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Conjunctival Melanocytic Lesions in Children
Conjunctival Melanocytic Lesions in Children JAN M. McDONNELL, MD, JAMES D. CARPENTER, BA, PHILIP JACOBS, CTR, W. LEE WAN, MD, JOHN E. GILMORE, MD
Abstract: Seventy-one conjunctival melanocytic proliferations in patients 20 years of age or younger were examined. Sixty-five (91.5%) were nevi; there were three cases (4.2%) of racial or acquired melanosis, and three patients were identified who had malignant melanoma of the conjunctiva. The melanoma patients are presented in detail, and additional cases of conjunctival melanoma in children and adolescents reported in the literature are reviewed to determine factors that might influence prognosis. The number of cases is so small, however, that factors cannot be identified with confidence. Follow-up data are presented. Conjunctival nevi are relatively common in children, and appear to carry no risk for the development of melanoma during childhood. However, conjunctival mel anomas do occur rarely in children and have a variable prognosis. Ophthalmology 96:986-993, 1989
Conjunctival nevi, like nevi at other sites, are often first noted in childhood if they become enlarged or pigmented, although they may not be excised until later in life. In the largest series of excised conjunctival nevi to data, 282 were examined. 1 One hundred nine (38.6%) were from patients younger than 20 years of age. Conjunctival nevi are typically noted because of their location in the inter palpebral area and because they are pink or, less com monly, pigmented. 2 - 4 Most excisions are done because the lesions cause mechanical or cosmetic problems rather than because of any concern about malignancy. 2 •4 Oc casionally, however, a nevus will grow rapidly, and it is then excised to exclude malignancy. 2 •4 Melanoma, the malignant counterpart to the nevus, may also occur in the conjunctiva. The median age at diagnosis ranges from 49 to 55 years. 1•5- 14 Reports ofcon junctival melanoma in children are extremely uncom mon. In the past 50 years, there have been only three Originally received: October 8, 1988. Revision accepted: February 20, 1989. From the A. Ray Irvine, Jr., MD, Eye Pathology Laboratory, Doheny Eye Institute, Los Angeles and University of Southern California School of Med icine, Los Angeles. Presented at the American Academy of Ophthalmology Annual Meeting, Las Vegas, October 1988. Reprint requests to Jan M. McDonnell, MD, 1355 San Pablo St, Los An geles, CA 90033.
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reported cases ofchildhood conjunctival melanoma. One was a 10-year-old boy who had had a lesion at the cor neosclerallimbus for 4 years before biopsy. 12 The second case was that of a 13-year-old boy, included in a series of 56 patients. 14 No other details were provided about either patient. The third reported case ofconjunctival melanoma in a child was that in an 11-year-old boy who had a pig mented spot at the limbus present at birth. At the time of eventual exenteration, the tumor was 27 X 12 mm, with a satellite nodule 10 X 8 X 3 mm. The patient had extensive systemic metastases at the time of the report. 15 At least three additional conjunctival melanomas have been reported in young adults: a 20-year-old woman 5 and two 21-year-old men 1 about whom few details are stated. Crawford's6 series of 19 patients includes none younger than 28 years of age, but since five of the eight fatal cases occurred in patients who were younger than 37 years of age at diagnosis, he concluded that "conjunctival mela noma in younger patients have a poorer prognosis." 6 There are no other insights in the literature as to the prog nosis of conjunctival melanoma in children. During a 14-month period at the Doheny Eye Institute (DEI), we identified two children with conjunctival mel anomas. Only one additional pediatric melanoma patient was found in the files of DEI from the preceding 40 years. We describe these three cases of conjunctival melanoma in children, including follow-up, and provide data con cerning the risk of melanoma in children who have had conjunctival nevi excised.
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PATIENTS AND METHODS PATIENT IDENTIFICATION AND HISTORY
The pathology files of the DEI were searched for cases ofconjunctival nevi, primary acquired melanosis (PAM), and melanoma diagnosed between January 1971 and March 1988 in patients younger than 21 years ofage. The pathology files from 1947 through March 1988 were searched for additional cases of conjunctival melanoma in patients younger than 21 years of age. Clinical infor mation was obtained from the information sheet sub mitted with the biopsy specimen. HISTOPATHOLOGY
Hematoxylin-eosin-stained sections were examined from each case where a slide or paraffin block was available in our files. Specimens were examined to note the type of nevus (junctional, compound, subepithelial, Spitz, 16 blue, 16 other), PAM, congenital melanosis, or melanoma. We considered nests of nevus cells along the walls of ep ithelial "cysts" to be a junctional rather than a subepi thelial component. In nevi, we noted the presence or ab sence ofcystic structures and oflarge or pleomorphic cells. We evaluated specimens for the presence or absence of inflammation. The degree of inflammation was graded along a spectrum from + 1 to + 3, and an individual case was considered to be inflamed if it received a grade of+2 or more. The presence ofoccasional chronic inflammatory cells ( + 1) was determined to be within normal limits for the conjunctiva. Specimens were also examined for the presence of loosely cohesive nests of nevus cells and for mitotic figures. In addition, we noted the presence or ab sence of intraepithelial nests of nevus cells separated from the main nevus, a finding reported in dysplastic conjunc tival nevi. 17 Lesions were also examined for the presence ofconnective tissue proliferation or disruption in the sub stantia propria indicative ofsolar exposure. Finally, lesions were examined for the presence of nevus cells at the edge of the specimen. If nevus cells were present, a lesion was considered incompletely excised. FOLLOW-UP INFORMATION
In each case, the surgeon was contacted by telephone and in writing to supply follow-up information. Standard follow-up questionnaires requested the following infor mation: date oflast ophthalmologic examination; presence or absence of local recurrence, melanoma, or acquired melanosis; presence or absence of melanocytic processes in the other eye; description of other ocular problems. We also inquired as to whether the patient had any cu taneous dysplastic nevi or melanomas.
