountingfor only 5% of thyroid neoplasms and less than 2% ofextranodal lymphomas [1]. The majority of patients havediffuse large B-cell lymphoma [125], which clinicallyis often reflected by a rapidly enlarging neck massaccompanied by compression of surrounding structuressuch as the larynx or the oesophagus [103]. Elderlywomen are most often affected, perhaps because of thetendency of this neoplasm to occur against a back-ground of Hashimoto's thyroiditis [126, 127]. The preva-lence of aggressive histologies in most series may appearsomewhat surprising, since most thyroid lymphomas arethought to arise from the MALT acquired in the courseof Hashimoto's thyroiditis [8, 127], and it has beenproposed that all of the thyroid lymphomas could beconsidered of MALT derivation [8]. Indeed, transforma-tion of low-grade MALT lymphomas to high-gradelesions can be documented, and, unlike other high-gradeMALT lymphomas, lymphoepithelial lesions are oftenpresent also in high-grade tumours of the thyroid [8].

The optimal treatment of thyroid lymphoma is nolonger controversial, since the combination of anthra-cycline-based chemotherapy and irradiation is currentlyconsidered as the most appropriate approach. Surgerywas used extensively in older studies, but since theintroduction of thyroid biopsy and fine-needle aspira-tion, surgery has ceased to play a major role and debulk-ing surgery should in any case be discouraged [9, 12, 91].It is important to note that, although MALT-derivedlymphomas are usually considered to remain confinedat the site of origin, in thyroid lymphoma distant relap-ses occur twice as often as local failure and more than30% of thyroid lymphomas with localised disease willrelapse at a distant site when treated with local therapyalone. Two hundred and eleven patients with stages IEand HE thyroid lymphoma were reviewed in detail inan evaluation of the relative merits of radiotherapy andchemotherapy [125]. Distant and overall relapse rates

were significantly lower in the group that received com-bined-modality treatment (chemotherapy and radio-therapy) than in those given radiotherapy alone. Therewere also fewer local relapses, but the difference was notstatistically significant. Combined-modality treatment,therefore, appears to significantly reduce distant andoverall recurrence and should therefore be regarded asthe treatment of choice in most patients. The successof chemotherapy alone in both systemic and localisedextranodal lymphomas [128] raises the question of therole of radiation. The propensity for patients with thy-roid lymphoma to have bulky local disease, however,might be an adverse risk factor for local control withchemotherapy alone, and a 25% recurrence rate hasbeen reported [9, 12]. It would therefore seem thatradiation therapy still has a role in the local control ofthyroid lymphoma.

E. Primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL)is defined as lymphoma arising in and confined to thecranial-spinal axis (brain, eye, leptomeninges and spinalcord). Formerly a rare tumour, PCNSL showed increasedincidence both in immunocompromised (congenital, ac-quired or iatrogenic) high-risk groups and in the generalpopulation [129-131]. PCNSL accounts for l%-2% ofmalignant brain tumours and 2%-4% of all extranodallymphomas [1, 2, 23, 131]. Secondary involvement of theCNS occurs in 5%-3O% of systemic non-Hodgkin'slymphoma and is exceedingly rare, but described, inHodgkin's disease [131]. For the sake of clarity, it shouldbe pointed out here that primary orbital lymphomarepresents a different entity and must not be confusedwith lymphoma of the eye.

Primary lymphoma of the brain

Initial symptoms encompasses signs of increased intra-cranial pressure, cranial nerve palsies, neurologic defi-cits and, fairly often, a significant impairment of mentalfunction [130, 131].

PCNSL is usually disseminated within the nervoussystem at diagnosis, in approximately 40%-50% of im-munocompetent and in nearly 100% of AIDS patients.About 40% of patients have a demonstrable involvementof the spinal fluid and 20% of the eyes. Therefore, inaddition to the usual procedures, staging requires con-trast-enhanced CT scan and MRI with gadolinium ofthe brain and orbits, before steroids are started becauseof the rapid radiographic disappearance of tumour fol-lowing the administration of steroids ('ghost tumour'),a peculiar feature of PCNSL not shared by any otherintracranial malignant tumour. Most typically, PCNSLappears as a mass in the supratentorial white matter,which, with MRI, is isointense or slightly hypointenseon Tl-weighted imaging. On both the proton density-weighted and T2-weighted images the central tumour


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core is relatively iso- to hypointense to surroundingnormal brain [130]. An ophthalmologic evaluation withsplit-lamp examination should also be performed.Histological confirmation is essential, by stereotacticbiopsy, lumbar puncture demonstrating a frank positivecytology, or vitreous biopsy [130, 131]. Histologically, thevast majority of lymphomas are of diffuse large B-celltype [129, 130]. No follicular lymphomas have thus farbeen reported, but cases of T-cell origin have been[132]. Lumbar puncture, besides enabling cytologicaland routine studies of cerebrospinal fluid (CSF), shouldcomprise a dosage of |32-microglobulin and lactate de-hydrogenase. Lymphocyte immunophenotyping and/orpolymerase chain reaction for rearrangement of theimmunoglobulin heavy chain genes can be performedon the CSF to improve diagnosis [133].

