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Completely Regressed Cutaneous Melanocytic Lesion: Was It Benign or Was It Malignant?
CURRENT CLINICAL PRACTICE
Completely Regressed Cutaneous Melanocytic Lesion: Was It Benign or Was It Malignant? Adam C. Berger, Edward F. McClay, Mary Toporcer, Jedd D. Wolchok, and Gloria J. Morris
At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each ”Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers’ comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at [email protected]. I look forward to a lively discussion. Gloria J. Morris, MD, PhD Current Clinical Practice Feature Editor
O
f patients presenting to melanoma centers with metastatic disease, about 5% to 10% have an occult primary lesion. The clinical presentation is most commonly of peripheral lymphadenopathy.1– 4 Often but not always there is historical or physical evidence of a Address correspondence to Gloria J. Morris, MD, PhD, Editor, Current Clinical Practice, Hematology and Oncology Associates of Northeastern PA, PC, 1100 Meade St, Dunmore, PA 18512. E-mail: dr.morris@ hemonc1.com 0270-9295/09/$ - see front matter © 2009 Published by Elsevier Inc. doi:10.1053/j.seminoncol.2009.07.010
regressed pigmented lesion regional to the lymphadenopathy. That a primary cutaneous melanoma can seed a nodal or distant site and then regress completely is well established. What is unknown is the frequency with which a primary melanoma regresses without seeding metastases. These individuals do not seek medical attention. An inkling as to how often this event occurs perhaps could be gleaned from our understanding of the phenomenon of halo nevus.5 A halo nevus is characterized clinically by an acquired zone of depigmentation surrounding a pigmented compound nevus. These lesions most commonly occur on the backs of children and young adults. The pigmented lesion typically regresses over months and the area may repigment. Histologically a lymphocyte infiltrate surrounds nevus cells, which cytologically are atypical. Although concerning microscopically, the clinical behavior of these lesions is considered to be benign. The incidence of halo nevi in the population is thought to be about 1%.6
THE PROBLEM The patient is a 59-year-old white male who was seeing his dermatologist approximately every 6 months for cutaneous evaluations because of a history of heavy sun exposure as a youngster. He spent his summers at the seashore. On the exposure to the sun, he would burn and get only a light tan. There were multiple episodes of blistering sunburns
Seminars in Oncology, Vol 36, No 5, October 2009, pp 375-379
in his youth and teen years, several of which were of sufficient intensity to be characterized as “sun poisoning.” On a routine skin examination a lesion was noticed on his right flank. Clinically, the lesion had the appearance of a “pigmented basal cell carcinoma.” A biopsy was performed and it was interpreted as showing complete regression of a pigmented lesion (Figures 1 and 2). The papillary dermis was thickened and demonstrated a delicate fibroplasia, as well as a patchy lymphocyte infiltrate, numerous melanophages, and vascular proliferation. There is no history of there having been a pre-existing nevus in this area nor is there a history of any regression. However, the area was not readily visible to the patient. At the time of referral, his physical examination revealed the operative site to be well healed with no clinical evidence of residual abnormality. His pigmented lesions were present on sun-exposed portions of the body, numbered less than 20, were less than 5 mm in diameter, and did not show any clinical evidence of dysplasia. The peripheral lymph nodes were negative. The patient presented for a discussion of the etiology of this lesion, its treatment and his prognosis. What do you tell a patient who has a completely regressed cutaneous melanocytic lesion with no history of an antecedent pigmented lesion, despite regular skin examinations by a dermatologist, and a normal pattern of moles but with sun-sensitive 375
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Figure 1. Cytologically and architecturally normal epidermis with dense lymphocyte infiltrate and a few pigment-laden macrophages in the dermis.
skin and a history of multiple blistering sunburns?