CASE REPORTS Three cases of conjunctival melanoma were identified. Two were available for our histologic review. The third, in the files
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of the Armed Forces Institute of Pathology (AFIP), was reviewed for purposes of this report at AFIP, and Kodachrome photo graphs were available for our review. Case 1. A 12-year-old white boy had a conjunctival mass since 8 years of age. Excised tissue examined at the DEI and the AFIP was interpreted as malignant melanoma (Fig 1). The patient is now free of disease 18 years after simple local excision. Case 2. A 12-year-old white boy had a pigmented limbal mass on the right eye for 3 to 4 years. The lesion began to grow in the 6 to 7 months before biopsy (Fig 2). The biopsy specimen was diagnostic of melanoma. The tumor had a thickness of 4 mm and extended to the resected margin. Accordingly, addi tional surgery was done, and the melanoma was excised com pletely. Nevus cells were not identified at the base of the tumor. An initial systemic evaluation was negative, but 6 weeks after the negative workup and 5 months after the initial biopsy, an enlarged ipsilateral parotid lymph node developed. The biopsy specimen showed metastatic melanoma (Fig 3). Systemic che motherapy (cyclophosphamide and decarbozine) was adminis tered on an outpatient basis over an 8-month period. At the most recent follow-up, the patient was free oflocal and systemic disease 20 months after his original biopsy was done. Case 3. A 16-year-old Hispanic girl had a limbal mass present for many months before biopsy was done in January 1987 in El Salvador. The tumor recurred 5 months later; the mass was reexcised in June 1987 and diagnosed as a benign nevus. The patient was observed, and in December 1987, pigment reap peared in the same location. There was an associated inflam matory reaction. Wide excision and conjunctival grafting were planned, but the patient elected to come to the United States for additional care. The second pathology report, but no addi tional information or slides, was available for review. On presentation, she had a temporal limbal mass in the left eye that contained a small dot of pigment (Fig 4). The initial clinical impression was of a papilloma. The biopsy specimen was diagnostic for melanoma, incompletely excised, with a thickness of 2.5 mm (Fig 5). Additional surgery was done with frozen-section monitoring of the surgical margins because the tumor extended to clinically normal conjunctiva. The tumor was completely excised, and nevus cells were not present at its' base. A systemic evaluation disclosed a single, enlarged ipsilateral parotid lymph node. Aspiration biopsy ofthe node was negative for tumor. The patient was tree of local and systemic disease at the most recent follow-up, 20 months after her original biopsy·· and 8 months after the diagnosis of melanoma.
RESULTS PATIENT INFORMATION
We identified conjunctival melanocytic lesions in 71 patients 20 years of age or younger. Of the 68 patients with benign processes, the age range was 3 to 20 years (median, 11.6 years). Among the 50 patients in this group whose ethnicity was stated, 46 (92%) were white (8 of whom were Hispanic), one (2%) was black, and three (6%) were oriental. Twenty-nine (42.6%) were boys, and 39 (57.4%) were girls. Information about the duration ofthe lesion before biopsy was available for 40 patients. The median duration was 46 months (range, 1-2 weeks to 18 years). Five lesions had been present from birth in patients who were 13, 15, 16, 16, and 18 years of age at biopsy. One specimen from a 9-year-old girl was a lesion previ 987
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Fig I. Malignant melanoma in a 12-year-old boy. Top lefi , notice the large cells with an inflammatory infiltrate (he matoxylin-eosin; original magnification, XI 00). Sec ond row lefi, tumor cells are predominantly epithelioid, with extensive pleomor phism (hematoxylin-eosin; magnification, original X400). Fig 2. Third row lefi, melanoma, case 2. Limbal mass with patchy pigmentation, overgrowing cornea. Fig 3. Fourth row lefi, parotid gland and cervical lymph node containing metastatic melanoma in patient 2 (hematoxylin-eosin; original magnification, X25). Bottom lefi , at higher magnification tumor cells can be clearly distinguished from the smaller lymphocytes (hematoxylin-eosin; original magnification, X400). Fig 4. Clinical photographs of melanoma in patient 3. Top right, a large, pale limbal mass has a single dark spot centrally. Center right, after initial biopsy, the tumor recurred rapidly and involved peripheral corneal stroma. Fig 5. Bottom right, high magnification of melanoma in patient 3. Epithelioid cells with patchy pigment and numerous mitotic figures, including one with a circular configuration (hematoxylin-eosin; original mag nification, X400).
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Table 1. Histopathology of 57 Conjunctival Nevi No. of Nevi (%) Type of nevus Compound Junctional Subepithelial Spitz Cellular blue Additional features • Cystic Inflamed Loosely cohesive nests Enlarged/multinucleated cells Solar change Lateral extension Mitotic figures
41 (71.9) 12 (21.1) 2 (3.5) 1 (1 .8) 1 (1.8) 32 (56.0) 16 (28.0) 12 (21.0) 4 (6.7) 4 (6.7) 2 (3.5) 0 (0.0)
• Some nevi have more than one histologic feature.
Fig 7. The presence of hyperchromatic, enlarged or multinucleated cells (arrow) were present in 6.7% of nevi (hematoxylin-eosin; original mag nification, X368).
Fig 6. Loosely cohesive nests of nevus cells within the junctional com ponent were present in 21 % of the nevi examined histologically. This nevus was found in a 13-year-old girl and had been present since birth (hematoxylin-eosin; original magnification, X505).
ously biopsied and diagnosed as a nevus when she was 3 years old. HISTOPATHOLOGY
Slides were available for review from 60 benign mela nocytic lesions. Fifty-seven were nevi (Table 1). Forty one (71.9%) of the nevi were compound, 12 (21 .1%) were junctional nevi, and two (3.5 %) were subepithelial nevi. One (1.8%) was a Spitz nevus, and one (1.8%) was a cel lular blue nevus. Thirty-two (56%) of the 57 nevi were cystic. Inflammatory cells were present in 49 (86%) ofthe biopsy specimens, usually consisting of lymphocytes and plasma cells, but occasionally also including eosinophils (Table 1). Sixteen (28%) had severe enough infiltrates to be considered inflamed by our criteria. Twelve (21 %)
specimens had loosely cohesive nests (Fig 6). Four (6.7%) had occasional enlarged or multinucleated nevus cells (Fig 7). Four (6.7%) other specimens had solar change in the substantia propria. An additional two (3.5%) specimens had lateral extension of intraepithelial nests beyond the main mass of the nevus (Fig 8), a finding described in dysplastic nevi 16• 17 ; in one of these there were also loosely cohesive nests of nevus cells. There were no lesions with mitotic figures. The original pathologic diagnosis was of an "atypical" nevus in six (9.2%) ofthe nevi. Upon review, one ofthese was found to be a Spitz (spindle and epithelioid cell) nevus, and one a cellular blue nevus. Of the remaining four cases, one had slight noncohesiveness ofjunctional nests, a find ing seen in 21% of our specimens. The final three had no changes that we could label as atypical, although one specimen exhibited occasional enlarged nevus cells. Two patients whose lesions had no identifiable atypical changes were free of disease 10 and 15 years after diagnosis. The others could not be located. Some form of melanosis, rather than a nevus, was pres ent in three (5%) cases available for review. One was in a 9-year-old with an Hispanic surname whose lesion showed contiguous junctional hypermelanosis and subepithelial pigment incontinence without nesting (Fig 9). We were unable to determine the age of onset of the pigmentation 989
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Fig 8. This compound nevus had several nests of nevus cells (small arrows) some distance away from the main bulk of the tumor (large arrow), present at only one side. The presence of lateral nests is a feature that has been described in dysplastic nevi of the skin (hematoxylin-eosin; original magnification, X93).
