U n u s u a l Pres e n t a t i o n s o f Melanoma Melanoma of Unknown Primary Site, Melanoma Arising in Childhood, and Melanoma Arising in the Eye and on Mucosal Surfaces Vernon K. Sondak,
MD
a,b,c,
*, Jane L. Messina,
MD
a,d,e,f
KEYWORDS Melanoma Unknown primary Pediatric melanoma Mucosal melanoma Uveal melanoma Immunotherapy Targeted therapy Adjuvant therapy KEY POINTS Major advances have occurred in our understanding of cutaneous melanoma in adults, but these have not yet translated into significant breakthroughs for the management of melanomas arising in noncutaneous locations such as the eye and mucosal surfaces. Management of melanoma arising in children remains controversial. Melanoma presenting in regional lymph nodes without a known cutaneous primary site behaves in a manner entirely consistent with recurrence after removal of a known primary, and should therefore be managed in an analogous fashion. New molecular tests, including gene expression profiling and comparative genomic hybridization, have been introduced for evaluation of uveal and pediatric melanomas, but their optimal role in patient management remains to be defined.
Financial Disclosures: Dr V.K. Sondak is a compensated consultant for Bristol-Myers Squibb, GlaxoSmithKline, Merck, Navidea, Novartis and Provectus. a Department of Cutaneous Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; b Department of Oncologic Sciences, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA; c Department of Surgery, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA; d Department of Anatomic Pathology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; e Department of Pathology & Cell Biology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA; f Department of Dermatology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA * Corresponding author. Department of Cutaneous Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612. E-mail address: [email protected] Surg Clin N Am 94 (2014) 1059–1073 http://dx.doi.org/10.1016/j.suc.2014.07.010 surgical.theclinics.com 0039-6109/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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INTRODUCTION
More than 90% of all melanomas present as primary tumors on the skin surface, and most are diagnosed during adulthood. About 5% of all melanomas arise in the eye, and 1% to 2% arise on the mucosal surfaces or present as apparently metastatic disease somewhere other than on the skin without any known history of a cutaneous primary melanoma.1 Melanoma is being diagnosed in pediatric age patients more frequently than ever before.2 Surgeons need to be aware of these unusual presentations of melanoma, and in particular to understand the important site-specific differences in biology and management compared with the ‘typical’ adult patient presenting with a cutaneous primary melanoma. UNKNOWN PRIMARY MELANOMA IN REGIONAL NODES
A review of the National Cancer Data Base found that 2.2% of all melanoma patients presented without a known primary site.1 The same review found that 23.1% of cutaneous melanoma patients presented with stage III disease (nodal or intralymphatic involvement). Among melanoma patients presenting with palpable lymph nodes, however, between 13% and 17% have no known primary site.3,4 Potential explanations for this unusual presentation include removal of the original primary on the skin without recognizing it as malignant (eg, cryoablation of a presumed nonmelanoma skin cancer, misdiagnosis of a biopsy specimen as a benign nevus, unrecognized accidental or traumatic amputation of the primary), regression of the original primary with persistence of a clone of metastatic cells in the regional node, and primary malignant degeneration of intranodal melanocytes (nodal nevus cells). However, it is not unusual for a careful physical examination to turn up an occult primary site in a patient referred in with “an unknown primary.” Initial Evaluation
Initial evaluation of the patient includes evaluating these various potential explanations, as well as the typical evaluation of the stage III melanoma patient for resectability and the possibility of occult distant metastatic disease. A thorough history includes detailed questioning about traumatized, regressed, ablated, or removed pigmented or amelanotic lesions located anywhere in the draining field of the involved nodal basin. For the inguinal nodes, the questioning should also encompass any history of hemorrhoids and lesions on the genitalia, as well as on the toes and soles of the feet. If the patient relates a history of a benign nevus having been removed from the relevant anatomic region, efforts to secure the pathology report and/or the slides for secondary review can be helpful. If the patient relates a history of a regressed pigmented skin lesion, they may have old photographs that document the lesion’s original appearance. Physical examination should follow up on any areas identified during the history, and look for unrecognized pigmented or amelanotic lesions and unexplained scars or hypopigmented areas. The physical can be supplemented by examination using a Wood’s lamp (“black light”) to highlight areas of hypopigmentation for further evaluation. Direct ophthalmoscopy can be carried out, but the likelihood that a nodal metastasis is arising from a uveal primary site is extremely remote, and routine referral to an ophthalmologist is not required in the absence of visual symptoms or suspected abnormalities seen on ophthalmoscopy. For inguinal lymphadenopathy, rectal and (for females) pelvic examinations are appropriate, with more detailed evaluation or referral for gynecologic examination or endoscopy if findings warrant. For cervical lymphadenopathy, the possibility of a nasal or oropharyngeal mucosal primary should be entertained, and referral for endoscopy considered.
