Histopathological Diagnosis

An important clinical decision involves knowing when to biopsy a major salivary gland to rule out lymphoma and how to interpret the results. Clinical guidelines for the evaluation of patients with parotid gland swelling or lymphadenopathy have been published [203-205]. If malignancy is clinically suggested in a patient with SS, a biopsy must be performed to rule out NHL. Although minor salivary gland biopsy is certainly the most widely used test specific for the salivary component in SS, in patients whose main complaint is persistent parotid gland swelling and in whom lymphoma associated to SS is suggested, parotid biopsy should be considered instead of minor salivary gland biopsy [206-207], On the other hand, biopsy material may be readily accessible from superficially affected tissues, e.g., lymph nodes, but is more difficult to obtain when deeper structures are involved, particularly the lungs. Precise assessment of hematopathologic specimens depends, in large part, on adequate sampling and proper handling of tissues, both of which may be influenced significantly by clinicians. The largest lymph node or mass lesion generally provides the most useful material for accurate diagnosis and should undergo surgical biopsy. Needle biopsies and aspirates are not recommended for initial diagnosis of malignant lymphomas because these small samples can miss focal lesions, provide little or no evaluable tissue architecture, and limit the number of ancillary studies that can be performed; these specimens can be used for staging purposes and for demonstrating recurrences in patients with documented lymphomas.

Strict pathologic criteria remain, at present, the "conditio sine qua non" for the diagnosis of a frank B-cell NHL in SS. The present clinical situation is patently unsatisfactory, since some borderline cases can be rather difficult to define as either benign or low-grade malignant by histopathologic evaluation, and since the clinical behavior does not always correlate with the histopathological findings. Furthermore, the simple detection of B-cell clonality cannot be used as a criterion for the diagnosis of B-cell malignancy, when a definite diagnosis by histopathologic evaluation alone is problematic. In fact, B-cell clonal expansion is a common event in SS (whereas overt lymphoma develops in a minority of patients [155, 208],

In the salivary glands, features of lymphoma include sheets of monotonous small to medium lymphocytes which have abundant pale cytoplasm and produce a pale staining zone around the epithelial islands. These cells frequently have irregular cleaved nuclei and have been termed centrocyte-like (CCL) cells [205]. However, their appearance is variable and they may also appear monocytoid [119, 210], may resemble typical lymphocytes or may occasionally show plasmacytoid differentiation. Immunoblasts and plasma cells are often scattered throughout the infiltrate and large epithelioid and Reed-Sternberg-like cells may also be seen [157]. An important criterion for diagnosis of lymphoma is the demonstration of k or A. light-chain restriction among these cells.

Reactive follicles are characteristic and almost always accompany a MALT lymphoma. Occasionally, these may be infiltrated by CCL cells to produce an appearance similar to follicle centre-cell lymphoma [211], This strong association with reactive follicles lends weight to the concept that the lymphoma is a result of escape of a neoplastic clone of B cells following persistent antigenic stimulation. Indeed, there is evidence that the lymphoma itself may be antigen dependent, since low-grade B-cell gastric lymphomas of MALT have been shown to regress after eradication of H. pylori infection.

The distinction between lymphoma versus reactive clonal expansion of lymphoid cells is often extremely difficult, especially since the accepted criteria for diagnosis of NHL do not apply well to lymphomas arising in mucosal tissues such as salivary gland [115]. Lymphomas may remain localized for many years, and low-grade lymphomas may undergo spontaneous remissions in the absence of therapy [8, 9]. The clinical situation in patients with SS, however, seems analogous to the diagnostic problem in patients with benign monoclonal gammopathy, where the circulating paraproteins probably reflect an expanded B-cell population and the patients have an increased risk of developing subsequent lymphoid malignancy [212]. In patients with either SS pseudolymphoma or benign monoclonal gammopathy, laboratory results (includ-

Table 7. Clinical and immunological findings suggesting malignant lymphoproliferation in primary SS

(a) Clinical features

- Persistent enlargement of parotid glands

- Splenomegaly

- Adenopathy

- Mediastinal or hilar lymph nodes

- Lung nodules

- Persistent fever

(b) Immunological findings

- Lowered serum IgM

- Negative rheumatoid factor (having been positive)

- High serum -microglobulin

- Monoclonal gammopathy

- Mixed cryoglobulinemia -Cross-reactive idiotypes (17-109, G6, SF18/2)

ing DNA analysis) must be taken together with the overall clinical picture to determine when neoplastic transformation (and the need for aggressive therapeutic intervention) has occurred.

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