A surgical procedure more extensive than stereotacticbiopsy is rarely indicated. Aggressive surgical decom-pression with partial or gross total removal of thetumour has benefit (median survival of 1-5 months)[9, 130, 131]. Historically, whole brain radiation hasbeen the treatment of choice, but, despite differentradiation schedules with good initial responses, over90% of patients recur in the brain, often in sites remotefrom the initial ones [9, 12, 130, 131]. Systemic dis-semination occurs in only 10% of the cases. The prog-nosis for unselected patients with immunocompetentPCNSL treated with irradiation alone is very poor; thefive-year survival rate is 5%-10% with a median survivalof 12 to 18 months [134]. The addition of spinalaxis radiation does not affect survival because it doesnot prevent cerebral relapse. The results obtained withradiation therapy alone have been poor, so new ap-proaches have been developed. Because of the frequentleptomeningeal involvement, some authors have addedintrathecal chemotherapy. On the other hand, severalsingle-institution reports have described encouragingresults with systemic chemotherapy alone, with osmoticblood-brain barrier disruption or combined with radio-therapy, with a five-year projected overall survival of30%-50% and a median survival of 2-3 years [135-142].These better results with chemotherapy alone or withcombination chemotherapy versus radiation alonemight, at least partially, be due to a selection bias forpatients with younger age and better performancestatus. Nevertheless, these trials suggest that the use ofcytostatics which penetrate the blood-brain barrier (e.g.,high-dose methotrexate or cytarabine) may be able toeradicate the lymphoma. In general, the most recentstudies seem to suggest that radiation therapy alone isunable to provide significant long-term survivals - withthe possible exception of young patients with smallbulk disease-, may interfere with later chemotherapyand may increase the risk of treatment-induced dementia.Evidence is mounting that initial chemotherapyshould be the treatment of choice, reserving irradiationfor resistant or relapsing disease, however, only random-ised trials will be able to clarify this controversialissue.

Primary ocular lymphoma

Primary ocular lymphoma - i.e., restricted to the globe,usually the vitreous, retina, and chorioid - is exceed-ingly rare. Ocular involvement is bilateral in 80% ofcases, even if asymmetric, and more than half of thepatients will develop brain lesions after a median of 25months [143]. Diagnosis of primary ocular lymphoma isdifficult. Cytological and immunophenotypic studies ofvitreous specimens from vitrectomy can provide thedefinitive diagnosis, but often they can be inconclusivebecause of previous topical or, occasionally, systemiccorticosteroids due to clinical diagnosis of chronicuveitis or vitritis.

Radiotherapy to both eyes has been the standard treat-ment, and, as in the other PCNSL, the combination withsystemic chemotherapy is being investigated [130, 131,143, 144]. The addition of intravitreal methotrexate to sys-temic chemotherapy was recently proposed as a possiblemeans for reducing the long-term side effects of radio-therapy [145], but this approach is still investigational.

Primary leptomeningeal lymphoma

In rare instances, malignant lymphoma presents as alocalised leptomeningeal disease in the absence of pa-renchymal brain involvement [146]. Diagnosis is com-monly made on the basis of positive CSF cytology ormeningeal biopsy; detection of a monoclonal lympho-cytic population by PCR analysis and flow cytometricstudies is helpful. Gadolinium-MRI of the cranial-spinalaxis might reveal meningeal enhancement or hydro-cephalus [130]. The therapeutical approach is similar tothe one for primary brain lymphomas. The survivalprognosis is poor despite aggressive treatments.

A completely different type of primary meningeallymphoma, the primary low-grade lymphoma of theintracranial dura which shows features of a low-gradeB-cell MALT lymphoma, has recently been described[147]. In contrast to other types of CNS lymphomas, itsprognosis can be very good with radiotherapy possiblycombined with chemotherapy. This argues for theimportance of its recognition as a distinct clinico-patho-logical entity.

F. Primary extranodal lymphoma - other sites

Primary extradural lymphoma

Primary extradural lymphoma represents approximately1% of all localised NHLs; it most often presents withspinal cord compression at thoracic level [I, 12, 23, 148].The diagnosis is generally obtained at the time ofdecompressive surgery, with diffuse large-cell lympho-ma being the most common histology. MRI is theexamination of choice; CSF study results are negative atdiagnosis. Data on pattern of relapse are discordant, butCNS relapses seem to be rare [14, 83, 148]. Good results


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have been obtained with radiotherapy and systemicchemotherapy [12, 148].

Primary lymphoma of bone

Non-Hodgkin's lymphoma involving bone is relativelycommon in patients with advanced disease, but consti-tutes less than 5% of localised extranodal presentations[1, 23, 149]. The most common sites of presentation arethe femur and long bones followed by the ileum andscapula. Pain is the usual symptom and radiologicalfindings comprise a lytic and, less commonly, a scleroticor mixed lesion [23]. The vast majority of the cases arediffuse large B-cell lymphomas in adults and lympho-blastic lymphomas in children [149-151]. Only a fewcases of low-grade histology have been described andthey usually have plasmacytoid features [151]; no fol-licular lymphomas seem thus far to have been reported.The median age of patients with primary lymphoma ofbone is 55 years, but about 3% of all lymphomas inchildren are localised to bone [150, 152].

Most patients will present with lymphoma localisedto the bone (stage IE), with about one of five presentingregional lymph nodes (stage HE) at diagnosis. His-torically, radiotherapy alone has resulted in an overallfive-year survival rate of 40%-50% [23, 149, 150]. Mostseries show no advantage for doses in excess of 40 Gy[23]. Risk factors for loco-regional relapse include largetumour bulk and the use of radiation fields restricted togross disease with a limited margin [23].

A combined-modality approach has recently beenadvocated as the standard therapy in adults [23, 149,153]. Significantly better survival for adult patientstreated by both anthracycline-based chemotherapy andradiation therapy than for those who received radio-therapy alone has been reported in non-randomisedstudies [153-155]. At least in adults, long-term follow-uprevealed only modest morbidity related to radiationfields [23]. In children, however, the addition of radio-therapy to modern, intense combination chemotherapymay be superfluous, especially in view of its potential forcausing serious long-term effects [150]. In a series of 11children treated with an adriamycin-containing regimenconcomitant with radiation therapy (median tumourdose 50 Gy), the overall eight-year actuarial survivalwas 83% and no relapses were seen, however, twopatients developed second bone tumours in the radia-tion field [152].

