The concept of in situ neoplasia, long established in epithelial tumors, has now been extended to lymphoid neoplasms.1 In both conditions, ie, in situ lymphoma and in situ carcinoma, the concept is appropriate when the bulk of the neoplastic cells is localized and confined within a specific anatomic district that is occupied by the normal counterpart of the tumor cells without invasion of surrounding structures. Among germinal center (GC)-derived lymphomas,2 a type of “in situ follicular lymphoma (FL)” has been described in which t(14;18)-positive cells that strongly express BCL2 are observed in histologically abnormal follicles present in lymph node biopsy specimens from individuals without overt disease.1, 3 “In situ FL” may be regarded as a distinct step in pathogenesis leading to overt lymphoma (for review, see Carbone and Santoro3), because overt FL develops with time in a subgroup of these individuals.
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), another GC-derived2 lymphoma, is characterized by a nodular proliferation or a nodular and diffuse proliferation that contains peculiar neoplastic cells, known as lymphocyte-predominant (LP) cells.2 During the daily observation of lymphomas, I have come up against some NLPHL cases with a micronodular or exclusive nodular pattern in which small GCs or broken-up GCs are present within nodules. Among the 80 patients who were diagnosed with NLPHL at the Aviano Oncology Referral Center during the last 2 decades, 4 patients exhibited this histologic pattern. All 4 patients, who received treatment in the Medical Oncology Department, are alive and well 14 years, 16 years, 18 years, and 20 years after the initial diagnosis and still are in follow-up (M. Spina, U. Tirelli, unpublished data).
This finding was first described as a morphologic variant of NLPHL by Fan et al.4 In these cases, I observed that LP cells expressing CD20 and BCL6, but not CD30 or CD15, usually were restricted to a nodular background of reactive cells, including a meshwork of CD23-positive dendritic cells, CD20-positive and BCL6-positive small B-cells, and small T-cells consistent with a normal GC. Therefore, I suggest that this NLPHL variant should be regarded as an early lesion limited to GCs (Fig. 1), and, as in “in situ FL,” it is likely to be an in situ step potentially leading to overt lymphoma. It is noteworthy that the presence of numerous LP cells outside the nodules predicts for progression to a diffuse pattern.4
The exact identification by the pathologist of such an early lesion, ie, nodular-intrafollicular NLPHL without evidence of extension of LP cells outside the nodules, represents for the physician the cutoff between either therapy or no therapy at all. Further studies on large case series will be necessary to corroborate this suggestion. Things change when the early lesion is complicated by transformation to either a diffuse NLPHL or T-cell-rich B-cell lymphoma. In this occurrence, the disease must be managed with appropriate treatment.5