DERMATOLOGIST’S EXPERT OPINION The adult patient illustrated in the case report with a regressing pigmented lesion without a specific histopathological diagnosis is a noteworthy management problem. The decrease in number of melanocytes in the epidermis, the accompanying inflammatory infiltrate, and the melanophages in the dermis lead one to believe that this lesion represents a melanocytic lesion that has regressed. This is quite a common phenomenon in children in the setting of benign halo nevi. However, in the adult population, the management of such a lesion is less clear. Halo or regressed nevi are not common occurrences in adult patients. There is a level of concern that the underlying melanocytic lesion may have represented a regressed malignancy. This is similar to our concerns regarding Spitz nevi in adults. There is abundant literature stressing the banal nature of Spitz nevi in children less than 11 years of age. When Spitz nevi are diagnosed in adults, the current literature suggests complete clinical and histopathological removal. This is because the clinical behavior of Spitz nevi in adults over the age of
40 years may not be benign.7,8 Some authors question the value of sentinel lymph node (SLN) biopsy to help resolve the diagnostic quandary regarding the primary lesion.9 I suggest that the same algorithm should be applied to regressed nevi in adults. One must err on the side of caution and completely remove all clinical and histopathological evidence of this lesion, most likely with 0.5- to 1-cm margins if possible. To date, there is no definitive evidence to support the use of lymph node mapping and selective lymph node dissection in regressed melanocytic lesions, as this procedure has been found to be beneficial
in only the intermediate level melanomas. However, as with atypical Spitz nevi, there may be great value in future controlled studies of SLN biopsies in these cases. For now, clinical examination of the lymph nodes, liver, and spleen along with a baseline chest x-ray and laboratory studies to include a complete blood cell count, liver function chemistries, and lactate dehydrogenase determination are valuable as baseline measures and are low-risk procedures for the patient. I advise continued total body skin examinations every 6 months, with particular attention to all lymph node sites, liver, and spleen. The patient likewise needs to be counseled to perform monthly self-examination. Unfortunately, there is no way to turn back the clock on a regressed lesion, but careful clinical observation may identify recurrent or subsequent lesions at a time when the patient may benefit from additional aggressive therapeutic measures. Mary Toporcer, MD Dermatology and Dermatologic Surgery Doylestown, PA
SURGICAL ONCOLOGIST’S EXPERT OPINION I have read with interest the case report of the 59-year-old man who
Figure 2. Melanin laden macrophages in a sea of melanocytes strongly suggestive of a regressed melanocytic neoplasm.
Completely regressed cutaneous melanocytic lesion
presented with a completely regressed pigmented lesion. Briefly, on routine physical examination, a lesion that clinically resembled a pigmented basal cell carcinoma was noted on his flank. This was excised and histology showed a lymphocytic infiltrate, numerous melanophages, and vascular proliferation. On consultation this was felt to be a completely regressed melanocytic neoplasm. As many medical professionals who care for patients with melanoma know, melanoma is a very immunogenic tumor. The majority of approved therapies, as well as experimental ones, are based on manipulation of the host immune system (interferon, interleukin-2, vaccines). Additionally, approximately 5% to 10% of patients who present with stage 3 or 4 melanoma will do so from an unknown primary site.1 In the majority of these patients, the primary melanoma is never found. It is presumed that these melanomas have undergone complete regression. It is also known that patients presenting with metastases from an unknown primary site appear to have a better survival than other patients with metastatic disease from known primaries.10 The reason for this has not been fully elucidated. However, it is my opinion that these patients have immune systems that are much more reactive to the melanoma and are therefore able to keep it at bay for longer periods of time. As previously pointed out, it is quite possible that there are numerous individuals who have spontaneous regression of pigmented cutaneous lesions and do not develop metastases and thus never come to our attention. I personally treated a patient who presented with an axillary lymph node metastasis, as well as an in-transit metastasis, but no primary skin lesion. On further examination, an area of depigmented skin was found in the drainage basin. This was completely excised and no evidence of melanoma was found.