Primary lymphoma of the breast

Primary lymphoma of the breast comprises approxi-mately 2% of all localised extranodal lymphomas [1. 2].and less than 0.5% of breast tumours. Review of theliterature shows two distinct clinicopathologic groups[156, 157]. One, which affects young women, is fre-quently bilateral, often associated with pregnancy, andit is generally a high-grade malignancy lymphoma [156,157]. The second group affects older women, presents

clinical features identical to epithelial breast cancer. Inthis second presentation, the most common histology isthe diffuse large B-cell type [23, 156, 157]. However, afew cases of low-grade lymphomas have been described[157]; some of MALT origin have been reported in theWestern world [95,136,156,158].

The lymphoma usually presents with a breast mass,frequently rather large, with or without ipsilateraladenopathy. Lymphomatous involvement of the breastis generally depicted on the mammogram as a cir-cumscribed mass without tumour calcifications [9]. Itsappearance, however, is generally non-specific, compro-mising an accurate diagnosis, which requires fine-needleaspiration cytology or biopsy. Historically, radiotherapyto the breast and the regional lymph nodes has beenemployed following surgery. With doses of 35-40 Gy,local control is achieved in four of five patients andoverall survival rates of 40%-60% at 10 years are re-ported [23]. Despite good local control, systemic failureoccurs in at least half of the patients. Prognostic factorsfor disease progression include large tumour bulk andnodal involvement. Combined modality treatment hasmost recently been recommended [159, 160]. Long-termresults with the addition of combination chemotherapyare still sparse and therefore the relative merits of thismodality can as yet not be assessed. It would, however,seem reasonable to treat these patients according to thehistology. Therefore radiation alone should not be givento the diffuse large cell lymphomas but might have a rolein the rare localised indolent lymphomas of follicular orMALT type.

Primary lymphoma of the lung

While lung is frequently involved by disseminated lym-phoma, isolated pulmonary lymphoma is rare, accountingfor less than 1% of all extranodal localised disease [23].

Three categories of primary pulmonary lymphomacan be distinguished: in rare instances, large-cell lym-phoma can present primarily in the lung [23, 161]; asecond variant is represented by T-cell lymphoma pre-senting as an angiocentric process within the frameworkof the lethal midline granuloma [110]. However, themost common histologic type is represented by low-grade MALT lymphoma, often in the past consideredas a pseudotumour because of its long indolent naturalhistory. Principles of treatment vary with histology. TheMALT type lesions should be treated like localised, low-grade lymphomas [23]. However, difficulties with safedelivery of irradiation to the lungs often lead to indi-vidualised therapy with not well documented results.

Other primary lymphomas of the upper airways

Tracheal involvement usually occurs with disseminatedlymphoma. Primary tracheal lymphoma is a rare entity.Reported histologies are varied, with a predominanceof low-grade lesions, sometimes including lymphomasof MALT type [162]. The therapeutic approach for


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localised disease should comprise combined chemo-radiotherapy [162]. Primary laryngeal lymphomas arealso very rare and may arise from the MALT [163].

Primary splenic lymphoma

The spleen is frequently involved by Hodgkin's and non-Hodgkin's lymphomas of nodal type and by acute andchronic leukaemias during the course of these diseases.About 20% of nodal non-Hodgkin's lymphomas showevidence of spleen involvement at presentation. How-ever, primary lymphomas of the spleen are quite uncom-mon. Several cases of low-grade lymphoma involvingthe marginal zone of the splenic white pulp have meritedparticular attention in the recent literature [4,164]. Mostof these cases appear to have the characteristics of themarginal zone B-cell lymphoma [4]. An entity related tothis one is the splenic lymphoma with circulating villouslymphocytes [165, 166]. Some investigators believe thatit corresponds to the leukemic phase of the marginalzone B-cell lymphoma [4, 167]. Further studies are alsorequired to definitely clarify the relationship between thesplenic marginal zone B-cell lymphoma and the nodal(monocytoid) and extranodal (MALT-type) B-cell lym-phomas of the marginal zone [4, 168]. Patients, typicallyin advanced age, present with splenomegaly, sometimeswith bone marrow and peripheral blood involvementwithout lymphoadenopathy. A serum monoclonal gam-mopathy is often detectable, together with anemia andthrombocytopenia, mostly due to the hypersplenism.Treatment depends on symptomatic splenomegaly andwhite cell count. In our opinion, a wait-and-see policymay be followed in several instances, as in other low-grade B-cell malignancies. Splenectomy is indicated tocorrect the hypersplenism and related cytopenia and incases of splenic lymphoma with villous lymphocyteswith rapidly rising white cell counts. The role of chemo-therapy is uncertain [166, 169].

Together with the liver, spleen is the primary site ofinvolvement of the rare hepatosplenic gamma/deltaT-cell lymphoma. This disease affects young patientswho present marked hepatosplenomegaly, commonlywith bone marrow involvement and without lympha-denopathy or significant peripheral blood lymphocytosis.The clinical course is usually very aggressive, with amedian survival of less than one year despite the possi-bility of initial response to multiagent chemotherapy [170].

Primary lymphoma of the liver

Liver involvement by lymphoma is relatively commonand usually indicates advanced disease. However, pri-mary lymphoma of the liver is exceedingly rare, with lessthan 100 cases reported in the literature [171]. A possiblepathogenetic role of hepatitis B and C viruses has beenproposed, but thus far there has not been enough evi-dence to support these viruses as important etiologicfactors [171]. It typically occurs in the fifth decade with amale predominance. The majority of the cases have

diffuse large B-cell histologies, but peripheral T-celllymphomas and primary low-grade MALT lymphomashave also been reported [172, 173].