Fig 10. Benign melanosis in a 17-year-old boy. Intermittent hyperpig mentation of the basal epithelial cells is present (arrow). There is also disruption of subepithelial connective tissue consistent with solar damage (hematoxylin-eosin; original magnification, X93).
Fig 9. Benign melanosis in a 9-year-old girl. There is diffuse hyperpig mentation ofthe basal epithelial cells and associated pigment incontinence but no nesting of melanocytes (hematoxylin-eosin; original magnification, X368).
and do not know if it was bilateral. However, in an His panic child, the hyperpigmentation probably represents racial melanosis. Another patient, a 17-year-old boy, had intermittent, marked hypermelanosis of basal epithelial cells without nesting and without subepithelial findings (Fig 10). The duration of the lesion was not stated. The histologic findings are consistent with either congenital epithelial melanosis ephelis (freckle) or early PAM without atypia. An additional lesion from the tarsal conjunctiva of a 16-year-old boy contained contiguous junctional hy permelanosis with only rare ballooned cells and no nests. In the subepithelial area there was pigment incontinence
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with rare nests of nevus cells. The intraepithelial com ponent is consistent with the diagnosis of congenital mel anosis (ephelis) or of PAM. Again, the clinical details are unavailable. This child's lesion occurred with a subepi thelial nevus; the coexistence of PAM and nevus has been previously reported by others. 18 Based on an assessment of the presence or absence of nevus cells at any of the tissue margins, 34 of the total benign specimens (56.7%} were completely excised. Thir teen (21.6%) were incompletely excised, and the extent of excision could not be determined in the remaining 13 cases. FOLLOW-UP
Follow-up information was obtained for 23 (33.8%) of the 68 patients with nonmalignant melanocytic prolifer ations (Table 2). The average length of follow-up was 8.7 years (range, 2-16 years). The point of most recent follow up for most patients was the date of their last ophthal mologic examination. Most patients (45, 66.2%) were lost to follow-up by the physician and clinic or hospital and could not be located in the Los Angeles area. None of the 23 patients experienced any intra- or post operative complications. Three lesions had been incom pletely excised. In three patients ( 13.0%}, the lesions re
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Table 2. Follow-up of Benign Conjunctival Pigmented Lesions Local Recurrence
PAM or Melanoma
Histopathology
No. of Lesions
Compound nevus Subepithelial nevus Junctional nevus Spitz nevus Cellular blue nevus Racial melanosis Lateral nests
16 2 1 1 1 1 1
1* 0 1* 0 1 0 0
0 0 0 0 0 0 0
Total
23
3 (13%)
0
PAM = primary acquired melanosis. * Initial excision was complete. Table 3. Conjunctival Melanoma in Children
Age (yrs)/RacejSex
Tumor Thickness (mm)
Metastatic Interval
Outcome/ Interval
1012 /NA/M 1313 /NA/NA 11 15/W/M 12/W/M 12/W/M 16/W/F
NA NA 27 NA 4 2.5
NA NA Systemic, NA None Local, 5 mos None
NA NA NA NED/18 yrs NED/20 mos NED/20 mos
NA
=
not available; NED
=
no evidence of disease.
curred locally. Two lesions had been completely excised initially, but one, a cellular blue nevus, had numerous nevus cells present at the tissue margins of the biopsy and was judged to be incompletely excised. The lesions that recurred locally were in addition to the patient whose re current biopsy was included in the series and for whom we were unable to obtain follow-up. Additional nevi did not develop in either eye in any of the patients, and there were no cases of recurrent acquired or congenital mela nosis or development of melanoma in any of these pa tients. The ophthalmologists who were contacted were not aware of melanocytic abnormalities in the skin ofany of the patients. Specifically, there were no cutaneous dys plastic nevi or melanomas among these patients. One pa tient had bilateral chronic blepharitis and another had high myopia; a third child had blue sclera attributed to osteogenesis imperfecta. There were no other ocular problems in any of the 23 patients about whom follow up information was obtained.