If this patient has undergone complete excision of the regressed neoplasm, I would not advocate further excision. The chance of local recurrence is extremely small. However, if there are any doubts about the margins, I think that it would be reasonable to remove a few millimeters of normal skin. If the patient is to have lymph node mapping with blue dye, this procedure will remove the blue-stained tissue. As regards SLN mapping and biopsy, I would have a full discussion with the patient regarding the pluses and minuses of the procedures. Because there is a real possibility of lymph node metastases from a melanoma of unknown primary site, it would be advantageous to find this metastasis when it is microscopic. As the results of the Multicenter Selective Lymphadenopathy Trial-1 (MSLT-1) indicate, it appears that removal of stage 3 disease when it is microscopic appears to improve survival compared to not doing sentinel node biopsy.11 Finally, if re-excision and SLN biopsy fail to reveal any evidence of melanoma, I would have the patient undergo routine skin surveillance with his dermatologist but not undergo routine surveillance for metastatic disease. Adam C. Berger, MD, FACS Department of Surgery Thomas Jefferson University Philadelphia, PA
MEDICAL ONCOLOGIST’S EXPERT OPINION Implicit in the presentation of this clinical scenario is the question of the relationship of regression to primary melanoma and the metastatic process. Of the multiple histopathological factors identified in melanoma, the presence of regression remains controversial with regards to its importance. While data from the large University of Alabama–Southern Methodist University (UAB-SMU) database failed to support the importance of regression, Clark and others have demonstrated
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independent prognostic significance.12–15 These latter studies identified the presence of regression as associated with a poorer prognosis in multivariate analysis. Several studies have suggested that the presence of regression in more than 75% of the lesion represents a critical volume that is associated with metastatic potential.16,17 In my practice I have used regression as a poor prognostic finding and counsel patients accordingly. Therefore in this clinical situation I have viewed the presence of regression in this light. This patient presents with a difficult clinical problem that to some degree requires decision making without the entire information that one would like. The patient had a lesion that clinically looked like a pigmented basal cell carcinoma that on pathologic evaluation raises the specter of malignant melanoma. In the absence of a clear diagnosis of melanoma, clinicians must use their best clinical judgment as to the management of the patient. There are basically two diametrically opposed approaches that can be taken. In the first approach, the clinician assumes that this is a benign lesion, completely excised, and requires no further treatment. The other assumes just the opposite, that this is a completely regressed malignant melanoma requiring aggressive management. In this situation I have erred on the side of being aggressive. If we assume that this is a benign lesion and it actually is a regressed melanoma, we may potentially miss an opportunity to find recurrence at an earlier stage where an effective treatment with modest morbidity can be offered. If, however, we assume that this is melanoma and it is actually benign, we will potentially spend money and subject the patient to unnecessary procedures. Following the dictum of “Primum non nocere” (“First do no harm”), I believe the greater harm would be to assume this lesion to be benign. In my practice, I believe that this clinical situation requires extensive discussion with the patient as to the
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best approach. Having cared for more than 2,000 patients with melanoma, I must admit that I tend to err on the aggressive side. I would recommend re-excision of the primary site with a 1-cm border. The 1-cm border provides a reasonable margin to encompass potential intransit disease. I also would recommend both lymphatic mapping and the performance of SLN dissection. Some studies have identified regression as a predictor of metastasis to the SLN.18 Finally, I would recommend the performance of semi-annual surveillance scans (positron emission tomography [PET]/computed tomography [CT] or CT scans of the chest/abdomen/pelvis) for 2 years. Eighty-five percent of recurrences become clinically evident within the first 24 months after diagnosis. Fortunately this is not a common situation. I believe that given the lack of clear scientifically valid information, we must rely on clinical experience and judgment. Edward F. McClay, MD Director Melanoma Research Center of San Diego Encinitas, CA
MEDICAL ONCOLOGIST’S EXPERT OPINION In our practice we certainly do see the expected 5% to 10% of patients with metastatic disease and an occult (or undetectable) primary melanoma. I think that these patients are certainly a diagnostic and management challenge. As regards advising this patient with a suspicious completely regressed pigmented lesion, I would recommend wide excision of the primary site to achieve 2-cm margins as if this were a melanoma greater than 1 mm in Breslow thickness. Given the lack of morbidity and prognostic importance of lymph node mapping, I would favor performing this procedure. I am well aware of data from the randomized MSLT-1 trial11 show-
ing no evidence for a survival benefit for early intervention; however, given the absence of patients such as this from the analysis, I think that it is reasonable to proceed with the procedure. It certainly would be informative in helping to decide how to design a follow-up plan for the patient. In addition I have a small number of patients in my practice who presented with palpable nodal metastases and evidence of a regressed primary (hypopigmentation in an area draining to the nodes involved). With surgery alone, such patients may have long-term diseasefree survival. If the SLNs were benign, I would recommend physical examination every 4 – 6 months with emphasis on the draining nodal basin, chest x-ray once per year, and routine complete blood cell count and chemistries (including lactate dehydrogenase) with each visit. Jedd D. Wolchok, MD, PhD Associate Attending, MelanomaSarcoma Service Memorial Sloan-Kettering Cancer Center New York, NY
