Nevus Cell Aggregates in Lymph Nodes - CiteSeerX

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axillary lymph nodes, but they also have been identified in cervical and inguinal regions; involvement of visceral nodes is rare.4,8 In most cases, the cellular ...
AJCP / EDITORIAL

Nevus Cell Aggregates in Lymph Nodes James W. Patterson, MD DOI: 10.1309/JXE9EYQXD691LV2Y

The article by Holt et al1 in this issue of the Journal looks again at the issue of nevus cell aggregates in lymph nodes and contributes substantially to our understanding of the phenomenon. At the same time, like all good studies, it raises some important questions that remain to be answered. In this editorial, I briefly summarize what is known about the frequency of nevus cells in lymph nodes, their locations in terms of gross and microscopic anatomy, the means used to identify them, and the prevailing theories of how nevus cells might get there in the first place. Finally, I briefly mention some of the practical diagnostic dilemmas that can arise when nevus cells are found in lymph nodes. The occurrence of nevus cell aggregates in lymph nodes has been known at least since Stewart and Copeland’s 1931 report, and subsequent studies indicate that it no longer can be considered a rare phenomenon.2 Among patients with melanoma undergoing lymph node biopsy or lymphadenectomy, 3% to 22% have had nodal nevi.3,4 In patients with melanoma, nodal nevi have been found in 0.12% to 0.54% of nodes from full lymph node dissections,3,5 1.2% of nodes from selective lymph node dissections,4 and 3.9% to 13% of sentinel lymph nodes. 4,6 Their frequency is less in lymphadenectomy specimens for breast carcinoma, having been found in 0.33% of patients and in 0.017% to 0.1% of lymph nodes in this setting.3,4 Nevus cells also have been encountered in lymph nodes from patients with no known malignancy, as well as in regional nodes associated with adnexal carcinoma of the skin and squamous cell carcinoma of the tonsil.7 The greater frequency of nevus cell aggregates in sentinel nodes removed for melanoma, as opposed to nonsentinel nodes, has been demonstrated convincingly, although the search for

melanocytes in these sentinel nodes tends to be more vigorous, often including multiple levels and immunohistochemical analysis. Nevus cells have been found most often in axillary lymph nodes, but they also have been identified in cervical and inguinal regions; involvement of visceral nodes is rare.4,8 In most cases, the cellular aggregates have the appearance of conventional nevus cells. However, node involvement also has been seen with blue nevus, cellular blue nevus, and plexiform spindle cell nevus, as well as atypical spitzoid tumors.3,9-12 The most common locations of nevus cell aggregates, by far, are the capsule or trabeculae of lymph nodes.3,4,6 Occasionally they can be observed adjacent to small vessels4,9 or within lymphatic vessels surrounding the nodes.13 The nevus cells are surrounded by a delicate reticulin meshwork, a finding not associated with melanoma cells.14 However, there have been a number of reports of nevus cells within cortical or medullary parenchyma or in marginal sinuses3,13,15; Biddle et al7 recently reported 13 such cases. When present in nodes, cellular blue nevi often are found in the peripheral sinuses or parenchyma,16,17 a finding that has led some to postulate a different mechanism from the usual capsular site of conventional nevus cell aggregates.3,18 Nevus cell aggregates most often are found on H&E-stained sections, but additional cases are identified with immunohistochemical analysis.19 The cells most often are positive for S-100 or MART-1, but they are negative or only weakly positive for HMB-45.4,7 In contrast with metastatic melanoma cells, nevus cell aggregates tend to be negative for the proliferation marker Ki-67.7,20 The theories of how nevus cells arrive in or around lymph nodes can be divided into 2 broad categories: (1) arrested migration of neural crest progenitor cells during Am J Clin Pathol 2004;121:13-15

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Patterson / NEVUS CELL AGGREGATES IN LYMPH NODES