DISCUSSION Because of the unusual occurrence during a 14-month period of two cases ofconjunctival melanoma in children and the rapid development of regional lymph node me tastases in one-of these patients, we investigated several aspects of pigmented conjunctival lesions in children. Conjunctival melanoma in children is extremely un
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common. In the 11 series reported in the literature that we reviewed, there were 503 conjunctival melano mas, 1·5- 13·19 with only two (0.4%) occurring in patients younger than 20 years of age. There is a single additional case report of conjunctival melanoma in a child 15 (Table 3). By examining records dating back to 1947, we iden tified three cases in the files of the DEI. Duke-Elder men tions an additional five cases in children reported between 1894 and 19372 and cites a report of conjunctival mela noma arising in a child younger than 15 years of age with xeroderma pigmentosum. 20 The prognosis of conjunctival melanoma in children has not been clearly defined (Table 3). Of the pediatric patients reported in the past 50 years, follow-up is un available for two, 12·13 and one child had had extensive systemic metastases at the time of report. 15 Regional lymph node metastases developed in one of our patients who is apparently disease free after systemic chemother apy, 20 months after diagnosis. A second patient in our series is apparently disease free 8 months after histopath ologic diagnosis of melanoma and 20 months after the first biopsy of her conjunctival lesion. Our third patient has no evidence of disease 18 years after simple local ex cision of his melanoma. These data are of limited use in the statistical analysis of survival. We can only assume that conjunctival melanoma, in children as in adults, has the potential to cause death through systemic metastases, but we have no conclusive information as to how often that occurs. We also cannot draw any conclusions regarding factors that might predict the course of this disease, again because of the small number of cases and the incomplete infor mation available for many of them. Tumor thickness is used as a predictor of the risk of metastasis in adults. 5·8 Using either 0.8 mm 8 or 1.5 mm 5 as the cutoff point, all three of the pediatric patients who had tumor thickness measured would be expected to develop systemic metas tases; one has done so, 15 and a second has had regional lymph node metastases (patient 2). It seems reasonable to assume that tumor thickness will be helpful in pre dicting the prognosis of conjunctival melanoma in chil dren. Whether or not other cytologic or histologic features, such as the presence ofcoexisting nevus or PAM, cytologic features of the PAM, 18 and the cell type (spindle or epi thelioid) are helpful in determining prognosis of con junctival melanoma in children remains to be seen. Al though PAM with atypia is associated with progression to melanoma, 18 the diagnosis of PAM during childhood is problematic. There is disagreement in the literature as to the relative influence of other factors, such as mitotic index, on the prognosis of conjunctival melanoma in adults.s-13,19 Treatment in the reported cases has been surgical. One ofour patients had a response to chemotherapy. Pediatric cutaneous melanomas are more responsive to chemo therapy than are adult melanomas, with an overall survival of 10 to 20% even with metastatic disease. 21 -22 There is not enough information on pediatric conjunctival mela nomas to determine whether they as a group will also be amenable to chemotherapy. 991
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The origin ofconjunctival melanoma in children is un known. Is it possible that a proportion of conjunctival melanomas in children arise from preexisting nevi? There are no systematic studies of the relationship between con junctival nevi and melanoma in children. Conjunctival nevi in children are relatively common, and melanomas extremely uncommon, so it is clear that most nevi do not progress to melanoma in children. Although one patient reviewed here 15 and one of the patients we report (case 3) had histologic diagnoses of nevus preceding the diag nosis ofmelanoma, review ofthe published histopathology in the former case shows a very pleomorphic lesion that was probably a melanoma rather than a nevus at its in ception.15 For the latter patient, slides of the original bi opsy were unavailable to us, but the time course of growth of the lesion strongly suggests that the process was a mel anoma at the time ofthe first biopsy. There were no nevus cells at the base of the lesion removed in our hospital. We attempted to study the relationship between nevi and melanoma in children by obtaining systematic, if limited, follow-up information on the outcome ofbenign melanocytic processes in children. From this follow-up data it appears that most children who have a histologi cally confirmed conjunctival nevus are at little to no risk of developing recurrent or additional melanocytic pro cesses of either eye over an 8-year period. In addition, we learned that incomplete excision of the lesions apparently imparts no increased risk of progression over the follow up period we examined. There are many limitations to this study, the most se rious of which is the small percentage of follow-up. Most patients (66.2%) in the group did not return more than once to the surgeon who removed the original lesion. An other limitation is our inability to make any statements about the risk of progression of individual lesions, because the nevi in our study were excised. The difficulties in fol low-up of a large group of healthy children are abundant, and a properly designed study to determine the risk of progression of nevi to melanoma in children is unlikely to be done because of these difficulties. Another major limitation to our study is the length of average follow-up. Although 8. 7 years is a meaningful period over which to determine the prognosis of many malignancies, the me dian age for conjunctival melanoma in several large series is in the sixth decade. 1- 8·12·13 None of the children we fol lowed is yet at the age where the risk of melanoma is highest. We do not know whether these patients are at any greater risk than is the general population of PAM or other melanocytic proliferations developing when they reach adulthood. What we studied is whether children who have had nevi excised are at increased risk of mela noma developing in childhood. The answer, based on our limited information, appears to be no. Finally, we emphasize the importance of a conservative approach to the terminology used in the diagnosis of con junctival nevi in children. Most children appear to have no further problems with conjunctival nevi once they are excised. Although cellular atypia in the setting of PAM has recently been defined, 18 there is no report that clearly defines what is meant by "atypical nevus" in the con 992
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junctiva in children. We found that ophthalmic pathol ogists used that diagnosis to describe six (9.2%) ofthe 65 nevi we reviewed. It seems advisable that the term atypical nevus be used with great caution and that the diagnosis be accompanied by a descriptive notation to assure the clinician that "PAM with atypia" 18 and "atypical nevus" are not equivalent terms. Although the term active nevus, histopathologically defined by Jay 1 is an appealing one, we found that one feature used to denote activity, loosely cohesive nests of nevus cells, was present in over one-fifth of our specimens and could be considered within broad normal limits for conjunctival nevi in children. An additional problem in pediatric patients is the his topathologic distinction between a junctional nevus and PAM, and between simple compound nevus versus nevus with PAM. Reviewing the published photographs ofFal berg and co-workers, 18 one can see basilar nests of pro liferating melanocytes which in a 50-year-old patient were diagnostic of PAM with atypia. In a 2-year-old patient, we would consider the focus to be a junctional nevus, and in a 10-year-old patient with a subepithelial component, the same focus would be considered a loosely cohesive junctional component in a compound nevus. Although one patient in their series was 14 years of age, they do not give the histopathologic criteria they used to diagnose PAM rather than some form of nevus in the patient. 18 Thus, PAM is another term that is poorly defined in his tologic terms for young patients. Dysplastic nevi have been reported in the conjunc tiva,9·17·23 and one report mentioned progression to mel anoma.23 Dysplastic nevus is another term that we believe should be used sparingly in describing lesions in the con junctiva because ofwhat the diagnosis of dysplastic nevus implies about prognosis. It should perhaps be reserved for those patients whose conjunctival lesions have all of the histopathologic features of such nevi and who have cu taneous evidence of the dysplastic nevus syndrome. We found only two specimens that contained lateral nests of nevus cells. Neither had additional features (such as epi thelioid or lentiginous melanocytic atypia) suggestive of dysplastic nevus. 17 One of these patients was located for follow-up and had no evidence of conjunctival or cuta neous melanocytic disease 6 years after biopsy. In summary, the risk of a benign conjunctival mela nocytic lesion progressing to melanoma appears to be ex tremely low, especially during childhood. We were not able to identify any progression to diffuse conjunctival acquired melanosis (PAM) or to melanoma in 23 patients with histopathologically documented nevi, followed for an average ofslightly over 8 years. Nonetheless, as we and others have reported, conjunctival melanomas do occur in children, and their prognosis in some cases is guarded.