SUMMARY AND ASSESSMENT Partial and complete regression of benign and malignant melanocytic neoplasms is not uncommon. This phenomenon likely is not unique to melanocytic proliferations but simply is more readily evident because of their largely cutaneous location and the frequent residuum of telltale melanin deposition. The clinical presentation and microscopic findings of regression have been well documented. Data regarding the biological significance of this phenomenon remain confusing. Nowhere is this more evident than in the report by Clark et al,14 where in the presence of tumor-infiltrating lymphocytes (TILs) was determined to be a favorable prognostic feature. In as much as TILs are the presumed hallmark of an immune response mounted by the host against the melanoma, a favorable impact on
outcome is intuitive. Unexpectedly, histological evidence of melanoma regression, the anticipated result of an effective immune response, was an adverse prognostic feature. In the absence of evidencebased consensus guidelines, what does the reasonably prudent clinician recommend regarding treatment? Respondents were asked to address the following questions: 1. Would you re-excise the “primary site” to assure negative margins and if so, to what diameter? All respondents agreed that histologically clear margins were required. Recommended margins ranged from a few millimeters to as much as 2 cm. In as much as the flank location posed no functional or physical impediments, this patient’s “primary” site was re-excised to achieve 1-cm margins. There was no microscopic evidence of residual lesion. 2. Would you recommend lymph node mapping and sentinel lymph node dissection? As pointed out by Drs Toporcer and Wolchok, there are no data to support the use of lymph node mapping and SLN dissection in this setting. Dr Toporcer’s recommendation of clinical observation is quite reasonable, especially in light of the difficulty in demonstrating a survival benefit versus therapeutic regional lymph node dissection. However, the procedure is minimally invasive and negligibly morbid. As such, it is being employed with increasing frequency for informational purposes with a variety of neoplasms of uncertain biological significance, to include Spitz tumors in adults and severely dysplastic nevi. Drs Wolchok, McClay, and Berger all recommended lymph node mapping and SLN dissection. Indeed the procedure was performed and the
Completely regressed cutaneous melanocytic lesion
sentinel nodes were free of melanoma. 3. If the nodes are benign, would you recommend follow-up for possible metastases and if so how often and by what means? Clearly patients with melanoma of unknown primary site can present with visceral metastatic disease. With the exception of surgical resection of the occasional solitary lesion, the systemic therapies available to patients with visceral metastatic disease are of limited efficacy. Thus it is difficult to justify intense (and costly) surveillance for visceral disease about which little can be done.19,20 However, a minority of patients do experience profound and durable tumor regression in response to systemic therapy. Indeed, traditional wisdom suggests that the probability of response is inversely related to tumor burden. Because of concern regarding a negative impact of tumor regression, Dr McClay recommended intense surveillance, whereas Dr Berger did not recommend routine surveillance for visceral metastatic disease in the absence of regional lymph node involvement. Drs Toporcer and Wolchok took the middle ground of limited surveillance. Indeed, this was the path chosen for this patient. When confronted with a clinical circumstance of uncertain biological significance, it is reasonable and prudent to assume the worst and to plan accordingly. The proposed approach should weigh the perceived risk with the known physical and financial morbidity of the treatment. In the absence of a definitive diag-
nosis of malignancy, this must be accomplished without labeling the individual as a “cancer patient” as the emotional and societal consequences of such a designation can be considerable.
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11.
REFERENCES 1. Giuliano, AE, Moseley HS, Morton DL. Clinical aspects of unknown primary melanoma. Ann Surg. 1980; 191:98 –104. 2. Chang P, Knapper WH. Metastatic melanoma of unknown primary. Cancer. 1982;49:1106 –11. 3. Reintgen DS, McCarty KS, Woodard B, Cox E, Seigler HF. Metastatic malignant melanoma with an unknown primary. Surg Gynecol Obstet. 1983;156:335– 40. 4. Bodurtha AJ. Spontaneous regression of malignant melanoma. In: Clark WH Jr, Goldman LI, Mastrangelo MJ, editors. Human malignant melanoma. Orlando, FL: Grune & Stratton; 1978. p. 277–342. 5. Elder DE, Elenitsas R, Murphy GF, Xu X. Benign pigmented lesions and melanoma. In: Elder DE, editor. Lever’s histopathology of the skin. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 447–9. 6. Zabawski EJ Jr, Cockerell CJ. Halo nevus. Emedicine.medscape.com/ article/1057446-overview. 7. Schmoeckel C, Wildi G, Schafer T. Spitz nevus versus malignant melanoma: Spitz nevi predominate on the thighs in patients younger than 40 years of age, melanomas on the trunk in patients forty years of age or older. J Am Acad Dermatol. 2007;56:753– 8. 8. Pol-Rodriquez M, Lee S, Silvers DN, Celebi JT. Influence of age on survival in childhood Spitzoid melanomas. Cancer. 2007;109:1579 – 83. 9. Busam KJ, Pulitzer M. Sentinel lymph node biopsy for patients with diagnostically controversial Spitzoid melanocytic tumors? Adv Anat Pathol. 2008;15:253– 62. 10. Lee CC, Faries MB, Wanek LA, Morton DL. Improved survival after lymphadenectomy for nodal me-
12.
13.
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15.