Presentation may mimic hepatocellular carcinoma,since primary liver lymphoma may present as single ormultiple masses or even as a diffuse infiltration thatmay manifest itself as various liver diseases, or veryoccasionally as fulminant hepatic failure [172, 174]. Thedisease is often associated with several poor- prognosischaracteristics, i.e., advanced age, bulky disease, aggres-sive histology. It is difficult to make general treatmentrecommendations for such a rare type of lymphoma.Partial hepatectomy for solitary lesions has been pro-posed [172], but given the commonly registered extensiveintrahaepatic disease, adjuvant systemic chemotherapyseems to be mandatory. For most patients who presentwith adverse prognostic factors combination chemo-therapy with or without radiotherapy appears the mostappropriate strategy.

Primary lymphoma of the gallbladder

Primary malignant lymphoma of the gallbladder is ex-ceedingly rare; only nine well documented cases havebeen reported in the English-language literature [175].The histology can be variable, and occasional cases ofMALT lymphomas have been reported. [176]. The pos-sible growth of malignant lymphoma in the biliary ductshas also been described [177].

Primary lymphoma of the oesophagus

Although lymphoma may involve any part of thegastro-intestinal tract, either primarily or secondarily,oesophageal involvement is exceedingly rare [178]. Onlya few cases have been reported in the literature: diag-nosis is generally biopsy-related, since roentgenographicstudies and endoscopic findings are unspecified. Noexact therapeutic rules have been established, but com-bined radio-chemotherapy seems advisable [178].

Primary cardiac lymphoma

Primary malignant lymphomas of the heart are ex-tremely rare [179]. In a series of more than 500 primarytumours and cysts of the heart, only seven were primarylymphomas [180]. These tumours present with a varietyof clinical manifestations and very rarely are diagnosedante mortem.

Primary adrenal lymphoma

Adrenal involvement in disseminated lymphoma is arelatively common occurrence, however involvement ofthe adrenal glands as the sole manifestation of lympho-ma is very rare, with approximately 70 cases reported inthe literature over the past 40 years. The true incidenceof this neoplasm is not known. Most of the cases appearto be of B-cell origin with diffuse large cell histology.


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The disease is often bilateral. The presenting symptomsare non-specific and may be related to lymphoma or toan associated adrenal insufficiency that may be a lethalcomplication. Long delays between the onset of symp-toms and the diagnosis are frequent. In clinically silentcases, adrenal insufficiency may be latent and the diseaserevealed as an adrenal mass incidentally discovered bydiagnostic imaging [181, 182].

Primary lymphoma of soft tissues

Non-Hodgkin's lymphomas of various histologic sub-types, usually diffuse large B-cell (centroblastic) lym-phoma, have been described in some soft tissues[183]. This localisation is very rare, however, with anincidence not exceeding 2% of all soft tissue tumours. Indifferential diagnosis undifferentiated metastatic carci-nomas and round-cell sarcomas have to be considered,and immunohistochemistry studies are often decisive forthe final diagnosis. Intermuscular tissue is the mostcommon localisation but primary skeletal muscle in-volvement is also well described [184]. NHLs have beendescribed also in post-mastectomy lymphoedema and injuxta-articular tissues after prosthetic joint replacement[185,186].

Primary body-cavity-based lymphomas(primary-effusion lymphoma andpyothorax-associatedlymphoma)

Primary-effusion lymphoma and pyothorax-associatedlymphoma are two distinct extranodal lymphomas, show-ing a particular tropism for body cavities, i.e., pleural,peritoneal or pericardial spaces.

Primary-effusion lymphoma is a recently-describedentity with particular epidemiological, molecular andclinical features [187]. It occurs predominantly in HIV-infected individuals, representing 3% of all NHLs, butit has been reported even in HIV-seronegative cases(less than 1% of all high-grade NHLs) [188, 189].Median age at presentation is approximately 40 years inHIV-positive cases and nearly 80 years in seronegativepatients. AIDS-related primary-effusion lymphomausually occurs in very severely immunodeficient personsand tends to be a later manifestation of the HIV infec-tion. Histological features comprise immunoblastic oranaplastic cells, immunophenotypically related to a latestage of B-cell activation toward terminal plasma celldifferentiation [190]. DNA sequences from Kaposi'ssarcoma-associated herpesvirus (KSHV/HHV-8) andfrom EBV are detectable in tumour cells of the largemajority of cases, with the last virus apparently lessclosely associated with immunocompetent cases [189].Primary-effusion lymphoma typically presents as lym-phomatous effusions (pleural, pericardial, or ascitic)usually without a solid tumour mass. Its prognosisappears to be dismal and, because of the small numberof reported cases, no exact treatment rules can be given.

Pyothorax-associated lymphoma, principally reported

in Japan, affects elderly patients with a longer than 20-year history of pyothorax, usually related to chronictuberculosis [191]. Histologically, this extranodal lym-phoma is usually of the immunoblastic B-cell type. EBVgenome is found in the lymphoma cells in approximately85% of the cases [191]. In contrast to primary-effusionlymphoma, KSHV/HHV-8 DNA is usually absent andclinical manifestations always comprise a neoplasticmass associated with the pleural effusion [192].

Angiotropic lymphoma

Angiotropic (intravascular) lymphoma is a rare disease.Most cases are of diffuse large B-cell type, but there area few with T-cell phenotype [193, 194]. Neoplastic cellstypically grow trapped within small arteries, veins andcapillaries, and, only rarely, extravasate. Presentingclinical features are varied, often comprising bizarreneurologic symptoms and non-specific cutaneous mani-festations. Angiotropic lymphoma should always beconsidered as being Ann Arbor Stage IV and treatedwith systemic chemotherapy. The large number of casesreported post-mortem attests the difficulty in obtainingthe correct diagnosis; however, the prognosis for theproperly treated cases seems to be similar to that of theother diffuse large-cell lymphomas.