ACKNOWLEDGMENT Photographs of case 1 were provided through the courtesy of Ahmed Hidayat, MD.
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Abstract: Seventy-one conjunctival melanocytic proliferations in patients 20 years of age or younger were examined. Sixty-five (91.5%) were nevi; there were three cases (4.2%) of racial or acquired melanosis, and three patients were identified who had malignant melanoma of the conjunctiva. The melanoma patients are presented in detail, and additional cases of conjunctival melanoma in children and adolescents reported in the literature are reviewed to determine factors that might influence prognosis. The number of cases is so small, however, that factors cannot be identified with confidence. Follow-up data are presented. Conjunctival nevi are relatively common in children, and appear to carry no risk for the development of melanoma during childhood. However, conjunctival mel anomas do occur rarely in children and have a variable prognosis. Ophthalmology 96:986-993, 1989
Conjunctival nevi, like nevi at other sites, are often first noted in childhood if they become enlarged or pigmented, although they may not be excised until later in life. In the largest series of excised conjunctival nevi to data, 282 were examined. 1 One hundred nine (38.6%) were from patients younger than 20 years of age. Conjunctival nevi are typically noted because of their location in the inter palpebral area and because they are pink or, less com monly, pigmented. 2 - 4 Most excisions are done because the lesions cause mechanical or cosmetic problems rather than because of any concern about malignancy. 2 •4 Oc casionally, however, a nevus will grow rapidly, and it is then excised to exclude malignancy. 2 •4 Melanoma, the malignant counterpart to the nevus, may also occur in the conjunctiva. The median age at diagnosis ranges from 49 to 55 years. 1•5- 14 Reports ofcon junctival melanoma in children are extremely uncom mon. In the past 50 years, there have been only three Originally received: October 8, 1988. Revision accepted: February 20, 1989. From the A. Ray Irvine, Jr., MD, Eye Pathology Laboratory, Doheny Eye Institute, Los Angeles and University of Southern California School of Med icine, Los Angeles. Presented at the American Academy of Ophthalmology Annual Meeting, Las Vegas, October 1988. Reprint requests to Jan M. McDonnell, MD, 1355 San Pablo St, Los An geles, CA 90033.
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reported cases ofchildhood conjunctival melanoma. One was a 10-year-old boy who had had a lesion at the cor neosclerallimbus for 4 years before biopsy. 12 The second case was that of a 13-year-old boy, included in a series of 56 patients. 14 No other details were provided about either patient. The third reported case ofconjunctival melanoma in a child was that in an 11-year-old boy who had a pig mented spot at the limbus present at birth. At the time of eventual exenteration, the tumor was 27 X 12 mm, with a satellite nodule 10 X 8 X 3 mm. The patient had extensive systemic metastases at the time of the report. 15 At least three additional conjunctival melanomas have been reported in young adults: a 20-year-old woman 5 and two 21-year-old men 1 about whom few details are stated. Crawford's6 series of 19 patients includes none younger than 28 years of age, but since five of the eight fatal cases occurred in patients who were younger than 37 years of age at diagnosis, he concluded that "conjunctival mela noma in younger patients have a poorer prognosis." 6 There are no other insights in the literature as to the prog nosis of conjunctival melanoma in children. During a 14-month period at the Doheny Eye Institute (DEI), we identified two children with conjunctival mel anomas. Only one additional pediatric melanoma patient was found in the files of DEI from the preceding 40 years. We describe these three cases of conjunctival melanoma in children, including follow-up, and provide data con cerning the risk of melanoma in children who have had conjunctival nevi excised.
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PATIENTS AND METHODS PATIENT IDENTIFICATION AND HISTORY
The pathology files of the DEI were searched for cases ofconjunctival nevi, primary acquired melanosis (PAM), and melanoma diagnosed between January 1971 and March 1988 in patients younger than 21 years ofage. The pathology files from 1947 through March 1988 were searched for additional cases of conjunctival melanoma in patients younger than 21 years of age. Clinical infor mation was obtained from the information sheet sub mitted with the biopsy specimen. HISTOPATHOLOGY
Hematoxylin-eosin-stained sections were examined from each case where a slide or paraffin block was available in our files. Specimens were examined to note the type of nevus (junctional, compound, subepithelial, Spitz, 16 blue, 16 other), PAM, congenital melanosis, or melanoma. We considered nests of nevus cells along the walls of ep ithelial "cysts" to be a junctional rather than a subepi thelial component. In nevi, we noted the presence or ab sence ofcystic structures and oflarge or pleomorphic cells. We evaluated specimens for the presence or absence of inflammation. The degree of inflammation was graded along a spectrum from + 1 to + 3, and an individual case was considered to be inflamed if it received a grade of+2 or more. The presence ofoccasional chronic inflammatory cells ( + 1) was determined to be within normal limits for the conjunctiva. Specimens were also examined for the presence of loosely cohesive nests of nevus cells and for mitotic figures. In addition, we noted the presence or ab sence of intraepithelial nests of nevus cells separated from the main nevus, a finding reported in dysplastic conjunc tival nevi. 17 Lesions were also examined for the presence ofconnective tissue proliferation or disruption in the sub stantia propria indicative ofsolar exposure. Finally, lesions were examined for the presence of nevus cells at the edge of the specimen. If nevus cells were present, a lesion was considered incompletely excised. FOLLOW-UP INFORMATION
In each case, the surgeon was contacted by telephone and in writing to supply follow-up information. Standard follow-up questionnaires requested the following infor mation: date oflast ophthalmologic examination; presence or absence of local recurrence, melanoma, or acquired melanosis; presence or absence of melanocytic processes in the other eye; description of other ocular problems. We also inquired as to whether the patient had any cu taneous dysplastic nevi or melanomas.