16.
17.
18.
19.
20.
tastases from an unknown primary melanoma. J Clin Oncol. 2008;26:535– 41. Morton DL, Thompson JF, Cochran AJ, Mozzillo M, Elashoff R, Essner R, et al. Sentinel node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355: 1307–17. McGovern VJ, Shaw HM, Milton GW. Prognosis in patients with thin melanoma: influence of regression. Histopathology. 1983;7:673– 80. Wanebo HJ, Cooper PH, Hagar RW. Thin (less than or equal to 1 mm) melanomas of the extremities are biologically favorable lesions not influenced by regression. Ann Surg. 1985;201:499 –504. Clark WH, Elder D, Guerry DuPont IV, Braitman LE, Rock BJ, Schultz D, et al. Model predicting survival in stage I melanoma based on tumor progression J Natl Cancer Inst. 1989;81:1893–904. Paladuga RR, Yonemoto RH. Biological behavior of thin malignant melanomas with regressive changes. Arch Surg. 1983;118:41– 4. Ronan SG, Eng AM, Briele HA, Shioura NN, Das Gupta TK. Thin malignant melanomas with regression and metastases. Arch Dermatol. 1987;123:1326 –30. Byers HR, Bhawan J. Pathologic parameters in the diagnosis and prognosis of primary cutaneous melanoma. Hematol Oncol Clin North Am. 1988;12:717–35. Balch CM, Lange JR. Lymphatic mapping and sentinel node lymphadenectomy for cancer: an overview. Ann Surg Oncol. 2001;8 Suppl:1S– 4S. Weiss M, Loprinzi CL, Creagan ET, Dalton RJ, Novotny P, O’Fallon JR. Utility of follow-up tests for detecting recurrent disease in patients with malignant melanomas. JAMA. 1995;274:1703–5. Poo-Hwu W-J, Ariyan S, Lamb L, Papac R, Zelterman D, Hu GL, et al. Follow-up recommendations for patients with American Joint Committee on Cancer stages I-III malignant melanoma. Cancer. 1999;86:2252– 8.
Completely Regressed Cutaneous Melanocytic Lesion: Was It Benign or Was It Malignant? Adam C. Berger, Edward F. McClay, Mary Toporcer, Jedd D. Wolchok, and Gloria J. Morris
At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each ”Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers’ comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at [email protected]. I look forward to a lively discussion. Gloria J. Morris, MD, PhD Current Clinical Practice Feature Editor
O
f patients presenting to melanoma centers with metastatic disease, about 5% to 10% have an occult primary lesion. The clinical presentation is most commonly of peripheral lymphadenopathy.1– 4 Often but not always there is historical or physical evidence of a Address correspondence to Gloria J. Morris, MD, PhD, Editor, Current Clinical Practice, Hematology and Oncology Associates of Northeastern PA, PC, 1100 Meade St, Dunmore, PA 18512. E-mail: dr.morris@ hemonc1.com 0270-9295/09/$ - see front matter © 2009 Published by Elsevier Inc. doi:10.1053/j.seminoncol.2009.07.010
regressed pigmented lesion regional to the lymphadenopathy. That a primary cutaneous melanoma can seed a nodal or distant site and then regress completely is well established. What is unknown is the frequency with which a primary melanoma regresses without seeding metastases. These individuals do not seek medical attention. An inkling as to how often this event occurs perhaps could be gleaned from our understanding of the phenomenon of halo nevus.5 A halo nevus is characterized clinically by an acquired zone of depigmentation surrounding a pigmented compound nevus. These lesions most commonly occur on the backs of children and young adults. The pigmented lesion typically regresses over months and the area may repigment. Histologically a lymphocyte infiltrate surrounds nevus cells, which cytologically are atypical. Although concerning microscopically, the clinical behavior of these lesions is considered to be benign. The incidence of halo nevi in the population is thought to be about 1%.6
THE PROBLEM The patient is a 59-year-old white male who was seeing his dermatologist approximately every 6 months for cutaneous evaluations because of a history of heavy sun exposure as a youngster. He spent his summers at the seashore. On the exposure to the sun, he would burn and get only a light tan. There were multiple episodes of blistering sunburns
Seminars in Oncology, Vol 36, No 5, October 2009, pp 375-379
in his youth and teen years, several of which were of sufficient intensity to be characterized as “sun poisoning.” On a routine skin examination a lesion was noticed on his right flank. Clinically, the lesion had the appearance of a “pigmented basal cell carcinoma.” A biopsy was performed and it was interpreted as showing complete regression of a pigmented lesion (Figures 1 and 2). The papillary dermis was thickened and demonstrated a delicate fibroplasia, as well as a patchy lymphocyte infiltrate, numerous melanophages, and vascular proliferation. There is no history of there having been a pre-existing nevus in this area nor is there a history of any regression. However, the area was not readily visible to the patient. At the time of referral, his physical examination revealed the operative site to be well healed with no clinical evidence of residual abnormality. His pigmented lesions were present on sun-exposed portions of the body, numbered less than 20, were less than 5 mm in diameter, and did not show any clinical evidence of dysplasia. The peripheral lymph nodes were negative. The patient presented for a discussion of the etiology of this lesion, its treatment and his prognosis. What do you tell a patient who has a completely regressed cutaneous melanocytic lesion with no history of an antecedent pigmented lesion, despite regular skin examinations by a dermatologist, and a normal pattern of moles but with sun-sensitive 375
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Figure 1. Cytologically and architecturally normal epidermis with dense lymphocyte infiltrate and a few pigment-laden macrophages in the dermis.