Lymphomas arising from the thymus

Primary mediastinal large B-cell lymphoma with scle-rosis may derive from a special thymic medullary B-cellpopulation. This view is based mainly on the locationand on the frequent persistence of thymic epithelialstructure. It should not be surprising that the majororgan of T-cell development may be the site of a B-celllymphoma, since recent evidence has shown the presenceof a significant B-cell population in the thymic medulla[195]. Primary mediastinal large B-cell lymphoma is adistinct clinicopathological entity [4, 196], with a re-cently reported high frequency of specific chromosomalgain (e.g., chromosome 9p) not known for other NHLs[197]. It more frequently affects young women. Symp-toms at presentation are usually due to a large media-stinal mass which frequently invades lungs, superiorvena cava, pericardium, pleura and chest wall. Despitethis local aggressiveness, distant spread is relativelyuncommon, and is more likely to be extranodal, in-cluding kidneys, liver, gastrointestinal tract, ovaries andCNS. Involvement of the bone marrow is unusual.

There are conflicting data regarding the overall prog-nosis, the response to chemotherapy and the need ofirradiation [198-200]. However, consolidation radio-therapy to the bulky site appears beneficial in most ofthe reported series, suggesting that the control of intra-thoracic disease is essential. Therefore, combination ofaggressive chemotherapy and mediastinum irradiationmust be considered the standard therapeutic approach,at least until randomised trials show equivalence ofchemotherapy alone. [201]. Despite the good results of


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myeloablative chemotherapy followed by autologousstem cell transplantation reported in a recent series[202], in our opinion this strategy, as first-line therapy,should still be considered investigational.

In addition, very few cases of primary low-gradeB-cell MALT lymphoma have been reported in thethymus. It can mimic myoepithelial sialadenitis or bepreceded by a prolonged history of Sjogren's syndrome[203, 204].

References

102. Jacobs C, Hoppe RT. Non-Hodgkin's lymphomas of head andneck extranodal sites. Int J Radiat Oncol Biol Phys 1985; 11:357-64.

103. Chisin R.Weber AL. Imaging of lymphoma manifestations inthe extracranial head and neck region. Leuk Lymph 1994; 12:177-89.

104 Gospodarowicz MK, Sutcliffe SB. Brown et al. Patterns ofdisease in localised extranodal lymphoma. J Clin Oncol 1987; 5.875-80

105. Munro A. Lymphomas of the oral cavity and oropharynx. InStafford N, Waldron J (eds): Management of Oral Cancer. NewYork: Oxford University Press 1989, 196-200

106. Delecluse HJ, Anagnostopoulos I, Dallenbach F et al. Plasma-blastic lymphoma of the oral cavity: A new entity associatedwith human immunodeficiency virus infection. Blood 1997: 89.1413-20.

107. Royer B, Cazals-Hatem D, Sibilia J et al Lymphomas in patientswith Sjogren's syndrome are marginal zone B-cell neoplasms,arise in diverse extranodal and nodal sites, and are not associatedwith viruses. Blood 1997; 90- 766-75.

108. Harris NL. Lymphoid proliferations of the salivary glands. Am JClin Pathol 1999; 111 (Suppl 1). S94-103

109. Pisa EK, Pisa P, Kang HI et al. High frequency of t(14;l8)translocation in salivary gland lymphomas from Sjogren's syn-drome patients. J Exp Med 1991; 174. 1245-50.

110. Jaffe ES, Chan JKC, Su IJ et al. Report of the workshop on nasaland related extranodal angiocentric T/Natural Killer cell lym-phomas. Definitions, differential diagnosis, and epidemiology.Am J Surg Pathol 1996; 20: 103-11.

111. Weiss LM, Arber DA. Stickler JG. Nasal T-cell lymphoma. AnnOncol 1994; 5 (Suppl 1): S39-S42.

112. Weiss LM, Picker LJ, Grogan TM et al. Absence of clonal betaand gamma T-cell receptor gene rearrangements in a subset ofperipheral T-cell lymphomas. Am J Pathol 1988; 130: 436^12.

113. Borisch B. Hennig I, Laeng RH et al. Association of the subtype2 of the Epstein-Barr virus with T-cell non-Hodgkin's lym-phoma of the midline granuloma type. Blood 1993: 82: 858-64.

114. Kanavaros P. Lescs MC. Briere J et al. Nasal T-cell lymphoma:A clinicopathologic entity associated with peculiar phenotypeand with Epstein-Barr virus. Blood 1993: 81: 2688-95.

115. Gutierrez MI, Spangler G, Kingma D et al. Ebstein-Barr virusin nasal lymphomas contains multiple ongoing mutations in theEBNA-1 gene. Blood 1998; 92: 600-6.

116. Abbondanzo SL, Wenig BM. Non-Hodgkin's lymphoma of thesinonasal tract. A clinopathologic and immunophenotypic studyof 120 cases. Cancer 1995; 75: 1281-91.

117. HausdorfT J, Davis E, Long G et al. Non-Hodgkin's lymphomaof the paranasal sinuses: clinical and pathological features, andresponse to combined-modality therapy. Cancer J Sci Am 1997:3:303-11.

118. Cheung MM, Chang JK, Lau WH et al. Primary non-Hodgkin'slymphoma of the nose and nasopharynx: Clinical features,tumour immunophenotype, and treatment outcome in 113patients. J Clin Oncol 1998; 16: 70-7.

119. Li YX, Coucke PA, Li JY et al. Primary non-Hodgkin's lym-

phoma of the nasal cavity: prognostic significance of paranasalextension and the role of radiotherapy and chemotherapy. Can-cer 1998: 83: 449-56.

120. Logsdon MD. Ha CS. Kavadi et al. Lymphoma of the nasalcavity and paranasal sinuses: improved outcome and alteredprognostic factors with combined modality therapy. Cancer1997: 80: 477-88.

121. Wotherspoon AC. Diss TC. Pan LX et al. Primary low-gradeB-cell lymphoma of the conjunctiva: A mucosa-associated lym-phoid tissue type lymphoma. Histopathology 1993: 23: 417-22.