embryonic development and (2) transport of cells from cutaneous lesions to lymph nodes, also termed mechanical transport or benign metastasis. The following are among the findings that have been taken to favor arrested migration: (1) the usual capsular location with sparing of sinuses10,21; (2) the concurrence of embryonic migration of melanocytic precursors and development of the lymphatic system6; (3) the presence of blue nevus cells in other sites such as prostate, cervix, vagina, spermatic cord, and seminal vesicles2,22; (4) the lack of cutaneous melanocytic nevi in catchment areas of involved lymph nodes in some cases4; (5) the rarity of finding both metastatic melanoma and nevus cells in the same lymph node4; and (6) the common finding of congenital nevi in association with nodal nevus cell aggregates, suggesting that anomalous migration is responsible for the nodal and the cutaneous findings.6 Chemotactic factors might be responsible for melanocyte migration, and these theoretically could drain via the lymphatics.6 Ioannides23 suggested that nevus cells reside in soft tissue owing to arrested migration and that nearby lymph nodes, subjected later to antigenic stimulation such as that provided by a regional melanoma, enlarge and encroach on adjacent tissues, with the resulting capsular location of the nevus cells. In favor of the mechanical transport theory are the following arguments: (1) Nevus cell aggregates sometimes are found in nodal sinuses or parenchyma. (2) There are examples of intranodal deposits of other tissues, such as endometrium, endosalpinx, and breast epithelium.10 (3) Nevus cells are not found in nodes draining noncutaneous sites.4 (4) Noncutaneous nevus cell aggregates are found only in association with lymph nodes.5 (5) Nevus cell clusters are found within cutaneous lymphatics6,22,24 and in afferent lymphatics of lymph nodes, which are not known to have a role in embryonic migration of neural crest–derived cells.22 (6) Melanocytes “arrested” in their migration through the dermis are bipolar, whereas, in most cases, nevus cells in lymph nodes have the oval or cuboidal contours encountered in conventional cutaneous melanocytic nevi.9 A number of counterarguments could be made against the arrested migration theory. McCarthy et al25 postulated that nevus cells “home” to capsules of nodes because of the similarities to dermal connective tissue. Despite the concurrent timing of neural crest cell migration and lymphatic system development, lymphatics have no known role in this migration process.21,22 An apparent lack of cutaneous nevi in the catchment areas of involved nodes is difficult to prove, since nevus cells can be found incidentally in skin biopsy specimens when no obvious lesion is noted clinically. The deep dermal extension of congenital nevi and resulting increased likelihood of lymphatic involvement also could explain the propensity of these nevi for nodal involvement. 14 14

Am J Clin Pathol 2004;121:13-15 DOI: 10.1309/JXE9EYQXD691LV2Y

The findings of Holt et al 1 lend further support to the mechanical transport theory. Of their 72 patients with melanoma, 8 had nodal nevi. Six of these had an associated nevus (4 with congenital features). No correlation was seen between nodal nevi and a separate cutaneous nevus unassociated with the primary melanoma, and nodal nevus cells were not identified in nonsentinel lymph nodes. It is important to note that the incidence of nodal nevus correlated with the Breslow thickness of the primary cutaneous melanomas larger than 2.5 mm. These results strongly suggest that, within the cutaneous lesion, preexisting benign nevus cells somehow are displaced by neoplastic melanocytes, with resultant lymphatic transport. Although aberrant migration of neural crest cells cannot be excluded entirely, the balance of evidence now seems to favor the mechanical transport theory. Yet, a number of questions remain. Can this process truly be considered “metastasis”? It is doubtful that nevus cells are capable of completing the multistep process necessary for successful metastatic spread. Although these cells enter the lymphatic circulation and extravasate into the lymph node capsule or (uncommonly) the nodal parenchyma, they probably are not capable of proliferating as a secondary colony, while at the same time they are somehow able to escape immune killing.26 Could there be simple mechanical disruption of nevus cells by the melanoma, promoting passive entry into the lymphatic system, followed by “protection” within the immunologically privileged site of the lymph node capsule? Could cytokines released by the tumor impart limited capabilities for infiltration or “condition” the nodes for receipt of benign nevus cells?4 What can we learn from this phenomenon that might teach us about the metastatic process in general or lead to the development of novel anticancer therapies? Clearly, much work remains to be done to fully understand the process of nodal involvement by nevus cells. On a more practical level, the occurrence of nevus cell aggregates in lymph nodes continues to create diagnostic and management problems for pathologists and clinicians. We have encountered a few of these in our practice. There is the case of a diagnosed melanoma of the back with melanocytes in an axillary sentinel lymph node, which on review proved to be a congenital nevus with nevus cell aggregates in the nodal capsule. A spindle cell nevus developed in a prepubertal child, and 2 years later similar cells were identified in a regional lymph node. This discovery created medicolegal issues, but even after removal of the node, no reviewer was able to diagnose melanoma on the skin lesion, and there have been no sequelae 10 years later. A melanocytic lesion developed in a young person. Experts differed on a benign vs malignant diagnosis, but the lesion had some configurational changes of deep penetrating nevus. A sentinel lymph node showed similar pigmented cells in the capsule, although they © American Society for Clinical Pathology

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were not otherwise morphologically atypical. Was this metastatic melanoma, mechanical transport, or evidence for arrested embryonic migration? In the workup of primary cutaneous melanoma, polymerase chain reaction studies on sentinel lymph nodes sometimes produce a positive signal for tyrosinase messenger RNA, even though no melanoma cells are identified by routine histopathologic examination. Has the study detected a subtle metastatic melanoma, or could nodal nevus cells account for the findings?6 It is clear that such cases need to be studied with great care, and considerable caution should be exercised in interpreting the results. Moreover, it is incumbent on pathologists to educate surgeons, oncologists, and the legal community about the very real occurrence of nevus cell aggregates in lymph nodes. From the Departments of Pathology and Dermatology, University of Virginia Health System, Charlottesville.