skin and a history of multiple blistering sunburns?
DERMATOLOGIST’S EXPERT OPINION The adult patient illustrated in the case report with a regressing pigmented lesion without a specific histopathological diagnosis is a noteworthy management problem. The decrease in number of melanocytes in the epidermis, the accompanying inflammatory infiltrate, and the melanophages in the dermis lead one to believe that this lesion represents a melanocytic lesion that has regressed. This is quite a common phenomenon in children in the setting of benign halo nevi. However, in the adult population, the management of such a lesion is less clear. Halo or regressed nevi are not common occurrences in adult patients. There is a level of concern that the underlying melanocytic lesion may have represented a regressed malignancy. This is similar to our concerns regarding Spitz nevi in adults. There is abundant literature stressing the banal nature of Spitz nevi in children less than 11 years of age. When Spitz nevi are diagnosed in adults, the current literature suggests complete clinical and histopathological removal. This is because the clinical behavior of Spitz nevi in adults over the age of
40 years may not be benign.7,8 Some authors question the value of sentinel lymph node (SLN) biopsy to help resolve the diagnostic quandary regarding the primary lesion.9 I suggest that the same algorithm should be applied to regressed nevi in adults. One must err on the side of caution and completely remove all clinical and histopathological evidence of this lesion, most likely with 0.5- to 1-cm margins if possible. To date, there is no definitive evidence to support the use of lymph node mapping and selective lymph node dissection in regressed melanocytic lesions, as this procedure has been found to be beneficial
in only the intermediate level melanomas. However, as with atypical Spitz nevi, there may be great value in future controlled studies of SLN biopsies in these cases. For now, clinical examination of the lymph nodes, liver, and spleen along with a baseline chest x-ray and laboratory studies to include a complete blood cell count, liver function chemistries, and lactate dehydrogenase determination are valuable as baseline measures and are low-risk procedures for the patient. I advise continued total body skin examinations every 6 months, with particular attention to all lymph node sites, liver, and spleen. The patient likewise needs to be counseled to perform monthly self-examination. Unfortunately, there is no way to turn back the clock on a regressed lesion, but careful clinical observation may identify recurrent or subsequent lesions at a time when the patient may benefit from additional aggressive therapeutic measures. Mary Toporcer, MD Dermatology and Dermatologic Surgery Doylestown, PA
SURGICAL ONCOLOGIST’S EXPERT OPINION I have read with interest the case report of the 59-year-old man who
Figure 2. Melanin laden macrophages in a sea of melanocytes strongly suggestive of a regressed melanocytic neoplasm.
Completely regressed cutaneous melanocytic lesion
presented with a completely regressed pigmented lesion. Briefly, on routine physical examination, a lesion that clinically resembled a pigmented basal cell carcinoma was noted on his flank. This was excised and histology showed a lymphocytic infiltrate, numerous melanophages, and vascular proliferation. On consultation this was felt to be a completely regressed melanocytic neoplasm. As many medical professionals who care for patients with melanoma know, melanoma is a very immunogenic tumor. The majority of approved therapies, as well as experimental ones, are based on manipulation of the host immune system (interferon, interleukin-2, vaccines). Additionally, approximately 5% to 10% of patients who present with stage 3 or 4 melanoma will do so from an unknown primary site.1 In the majority of these patients, the primary melanoma is never found. It is presumed that these melanomas have undergone complete regression. It is also known that patients presenting with metastases from an unknown primary site appear to have a better survival than other patients with metastatic disease from known primaries.10 The reason for this has not been fully elucidated. However, it is my opinion that these patients have immune systems that are much more reactive to the melanoma and are therefore able to keep it at bay for longer periods of time. As previously pointed out, it is quite possible that there are numerous individuals who have spontaneous regression of pigmented cutaneous lesions and do not develop metastases and thus never come to our attention. I personally treated a patient who presented with an axillary lymph node metastasis, as well as an in-transit metastasis, but no primary skin lesion. On further examination, an area of depigmented skin was found in the drainage basin. This was completely excised and no evidence of melanoma was found.