122. Gaheni P, Polito E, Leccisotti A et al. Localised orbital lym-phoma. Haematologica 1997: 82: 436-9.

123. Baldini L. Blini M. GufTanti A et al. Treatment and prognosis ina series of primary extranodal lymphomas of the ocular adnexa.Ann Oncol 1998:9. 779-81.

124. LiesegangTJ. Ocular adnexal lymphoprohferative lesions. MayoClin Proc 1993; 68: 1003-10.

125. Doria R, Jekel JF, Cooper DL. Thyroid lymphoma: The case forcombined modality therapy. Cancer 1994; 73: 200-6.

126. Hyjek E. Isaacson PG. Primary B-cell lymphoma of the thyroidand its relationship to Hashimoto's thyroiditis. Hum Pathol1988; 19:1315-26

127. Anscombe AN. Wright DH Primary malignant lymphoma ofthe thyroid - a tumour of mucosa-associated lymphoid tissue:Review of seventy-six cases. Histopathology 1985; 9: 81-97.

128 Miller TP, Jones SE. Initial chemotherapy for clinically localisedlymphomas of unfavorable histology. Blood 1983; 62: 413-18.

129. Cote TR, Manns A. Hardy et al Epidemiology of brain lympho-ma among people with or without acquired immunodeficiencysyndrome. AIDS/Cancer Study Group. J Natl Cancer Inst 1996;88: 675-9.

130. De Angelis LM, Yahalom J. Primary central nervous systemlymphoma. In De Vita VT Jr. Hellman S, Rosenberg SA (eds):Cancer: Principles & Practice of Oncology (5th ed.) Philadel-phia- Lippincott-Raven 1997. 2233-42

131. Fine HA, Loeffler JS. Primary central nervous system lymphomaIn Canellos GP, Lister TA, Sklar JL (eds): The lymphomas.Philadelphia: WB Saunders 1998, 481-94

132 Matano S, Nakamura S, Ohtake S et al. Primary T-cell non-Hodgkin's lymphoma of the central nervous system. Case reportand review of the literature. Acta Haematol 1994: 91: 158-63.

133. Galoin S, Daste G. Apoil PA et al. Polymerase chain reactionon cerebrospinal fluid cells in the detection of leptomeningealinvolvement by B-cell lymphoma and leukemia: A novel strategyand its implications. Br J Haematol 1997; 99: 122-30.

134. Furst Nelson D, Martz Kl, Bonner H et al. Non-Hodgkin'slymphoma of the brain: Can high dose, large volume radiationtherapy improve survival? Report on a prospective trial by theRadiation Therapy Oncology Group (RTOG): RTOG 8315. IntJ Radiat Oncol Biol Phys 1992; 23: 9-17.

135. Abrey LE, De Angelis LM, Yahalom J. Long term survival inprimary CNS lymphoma. J Clin Oncol 1998; 16: 859-63.

136. Shibamoto Y. Tsutsui K, Dodo Y et al. Intracranial lymphomatreated by high-dose radiotherapy and systemic vincristine-doxorubicin-cyclophosphamide-prednisolone chemotherapy.Cancer 1990; 65: 1907-12.

137. Neuwelt EA, Goldman DL, Dahlborg SA et al. Primary CNSlymphoma treated with osmotic blood-barrier disruption: Pro-longed survival and preservation of cognitive function. J ClinOncol 1991; 9: 1580-90.

138. Blay JY, Bouhour D, Carrie C et al. The C5R protocol: Aregimen of high-dose chemotherapy and radiotherapy in pri-mary cerebral non-Hodgkin's lymphoma of patients with noknown cause of immunosuppression. Blood 1995: 86: 2922-9.

139. Fine HA. Treatment of primary central nervous system lympho-ma: Still more questions than answers. Blood 1995; 86: 2873-5.

140. Bessel EM, Graus F, Punt JAG et al. Primary non-Hodgkin'slymphoma of the CNS treated with BVAM or CHOD/BVAMchemotherapy before radiotherapy. J Clin Oncol 1996, 14: 945-54.


1032

141. Reni M, Ferreri AJM, Garancini MP, Villa E. Therapeuticmanagement of primary central nervous system lymphoma inimmunocompetent patients: Results of a critical review of theliterature. Ann Oncol 1997; 8: 227-34.

142. Sandor V, Stark-Vanes V, Pearson D et al. Phase II trial ofchemotherapy alone for primary CNS and intraocular lym-phoma. J Clin Oncol 1998; 16: 3000-6.

143. Peterson K, Gordon KV, Heinemann MH, De Angelis LM. Theclinical spectrum of ocular lymphoma. Cancer 1993; 72: 843-9.

144. Soussain C, Merle-Beral H, Reux I et al. A single-centre study of11 patients with intraocular lymphoma treated with conventionalchemotherapy followed by high-dose chemotherapy and autolo-gous bone marrow transplantation in 5 cases. Leuk Lymph 1996;23: 339-45.

145. Fishburne BC, Wilson DJ, Rosenbaum, Neuwelt EA. Intravitrealmethotrexate as an adjunctive treatment of intraocular lym-phoma. Arch Ophtalmol 1997; 115: 1152-6.

146. Lachance TH, O'Neill BP, Mac Donald DR et al. Primaryleptomeningeal lymphoma: Report of 9 cases, diagnosis withimmunocytochemical analysis and review of the literature. Neu-rology 1991; 41: 95-100.

147. Kumar S, Kumar D, Kaldjian EP et al. Primary low-grade B-celllymphoma of the dura. A mucosa associated lymphoid tissue-type lymphoma. Am J Surg Pathol 1997; 21: 81-7.

148. Rathmell AJ, Gospodarowicz MK, Sutcliffe SB et al. Localisedextradural lymphoma: Survival, relapse pattern and functionaloutcome. Radiat Oncol 1992; 24. 14-20.