CASE REPORTS Three cases of conjunctival melanoma were identified. Two were available for our histologic review. The third, in the files
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of the Armed Forces Institute of Pathology (AFIP), was reviewed for purposes of this report at AFIP, and Kodachrome photo graphs were available for our review. Case 1. A 12-year-old white boy had a conjunctival mass since 8 years of age. Excised tissue examined at the DEI and the AFIP was interpreted as malignant melanoma (Fig 1). The patient is now free of disease 18 years after simple local excision. Case 2. A 12-year-old white boy had a pigmented limbal mass on the right eye for 3 to 4 years. The lesion began to grow in the 6 to 7 months before biopsy (Fig 2). The biopsy specimen was diagnostic of melanoma. The tumor had a thickness of 4 mm and extended to the resected margin. Accordingly, addi tional surgery was done, and the melanoma was excised com pletely. Nevus cells were not identified at the base of the tumor. An initial systemic evaluation was negative, but 6 weeks after the negative workup and 5 months after the initial biopsy, an enlarged ipsilateral parotid lymph node developed. The biopsy specimen showed metastatic melanoma (Fig 3). Systemic che motherapy (cyclophosphamide and decarbozine) was adminis tered on an outpatient basis over an 8-month period. At the most recent follow-up, the patient was free oflocal and systemic disease 20 months after his original biopsy was done. Case 3. A 16-year-old Hispanic girl had a limbal mass present for many months before biopsy was done in January 1987 in El Salvador. The tumor recurred 5 months later; the mass was reexcised in June 1987 and diagnosed as a benign nevus. The patient was observed, and in December 1987, pigment reap peared in the same location. There was an associated inflam matory reaction. Wide excision and conjunctival grafting were planned, but the patient elected to come to the United States for additional care. The second pathology report, but no addi tional information or slides, was available for review. On presentation, she had a temporal limbal mass in the left eye that contained a small dot of pigment (Fig 4). The initial clinical impression was of a papilloma. The biopsy specimen was diagnostic for melanoma, incompletely excised, with a thickness of 2.5 mm (Fig 5). Additional surgery was done with frozen-section monitoring of the surgical margins because the tumor extended to clinically normal conjunctiva. The tumor was completely excised, and nevus cells were not present at its' base. A systemic evaluation disclosed a single, enlarged ipsilateral parotid lymph node. Aspiration biopsy ofthe node was negative for tumor. The patient was tree of local and systemic disease at the most recent follow-up, 20 months after her original biopsy·· and 8 months after the diagnosis of melanoma.
RESULTS PATIENT INFORMATION
We identified conjunctival melanocytic lesions in 71 patients 20 years of age or younger. Of the 68 patients with benign processes, the age range was 3 to 20 years (median, 11.6 years). Among the 50 patients in this group whose ethnicity was stated, 46 (92%) were white (8 of whom were Hispanic), one (2%) was black, and three (6%) were oriental. Twenty-nine (42.6%) were boys, and 39 (57.4%) were girls. Information about the duration ofthe lesion before biopsy was available for 40 patients. The median duration was 46 months (range, 1-2 weeks to 18 years). Five lesions had been present from birth in patients who were 13, 15, 16, 16, and 18 years of age at biopsy. One specimen from a 9-year-old girl was a lesion previ 987
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Fig I. Malignant melanoma in a 12-year-old boy. Top lefi , notice the large cells with an inflammatory infiltrate (he matoxylin-eosin; original magnification, XI 00). Sec ond row lefi, tumor cells are predominantly epithelioid, with extensive pleomor phism (hematoxylin-eosin; magnification, original X400). Fig 2. Third row lefi, melanoma, case 2. Limbal mass with patchy pigmentation, overgrowing cornea. Fig 3. Fourth row lefi, parotid gland and cervical lymph node containing metastatic melanoma in patient 2 (hematoxylin-eosin; original magnification, X25). Bottom lefi , at higher magnification tumor cells can be clearly distinguished from the smaller lymphocytes (hematoxylin-eosin; original magnification, X400). Fig 4. Clinical photographs of melanoma in patient 3. Top right, a large, pale limbal mass has a single dark spot centrally. Center right, after initial biopsy, the tumor recurred rapidly and involved peripheral corneal stroma. Fig 5. Bottom right, high magnification of melanoma in patient 3. Epithelioid cells with patchy pigment and numerous mitotic figures, including one with a circular configuration (hematoxylin-eosin; original mag nification, X400).
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Table 1. Histopathology of 57 Conjunctival Nevi No. of Nevi (%) Type of nevus Compound Junctional Subepithelial Spitz Cellular blue Additional features • Cystic Inflamed Loosely cohesive nests Enlarged/multinucleated cells Solar change Lateral extension Mitotic figures
41 (71.9) 12 (21.1) 2 (3.5) 1 (1 .8) 1 (1.8) 32 (56.0) 16 (28.0) 12 (21.0) 4 (6.7) 4 (6.7) 2 (3.5) 0 (0.0)
• Some nevi have more than one histologic feature.
Fig 7. The presence of hyperchromatic, enlarged or multinucleated cells (arrow) were present in 6.7% of nevi (hematoxylin-eosin; original mag nification, X368).
Fig 6. Loosely cohesive nests of nevus cells within the junctional com ponent were present in 21 % of the nevi examined histologically. This nevus was found in a 13-year-old girl and had been present since birth (hematoxylin-eosin; original magnification, X505).
ously biopsied and diagnosed as a nevus when she was 3 years old. HISTOPATHOLOGY
Slides were available for review from 60 benign mela nocytic lesions. Fifty-seven were nevi (Table 1). Forty one (71.9%) of the nevi were compound, 12 (21 .1%) were junctional nevi, and two (3.5 %) were subepithelial nevi. One (1.8%) was a Spitz nevus, and one (1.8%) was a cel lular blue nevus. Thirty-two (56%) of the 57 nevi were cystic. Inflammatory cells were present in 49 (86%) ofthe biopsy specimens, usually consisting of lymphocytes and plasma cells, but occasionally also including eosinophils (Table 1). Sixteen (28%) had severe enough infiltrates to be considered inflamed by our criteria. Twelve (21 %)
specimens had loosely cohesive nests (Fig 6). Four (6.7%) had occasional enlarged or multinucleated nevus cells (Fig 7). Four (6.7%) other specimens had solar change in the substantia propria. An additional two (3.5%) specimens had lateral extension of intraepithelial nests beyond the main mass of the nevus (Fig 8), a finding described in dysplastic nevi 16• 17 ; in one of these there were also loosely cohesive nests of nevus cells. There were no lesions with mitotic figures. The original pathologic diagnosis was of an "atypical" nevus in six (9.2%) ofthe nevi. Upon review, one ofthese was found to be a Spitz (spindle and epithelioid cell) nevus, and one a cellular blue nevus. Of the remaining four cases, one had slight noncohesiveness ofjunctional nests, a find ing seen in 21% of our specimens. The final three had no changes that we could label as atypical, although one specimen exhibited occasional enlarged nevus cells. Two patients whose lesions had no identifiable atypical changes were free of disease 10 and 15 years after diagnosis. The others could not be located. Some form of melanosis, rather than a nevus, was pres ent in three (5%) cases available for review. One was in a 9-year-old with an Hispanic surname whose lesion showed contiguous junctional hypermelanosis and subepithelial pigment incontinence without nesting (Fig 9). We were unable to determine the age of onset of the pigmentation 989
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Fig 8. This compound nevus had several nests of nevus cells (small arrows) some distance away from the main bulk of the tumor (large arrow), present at only one side. The presence of lateral nests is a feature that has been described in dysplastic nevi of the skin (hematoxylin-eosin; original magnification, X93).