If this patient has undergone complete excision of the regressed neoplasm, I would not advocate further excision. The chance of local recurrence is extremely small. However, if there are any doubts about the margins, I think that it would be reasonable to remove a few millimeters of normal skin. If the patient is to have lymph node mapping with blue dye, this procedure will remove the blue-stained tissue. As regards SLN mapping and biopsy, I would have a full discussion with the patient regarding the pluses and minuses of the procedures. Because there is a real possibility of lymph node metastases from a melanoma of unknown primary site, it would be advantageous to find this metastasis when it is microscopic. As the results of the Multicenter Selective Lymphadenopathy Trial-1 (MSLT-1) indicate, it appears that removal of stage 3 disease when it is microscopic appears to improve survival compared to not doing sentinel node biopsy.11 Finally, if re-excision and SLN biopsy fail to reveal any evidence of melanoma, I would have the patient undergo routine skin surveillance with his dermatologist but not undergo routine surveillance for metastatic disease. Adam C. Berger, MD, FACS Department of Surgery Thomas Jefferson University Philadelphia, PA
MEDICAL ONCOLOGIST’S EXPERT OPINION Implicit in the presentation of this clinical scenario is the question of the relationship of regression to primary melanoma and the metastatic process. Of the multiple histopathological factors identified in melanoma, the presence of regression remains controversial with regards to its importance. While data from the large University of Alabama–Southern Methodist University (UAB-SMU) database failed to support the importance of regression, Clark and others have demonstrated
377
independent prognostic significance.12–15 These latter studies identified the presence of regression as associated with a poorer prognosis in multivariate analysis. Several studies have suggested that the presence of regression in more than 75% of the lesion represents a critical volume that is associated with metastatic potential.16,17 In my practice I have used regression as a poor prognostic finding and counsel patients accordingly. Therefore in this clinical situation I have viewed the presence of regression in this light. This patient presents with a difficult clinical problem that to some degree requires decision making without the entire information that one would like. The patient had a lesion that clinically looked like a pigmented basal cell carcinoma that on pathologic evaluation raises the specter of malignant melanoma. In the absence of a clear diagnosis of melanoma, clinicians must use their best clinical judgment as to the management of the patient. There are basically two diametrically opposed approaches that can be taken. In the first approach, the clinician assumes that this is a benign lesion, completely excised, and requires no further treatment. The other assumes just the opposite, that this is a completely regressed malignant melanoma requiring aggressive management. In this situation I have erred on the side of being aggressive. If we assume that this is a benign lesion and it actually is a regressed melanoma, we may potentially miss an opportunity to find recurrence at an earlier stage where an effective treatment with modest morbidity can be offered. If, however, we assume that this is melanoma and it is actually benign, we will potentially spend money and subject the patient to unnecessary procedures. Following the dictum of “Primum non nocere” (“First do no harm”), I believe the greater harm would be to assume this lesion to be benign. In my practice, I believe that this clinical situation requires extensive discussion with the patient as to the
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best approach. Having cared for more than 2,000 patients with melanoma, I must admit that I tend to err on the aggressive side. I would recommend re-excision of the primary site with a 1-cm border. The 1-cm border provides a reasonable margin to encompass potential intransit disease. I also would recommend both lymphatic mapping and the performance of SLN dissection. Some studies have identified regression as a predictor of metastasis to the SLN.18 Finally, I would recommend the performance of semi-annual surveillance scans (positron emission tomography [PET]/computed tomography [CT] or CT scans of the chest/abdomen/pelvis) for 2 years. Eighty-five percent of recurrences become clinically evident within the first 24 months after diagnosis. Fortunately this is not a common situation. I believe that given the lack of clear scientifically valid information, we must rely on clinical experience and judgment. Edward F. McClay, MD Director Melanoma Research Center of San Diego Encinitas, CA
MEDICAL ONCOLOGIST’S EXPERT OPINION In our practice we certainly do see the expected 5% to 10% of patients with metastatic disease and an occult (or undetectable) primary melanoma. I think that these patients are certainly a diagnostic and management challenge. As regards advising this patient with a suspicious completely regressed pigmented lesion, I would recommend wide excision of the primary site to achieve 2-cm margins as if this were a melanoma greater than 1 mm in Breslow thickness. Given the lack of morbidity and prognostic importance of lymph node mapping, I would favor performing this procedure. I am well aware of data from the randomized MSLT-1 trial11 show-