149. Baar J, Burkes R, Blackstein ME et al. Primary non-Hodgkin'slymphoma of bone. A clinicopathologic study. Cancer 1994, 73:1194-9.

150. Coppes MJ, Patte C, Couanet D et al. Childhood malignantlymphoma of bone. Med Pediatr Oncol 1991; 19: 22-7.

151. Blasius S, Edel G, Vestring T et al. Non-Hodgkin's lymphomawith primary osseous manifestation, from the files of the BoneTumour Registry of Westphalia. Verh Dtsch Ges Pathol 1992, 76:146-50.

152. Loeffler JS, Tarbell NJ, Kozakewich H et al. Primary lymphomaof bone in children: Analysis of treatment results with adna-mycin, prednisone, oncovin (APO), and local radiation therapy.J Clin Oncol 1986; 4: 496-501.

153. Ferreri AJ, Reni M, Ceresoli GL et al. Therapeutic managementwith adriamycin-containing chemotherapy and radiotherapy ofmonostotic and polyostotic primary non-Hodgkin's lymphomaof bone in adults. Cancer Invest 1998; 16: 554-61

154. Fairbanks RK, BonnerJA, Inwards CYet al. Treatment of stageIE primary lymphoma of bone. Int J Radiat Oncol Biol Phys1994: 28: 363-72.

155 Rathmell AJ, Gospodarowicz MK, Sutcliffe SB, Clark RM.Localised lymphoma of bone: Prognostic factors and treatmentrecommendations. Br J Cancer 1992 66: 603-6.

156. Bobrow LG, Richards MA, Happerfield LC et al. Breast lympho-mas: A clinicopathologic review. Hum Pathol 1993; 24: 274-8.

157. Jeon HJ, Akagi T, Hoshida Y et al. Primary non-Hodgkinmalignant lymphoma of the breast. An immunohistochemicalstudy of seven patients and literature review of 152 patients withbreast lymphoma in Japan. Cancer 1991; 70: 2451-9.

158. Liberman L, Giess CS. Dershaw DD et al. Non-Hodgkin lym-phoma of the breast: Imaging characteristics and correlationwith histopathologic findings. Radiology 1994; 192: 157-60.

159. Giardini R. Piccolo C. Rilke F. Primary non-Hodgkin's lympho-mas of the female breast. Cancer 1992; 69: 725-35.

160. Ha CS, Dubey P. Goyal Lk et al. Localised primary non-Hodgkin lymphoma of the breast. Am J Clin Oncol 1998: 21:376-80.

161. Koss MN. Pulmonary lymphoid disorders. Sem Diagn Pathol1995: 12: 158-71.

162. Fidias P. Wright C. Harris NL et al. Primary tracheal non-Hodgkin's lymphoma. A case report and review of the literature.Cancer 1996; 77: 2332-8

163. Economopoulos T, Fountzilas G, Kostourou A et al. Malignant

lymphoma of mucosa-associated lymphoid tissue in the larynx.Eur Arch Otorhinolaryngol 1998; 255: 368-70.

164. Gobbi PG. Grignam GE, Pozzetti U et al. Primary spleniclymphoma: Does it exist? Haematologica 1994; 79: 286-93.

165. Isaacson PG, Matutes E, Burke M, Catowski D. The histo-pathology of splenic lymphoma with villous lymphocytes. Blood1994, 84: 3828-34.

166. Troussard X, Valensi F, Duchayne E et al. Splenic lymphomawith villous lymphocytes: Clinical presentation, biology andprognostic factors in a series of 100 patients. Br J Haematol1996; 93: 731-6.

167. Isaacson PG, Pins MA. Splenic marginal zone lymphoma. AdvAnat Pathol 1997; 4: 191-201.

168. Dierlamm J, Pittaluga S.Wlodarska I et al. Marginal zone B-celllymphomas of different sites share similar cytogenetic and mor-phologic features. Blood 1996; 87: 299-307

169. Bolam S, Orchard J, Oscier D. Fludarabine is effective in thetreatment of splenic lymphoma with villous lymphocytes. Br JHaematol 1997; 99: 158-61.

170. Cooke CB, Krenacs L, Stetler-Stevenson M et al HepatosplenicT-cell lymphoma: A distinct clinicopathologic entity of cytotoxicgamma delta T-cell origin Blood 1996; 88- 4265-74.

171. Lei Kl. Primary non-Hodgkin's lymphoma of the liver. LeukLymph. 1998; 29: 293-9.

172. Anthony PP, Sarsfield P. Clarke T Primary lymphoma of theliver: Clinical and pathological features of ten patients. J ClinPathol 1990; 43: 1007-13

173. Isaacson PG, Banks PM, Best PV et al. Primary low-gradehepatic B-cell lymphoma of mucosa-associated lymphoid tissue(MALT)-type. Am J Surg Pathol 1995; 19: 571-5.

174. Harris AC, Ben-Ezra JM, Contos MJ et al. Malignant lymphomacan present as hepatobihary disease. Cancer 1996: 78: 2011-9.

175. Chatila R, Fiedler PN, Vender RJ. Primary lymphoma of thegallbladder; case report and review of the literature Am JGastroenterol. 1996; 91: 2242-4.

176. McCluggage WG, Mackel E, Mccusker G. Primary low-grademalignant lymphoma of mucosa-associated lymphoid tissue ofgallbladder. Histopathology 1996; 29: 285-7.

177. Chiu KW, Changchien CS, Chen L et al. Primary malignantlymphoma of common bile duct presenting as acute obstructivejaundice, report of a case. J Clin Gastroenterol 1995; 20: 259-61.