Fig 10. Benign melanosis in a 17-year-old boy. Intermittent hyperpig mentation of the basal epithelial cells is present (arrow). There is also disruption of subepithelial connective tissue consistent with solar damage (hematoxylin-eosin; original magnification, X93).
Fig 9. Benign melanosis in a 9-year-old girl. There is diffuse hyperpig mentation ofthe basal epithelial cells and associated pigment incontinence but no nesting of melanocytes (hematoxylin-eosin; original magnification, X368).
and do not know if it was bilateral. However, in an His panic child, the hyperpigmentation probably represents racial melanosis. Another patient, a 17-year-old boy, had intermittent, marked hypermelanosis of basal epithelial cells without nesting and without subepithelial findings (Fig 10). The duration of the lesion was not stated. The histologic findings are consistent with either congenital epithelial melanosis ephelis (freckle) or early PAM without atypia. An additional lesion from the tarsal conjunctiva of a 16-year-old boy contained contiguous junctional hy permelanosis with only rare ballooned cells and no nests. In the subepithelial area there was pigment incontinence
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with rare nests of nevus cells. The intraepithelial com ponent is consistent with the diagnosis of congenital mel anosis (ephelis) or of PAM. Again, the clinical details are unavailable. This child's lesion occurred with a subepi thelial nevus; the coexistence of PAM and nevus has been previously reported by others. 18 Based on an assessment of the presence or absence of nevus cells at any of the tissue margins, 34 of the total benign specimens (56.7%} were completely excised. Thir teen (21.6%) were incompletely excised, and the extent of excision could not be determined in the remaining 13 cases. FOLLOW-UP
Follow-up information was obtained for 23 (33.8%) of the 68 patients with nonmalignant melanocytic prolifer ations (Table 2). The average length of follow-up was 8.7 years (range, 2-16 years). The point of most recent follow up for most patients was the date of their last ophthal mologic examination. Most patients (45, 66.2%) were lost to follow-up by the physician and clinic or hospital and could not be located in the Los Angeles area. None of the 23 patients experienced any intra- or post operative complications. Three lesions had been incom pletely excised. In three patients ( 13.0%}, the lesions re
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Table 2. Follow-up of Benign Conjunctival Pigmented Lesions Local Recurrence
PAM or Melanoma
Histopathology
No. of Lesions
Compound nevus Subepithelial nevus Junctional nevus Spitz nevus Cellular blue nevus Racial melanosis Lateral nests
16 2 1 1 1 1 1
1* 0 1* 0 1 0 0
0 0 0 0 0 0 0
Total
23
3 (13%)
0
PAM = primary acquired melanosis. * Initial excision was complete. Table 3. Conjunctival Melanoma in Children
Age (yrs)/RacejSex
Tumor Thickness (mm)
Metastatic Interval
Outcome/ Interval
1012 /NA/M 1313 /NA/NA 11 15/W/M 12/W/M 12/W/M 16/W/F
NA NA 27 NA 4 2.5
NA NA Systemic, NA None Local, 5 mos None
NA NA NA NED/18 yrs NED/20 mos NED/20 mos
NA
=
not available; NED
=
no evidence of disease.
curred locally. Two lesions had been completely excised initially, but one, a cellular blue nevus, had numerous nevus cells present at the tissue margins of the biopsy and was judged to be incompletely excised. The lesions that recurred locally were in addition to the patient whose re current biopsy was included in the series and for whom we were unable to obtain follow-up. Additional nevi did not develop in either eye in any of the patients, and there were no cases of recurrent acquired or congenital mela nosis or development of melanoma in any of these pa tients. The ophthalmologists who were contacted were not aware of melanocytic abnormalities in the skin ofany of the patients. Specifically, there were no cutaneous dys plastic nevi or melanomas among these patients. One pa tient had bilateral chronic blepharitis and another had high myopia; a third child had blue sclera attributed to osteogenesis imperfecta. There were no other ocular problems in any of the 23 patients about whom follow up information was obtained.