ing no evidence for a survival benefit for early intervention; however, given the absence of patients such as this from the analysis, I think that it is reasonable to proceed with the procedure. It certainly would be informative in helping to decide how to design a follow-up plan for the patient. In addition I have a small number of patients in my practice who presented with palpable nodal metastases and evidence of a regressed primary (hypopigmentation in an area draining to the nodes involved). With surgery alone, such patients may have long-term diseasefree survival. If the SLNs were benign, I would recommend physical examination every 4 – 6 months with emphasis on the draining nodal basin, chest x-ray once per year, and routine complete blood cell count and chemistries (including lactate dehydrogenase) with each visit. Jedd D. Wolchok, MD, PhD Associate Attending, MelanomaSarcoma Service Memorial Sloan-Kettering Cancer Center New York, NY
SUMMARY AND ASSESSMENT Partial and complete regression of benign and malignant melanocytic neoplasms is not uncommon. This phenomenon likely is not unique to melanocytic proliferations but simply is more readily evident because of their largely cutaneous location and the frequent residuum of telltale melanin deposition. The clinical presentation and microscopic findings of regression have been well documented. Data regarding the biological significance of this phenomenon remain confusing. Nowhere is this more evident than in the report by Clark et al,14 where in the presence of tumor-infiltrating lymphocytes (TILs) was determined to be a favorable prognostic feature. In as much as TILs are the presumed hallmark of an immune response mounted by the host against the melanoma, a favorable impact on
outcome is intuitive. Unexpectedly, histological evidence of melanoma regression, the anticipated result of an effective immune response, was an adverse prognostic feature. In the absence of evidencebased consensus guidelines, what does the reasonably prudent clinician recommend regarding treatment? Respondents were asked to address the following questions: 1. Would you re-excise the “primary site” to assure negative margins and if so, to what diameter? All respondents agreed that histologically clear margins were required. Recommended margins ranged from a few millimeters to as much as 2 cm. In as much as the flank location posed no functional or physical impediments, this patient’s “primary” site was re-excised to achieve 1-cm margins. There was no microscopic evidence of residual lesion. 2. Would you recommend lymph node mapping and sentinel lymph node dissection? As pointed out by Drs Toporcer and Wolchok, there are no data to support the use of lymph node mapping and SLN dissection in this setting. Dr Toporcer’s recommendation of clinical observation is quite reasonable, especially in light of the difficulty in demonstrating a survival benefit versus therapeutic regional lymph node dissection. However, the procedure is minimally invasive and negligibly morbid. As such, it is being employed with increasing frequency for informational purposes with a variety of neoplasms of uncertain biological significance, to include Spitz tumors in adults and severely dysplastic nevi. Drs Wolchok, McClay, and Berger all recommended lymph node mapping and SLN dissection. Indeed the procedure was performed and the
Completely regressed cutaneous melanocytic lesion
sentinel nodes were free of melanoma. 3. If the nodes are benign, would you recommend follow-up for possible metastases and if so how often and by what means? Clearly patients with melanoma of unknown primary site can present with visceral metastatic disease. With the exception of surgical resection of the occasional solitary lesion, the systemic therapies available to patients with visceral metastatic disease are of limited efficacy. Thus it is difficult to justify intense (and costly) surveillance for visceral disease about which little can be done.19,20 However, a minority of patients do experience profound and durable tumor regression in response to systemic therapy. Indeed, traditional wisdom suggests that the probability of response is inversely related to tumor burden. Because of concern regarding a negative impact of tumor regression, Dr McClay recommended intense surveillance, whereas Dr Berger did not recommend routine surveillance for visceral metastatic disease in the absence of regional lymph node involvement. Drs Toporcer and Wolchok took the middle ground of limited surveillance. Indeed, this was the path chosen for this patient. When confronted with a clinical circumstance of uncertain biological significance, it is reasonable and prudent to assume the worst and to plan accordingly. The proposed approach should weigh the perceived risk with the known physical and financial morbidity of the treatment. In the absence of a definitive diag-
nosis of malignancy, this must be accomplished without labeling the individual as a “cancer patient” as the emotional and societal consequences of such a designation can be considerable.
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