References 1. Holt JB, Sangueza OP, Levine EA, et al. Nodal melanocytic nevi in sentinel lymph nodes: correlation with melanomaassociated cutaneous nevi. Am J Clin Pathol. 2004;121:58-63. 2. Johnson WT, Helwig EB. Benign nevus cells in the capsule of lymph nodes. Cancer. 1969;23:747-753. 3. Ridolfi RL, Rosen PP, Thaler H. Nevus cell aggregates associated with lymph nodes: estimated frequency and clinical significance. Cancer. 1977;39:164-171. 4. Carson KF, Wen DR, Li PX, et al. Nodal nevi and cutaneous melanomas. Am J Surg Pathol. 1996;20:834-840. 5. Bautista NC, Cohen S, Anders KH. Benign melanocytic nevus cells in axillary lymph nodes: a prospective incidence and immunohistochemical study with literature review. Am J Clin Pathol. 1994;102:102-108. 6. Fontaine D, Parkhill W, Greer W, et al. Nevus cells in lymph nodes: an association with congenital cutaneous nevi. Am J Dermatopathol. 2002;24:1-5. 7. Biddle DA, Evans HL, Kemp BL, et al. Intraparenchymal nevus cell aggregates in lymph nodes: a possible diagnostic pitfall with malignant melanoma and carcinoma. Am J Surg Pathol. 2003;27:673-681. 8. Hart WR. Primary nevus of a lymph node. Am J Clin Pathol. 1971;55:88-92. 9. Azzopardi JG, Ross CM, Frizzera G. Blue naevi of lymph node capsule. Histopathology. 1977;1:451-461.

10. Barnhill R. Pathology of Melanocytic Nevi and Malignant Melanoma. Boston, MA: Butterworth-Heinemann; 1995:89,149-150, 166, 262-263. 11. Rodriguez HA, Ackerman LV. Cellular blue nevus: clinicopathologic study of forty-five cases. Cancer. 1968;21:393-405. 12. Su LD, Fullen DR, Sondak VK, et al. Sentinel lymph node biopsy for patients with problematic spitzoid melanocytic lesions: a report on 18 patients. Cancer. 2003;97:499-507. 13. Hara K. Melanocytic lesions in lymph nodes associated with congenital naevus. Histopathology. 1993;23:445-451. 14. Andreola S, Clemente C. Nevus cells in axillary lymph nodes from radical mastectomy specimens. Pathol Res Pract. 1985;179:616-618. 15. Fisher CJ, Hill S, Millis RR. Benign lymph node inclusions mimicking metastatic carcinoma. J Clin Pathol. 1994;47:245247. 16. Lambert WC, Brodkin RH. Nodal and subcutaneous cellular blue nevi: a pseudometastasizing pseudomelanoma. Arch Dermatol. 1984;120:367-370. 17. Lamovec J. Blue nevus of the lymph node capsule: report of a new case with review of the literature. Am J Clin Pathol. 1984;81:367-372. 18. Roth JA. Ectopic blue nevi in lymph nodes. In: Ackerman AB, ed. Pathology of Malignant Melanoma. New York, NY: Masson Publishing; 1981:293-296. 19. Messina JL, Glass LF, Cruse CW, et al. Pathologic examination of the sentinel lymph node in malignant melanoma. Am J Surg Pathol. 1999;23:686-690. 20. Lohmann CM, Iversen K, Jungbluth AA, et al. Expression of melanocyte differentiation antigens and Ki-67 in nodal nevi and comparison of Ki-67 expression with metastatic melanoma. Am J Surg Pathol. 2002;26:1351-1357. 21. Roth JA. Nevus cells in lymph nodes in a patient with malignant melanoma arising in a giant congenital nevus. In: Ackerman AB, ed. Pathology of Malignant Melanoma. New York, NY: Masson Publishing; 1981:285-292. 22. Subramony C, Lewin JR. Nevus cells within lymph nodes: possible metastases from a benign intradermal nevus. Am J Clin Pathol. 1985;84:220-223. 23. Ioannides G. Lymph node aggregates of nevus cells. In: Ackerman AB, ed. Pathology of Malignant Melanoma. New York, NY: Masson Publishing; 1981:297-300. 24. Bell ME, Hill DP, Bhargava MK. Lymphatic invasion in pigmented nevi. Am J Clin Pathol. 1979;72:97-100. 25. McCarthy SW, Palmer AA, Bale PM, et al. Naevus cells in lymph nodes. Pathology. 1974;6:351-358. 26. Stracke ML, Liotta LA. Multi-step cascade of tumor cell metastasis. In Vivo. 1992;6:309-316.

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