178. Gupta NM, Goenka MK, Jindal A et al. Primary lymphoma ofthe esophagus. J Clin Gastroenterol 1996; 23: 203-6.

179. Ceresoli GL, Ferreri AJ, Bucci E et al. Primary cardiac lympho-ma in immunocompetent patients: diagnostic and therapeuticmanagement. Cancer 1997: 80: 1497-506.

180. McCallister HA, Fenogho JJ. Tumours of the CardiovascularSystem. Atlas of Tumour Pathology, 2nd series, Fascicle 15Washington, DC: Armed Forces Institute of Pathology 1978;99-100.

181. Salvatore JR. Ross RS. Primary bilateral adrenal lymphoma.Leuk Lymphoma 1999; 34: 111-7.

182. Wang J, Sun NC, Renslo R et al. Clinically silent primaryadrenal lymphoma: A case report and review of the literature.Am J Hematol 1998; 58: 130 6.

183. Lanham GR. Weiss SW, Enziger FM. Malignant lymphoma: Astudy of 75 cases presenting in soft tissue. Am J Surg Pathol1989; 13: 1-10.

184. Bertoni F. Sanna P. Zucca E et al. Primary extranodal lymphomaof skeletal muscles: A report of four cases. Oncol Rep 1998: 5:605-7.

185. D'Amore ESG. Wick MR. Geisinger KR. Frizzera G. Primarymalignant lymphoma arising in postmastectomy lymphedema.Another facet of the Stewart-Treves syndrome. Am J Surg Pathol1990: 14: 456-63.

186. Radhi JM, Ibrahiem K, al-Tweigeri T. Soft tissue malignantlymphoma at sites of previous surgery. J Clin Pathol 1998: 5:629-32.

187. Nador RG. Cesarman E. Chadburn A et al. Primary effusionlymphoma: A distinct clinicopathologic entity associated with


1033

the Kaposi"s sarcoma-associated herpes virus. Blood 1996: 88:645-56.

188. Said JW. TasakaT. Tacheuchi Set al. Primary effusion lymphomain women: report of two cases of Kaposis sarcoma herpes virus-associated effusion-based lymphoma in human immunodefi-ciency virus-negative women. Blood 1996; 88: 3124-8.

189. Carbone A. Gaidano G. HHV-8-positive body-cavity-based lym-phoma: A novel entity. Br J Haematol 1997: 97: 515-22.

190. Gaidano G, Gloghini A, Gattei Vet al. Association of Kaposissarcoma-associated herpesvirus-positive primary effusion lym-phoma with expression of the CD138/Syndecan-1 antigen. Blood1997; 90: 4894-900.

191. Aozasa K. Pyothorax-associated lymphoma Int J Hematol1996; 65 9-16.

192. Cesarman E, Nador RG, Aozasa K et al. Kaposi's sarcoma-associated herpesvirus in non-AlDS related lymphomas occur-ring in body cavities. Am J Pathol 1996; 149: 53-7.

193. Demirer T, Dail DH, Aboulafia DM Four varied cases of intra-vascular lymphomatosis and a literature review. Cancer 1994; 73:1738-45.

194. Sanna P, Bertoni F, Roggero E et al. Angiotropic (intravascular)large cell lymphoma. A case report and short discussion of theliterature. Tumori 1997; 83: 772-5.

195. Isaacson PG, Norton AJ, Addis BJ. The human thymus containsa novel population of B lymphocytes. Lancet 1987; 2: 1488-90.

196. Lazzarino M, Orlandi E, Paulli M et al. Primary mediastinalB-cell lymphoma with sclerosis' An aggressive tumour withdistinctive clinical and pathologic features. J Clin Oncol 1993;11.2306-13.

197. Joos S, Otano-Joos Ml, Ziegler S et al Primary mediastinal(thymic) B-cell lymphoma is characterized by gains of chromo-somal material including 9p and amplification of the REL gene.Blood 1996; 87: 1571-8.

198. Lazzarino M, Orlandi E, Paulli M et al. Treatment outcome andprognostic factors for primary mediastinal (Thymic) B-cell lym-

phoma: A multicenter study of 106 patients. J Clin Oncol 1997:15: 1646-53.

199 Cazals Hatem D. Lepage E. Brice P et al. Primary mediastinallarge B-cell lymphoma: A clinicopathologic study of 141 casescompared with 916 nonmediastinal large B-cell lymphomas. aGELA ("Groupe d'Etude des Lymphomes de lAdulte) study.Am J Surg Pathol 1996: 20: 877-88.

200. Abou-Elella AA. Weisenburger DD, Vose JM et al. Primarymediastinal large B-cell lymphoma. A clinicopathologic studyof 43 patients from the Nebraska Lymphoma Study Group. JClin Oncol 1999; 17: 784-90.

201. Brugger W, Engelhardt R, Mertelsmann R. Kanz L. The man-agement of primary mediastinal B-cell lymphoma with sclerosis.Ann Oncol 1994: 5. 943-7.

202. Sehn LH, Antin JH, Shulman LN et al. Primary large B-celllymphoma of the mediastinum, outcome following high-dosechemotherapy and autologous hematopoietic cell transplanta-tion. Blood 1998; 91: 717-23.

203 Isaacson PG, Chan JKC, Tang C et al Low-grade B-cell lym-phoma of mucosa-associated lymphoid tissue arising in thethymus. A thymic lymphoma mimicking myoepithelial sialade-nitis. Am J Surg Pathol 1990; 14. 342-51.

204. Di Loreto C, Manuzzi L, DeGrassi A et al. B-cell lymphoma ofthe thymus and salivary gland. J Clin Pathol 1996; 49: 595-7.

Received 28 April 1999; accepted 1 July 1999.

Correspondence to:Emanuele Zucca, MDIstituto Oncologico della Svizzera ItahanaDivisione di Oncologia MedicaOspedale San Giovanni6500 BellinzonaSwitzerlandE-mail: [email protected]



Primary extranodal non-Hodgkin's lymphomas. Part 2: Head and ...

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