DISCUSSION Because of the unusual occurrence during a 14-month period of two cases ofconjunctival melanoma in children and the rapid development of regional lymph node me tastases in one-of these patients, we investigated several aspects of pigmented conjunctival lesions in children. Conjunctival melanoma in children is extremely un
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common. In the 11 series reported in the literature that we reviewed, there were 503 conjunctival melano mas, 1·5- 13·19 with only two (0.4%) occurring in patients younger than 20 years of age. There is a single additional case report of conjunctival melanoma in a child 15 (Table 3). By examining records dating back to 1947, we iden tified three cases in the files of the DEI. Duke-Elder men tions an additional five cases in children reported between 1894 and 19372 and cites a report of conjunctival mela noma arising in a child younger than 15 years of age with xeroderma pigmentosum. 20 The prognosis of conjunctival melanoma in children has not been clearly defined (Table 3). Of the pediatric patients reported in the past 50 years, follow-up is un available for two, 12·13 and one child had had extensive systemic metastases at the time of report. 15 Regional lymph node metastases developed in one of our patients who is apparently disease free after systemic chemother apy, 20 months after diagnosis. A second patient in our series is apparently disease free 8 months after histopath ologic diagnosis of melanoma and 20 months after the first biopsy of her conjunctival lesion. Our third patient has no evidence of disease 18 years after simple local ex cision of his melanoma. These data are of limited use in the statistical analysis of survival. We can only assume that conjunctival melanoma, in children as in adults, has the potential to cause death through systemic metastases, but we have no conclusive information as to how often that occurs. We also cannot draw any conclusions regarding factors that might predict the course of this disease, again because of the small number of cases and the incomplete infor mation available for many of them. Tumor thickness is used as a predictor of the risk of metastasis in adults. 5·8 Using either 0.8 mm 8 or 1.5 mm 5 as the cutoff point, all three of the pediatric patients who had tumor thickness measured would be expected to develop systemic metas tases; one has done so, 15 and a second has had regional lymph node metastases (patient 2). It seems reasonable to assume that tumor thickness will be helpful in pre dicting the prognosis of conjunctival melanoma in chil dren. Whether or not other cytologic or histologic features, such as the presence ofcoexisting nevus or PAM, cytologic features of the PAM, 18 and the cell type (spindle or epi thelioid) are helpful in determining prognosis of con junctival melanoma in children remains to be seen. Al though PAM with atypia is associated with progression to melanoma, 18 the diagnosis of PAM during childhood is problematic. There is disagreement in the literature as to the relative influence of other factors, such as mitotic index, on the prognosis of conjunctival melanoma in adults.s-13,19 Treatment in the reported cases has been surgical. One ofour patients had a response to chemotherapy. Pediatric cutaneous melanomas are more responsive to chemo therapy than are adult melanomas, with an overall survival of 10 to 20% even with metastatic disease. 21 -22 There is not enough information on pediatric conjunctival mela nomas to determine whether they as a group will also be amenable to chemotherapy. 991
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The origin ofconjunctival melanoma in children is un known. Is it possible that a proportion of conjunctival melanomas in children arise from preexisting nevi? There are no systematic studies of the relationship between con junctival nevi and melanoma in children. Conjunctival nevi in children are relatively common, and melanomas extremely uncommon, so it is clear that most nevi do not progress to melanoma in children. Although one patient reviewed here 15 and one of the patients we report (case 3) had histologic diagnoses of nevus preceding the diag nosis ofmelanoma, review ofthe published histopathology in the former case shows a very pleomorphic lesion that was probably a melanoma rather than a nevus at its in ception.15 For the latter patient, slides of the original bi opsy were unavailable to us, but the time course of growth of the lesion strongly suggests that the process was a mel anoma at the time ofthe first biopsy. There were no nevus cells at the base of the lesion removed in our hospital. We attempted to study the relationship between nevi and melanoma in children by obtaining systematic, if limited, follow-up information on the outcome ofbenign melanocytic processes in children. From this follow-up data it appears that most children who have a histologi cally confirmed conjunctival nevus are at little to no risk of developing recurrent or additional melanocytic pro cesses of either eye over an 8-year period. In addition, we learned that incomplete excision of the lesions apparently imparts no increased risk of progression over the follow up period we examined. There are many limitations to this study, the most se rious of which is the small percentage of follow-up. Most patients (66.2%) in the group did not return more than once to the surgeon who removed the original lesion. An other limitation is our inability to make any statements about the risk of progression of individual lesions, because the nevi in our study were excised. The difficulties in fol low-up of a large group of healthy children are abundant, and a properly designed study to determine the risk of progression of nevi to melanoma in children is unlikely to be done because of these difficulties. Another major limitation to our study is the length of average follow-up. Although 8. 7 years is a meaningful period over which to determine the prognosis of many malignancies, the me dian age for conjunctival melanoma in several large series is in the sixth decade. 1- 8·12·13 None of the children we fol lowed is yet at the age where the risk of melanoma is highest. We do not know whether these patients are at any greater risk than is the general population of PAM or other melanocytic proliferations developing when they reach adulthood. What we studied is whether children who have had nevi excised are at increased risk of mela noma developing in childhood. The answer, based on our limited information, appears to be no. Finally, we emphasize the importance of a conservative approach to the terminology used in the diagnosis of con junctival nevi in children. Most children appear to have no further problems with conjunctival nevi once they are excised. Although cellular atypia in the setting of PAM has recently been defined, 18 there is no report that clearly defines what is meant by "atypical nevus" in the con 992
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junctiva in children. We found that ophthalmic pathol ogists used that diagnosis to describe six (9.2%) ofthe 65 nevi we reviewed. It seems advisable that the term atypical nevus be used with great caution and that the diagnosis be accompanied by a descriptive notation to assure the clinician that "PAM with atypia" 18 and "atypical nevus" are not equivalent terms. Although the term active nevus, histopathologically defined by Jay 1 is an appealing one, we found that one feature used to denote activity, loosely cohesive nests of nevus cells, was present in over one-fifth of our specimens and could be considered within broad normal limits for conjunctival nevi in children. An additional problem in pediatric patients is the his topathologic distinction between a junctional nevus and PAM, and between simple compound nevus versus nevus with PAM. Reviewing the published photographs ofFal berg and co-workers, 18 one can see basilar nests of pro liferating melanocytes which in a 50-year-old patient were diagnostic of PAM with atypia. In a 2-year-old patient, we would consider the focus to be a junctional nevus, and in a 10-year-old patient with a subepithelial component, the same focus would be considered a loosely cohesive junctional component in a compound nevus. Although one patient in their series was 14 years of age, they do not give the histopathologic criteria they used to diagnose PAM rather than some form of nevus in the patient. 18 Thus, PAM is another term that is poorly defined in his tologic terms for young patients. Dysplastic nevi have been reported in the conjunc tiva,9·17·23 and one report mentioned progression to mel anoma.23 Dysplastic nevus is another term that we believe should be used sparingly in describing lesions in the con junctiva because ofwhat the diagnosis of dysplastic nevus implies about prognosis. It should perhaps be reserved for those patients whose conjunctival lesions have all of the histopathologic features of such nevi and who have cu taneous evidence of the dysplastic nevus syndrome. We found only two specimens that contained lateral nests of nevus cells. Neither had additional features (such as epi thelioid or lentiginous melanocytic atypia) suggestive of dysplastic nevus. 17 One of these patients was located for follow-up and had no evidence of conjunctival or cuta neous melanocytic disease 6 years after biopsy. In summary, the risk of a benign conjunctival mela nocytic lesion progressing to melanoma appears to be ex tremely low, especially during childhood. We were not able to identify any progression to diffuse conjunctival acquired melanosis (PAM) or to melanoma in 23 patients with histopathologically documented nevi, followed for an average ofslightly over 8 years. Nonetheless, as we and others have reported, conjunctival melanomas do occur in children, and their prognosis in some cases is guarded.
ACKNOWLEDGMENT Photographs of case 1 were provided through the courtesy of Ahmed Hidayat, MD.
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