Unusual Presentations of Melanoma
The staging workup is similar to that for palpable stage III melanoma from a known primary, and includes cross-sectional imaging (whole body positron emission tomography (PET)/computed tomography (CT) or CT of the chest and abdomen, with inclusion of the pelvis or neck depending on the site of nodal disease) and evaluation of the central nervous system (contrast-enhanced brain magnetic resonance imaging, with CT if magnetic resonance imaging is contraindicated or the patient is severely claustrophobic). We often add ultrasound evaluation of other nodal basins, particularly if we suspect that the original primary lesion might have arisen on an area of skin with ambiguous lymphatic drainage. Relevant Biology
Emerging data suggest that the mutational status of unknown primary melanomas within the regional nodes closely mirrors the pattern seen with known cutaneous primaries, with approximately half of cases harboring BRAF V600 mutations.5 This finding lends support to the notion that most, if not all, cases of nodal unknown primary melanoma represent metastases from an original cutaneous primary. Overall, the outcome for patients with unknown primary melanomas within the regional nodes is slightly better than that for all patients with macroscopic stage III melanoma from a known primary site. In one series, the 5-year survival rates were 55% for patients with an unknown primary compared with 42% for those with a known primary (P 5 .04),3 whereas in another the rates were 55% versus 44% (P 5 .002).4 This has led to speculation that an antitumor immune response led to regression of the primary site and potentially a favorable systemic response as well. However, available evidence suggests that in fact the prognosis for unknown primary patients is identical to known primary patients presenting with metachronous nodal metastasis, and that both groups have a more favorable survival than patients presenting with synchronous nodal metastasis at the time of diagnosis of the primary cutaneous melanoma.6,7 Moreover, in our experience with cases where a previous lesion has been biopsied on the skin and misdiagnosed as benign, subsequent pathology re-review generally has shown the lesion to be a relatively thin melanoma with nevus-like features and few or absent mitoses. If so, it would not be surprising that, when such lesions eventually metastasize, the outcome might be slightly more favorable than average. Surgical Management
Overall, we believe the prognosis of unknown primary melanoma presenting in the lymph nodes is identical to that for patients with known cutaneous primaries and metachronous lymph node metastases, and hence the surgical management is almost exactly the same, namely, radical lymphadenectomy. We are slightly less inclined to perform a pelvic lymphadenectomy for unknown primary patients presenting with inguinal nodal involvement and radiographically negative pelvic nodes than would be the case for known primary patients, because of the possibility that the original primary might have lymphatic drainage to both groins or to the groin and the axilla. If the preoperative evaluation uncovered any areas of hypopigmentation or other suspect skin lesions, these are removed at the time of radical lymphadenectomy for histopathologic evaluation. Adjuvant Therapy
Postoperatively, identical criteria are used for decision making about adjuvant systemic therapy and adjuvant radiation as would be employed for patients with a known cutaneous primary. Adjuvant interferon (IFN) alfa-2b has been repeatedly shown in multiple clinical trials to improve relapse-free survival8,9 and, in metaanalyses, to
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have a small but statistically significant impact on overall survival.10 Its use should be considered in appropriately selected patients. Most important, patients with unknown primary melanoma in regional nodes should be considered appropriate candidates for participation in clinical trials testing new forms of adjuvant therapy, and not excluded from these trials because of an anticipated difference in prognosis and natural history from other types of stage III melanoma patients. Examples of recent adjuvant therapy trials that successfully included unknown primary stage III melanoma patients are the Southwest Oncology Group trial S0008 (NCT00006237) and the Eastern Cooperative Oncology Group trial E1609 (NCT01274338), which compare high-dose IFN with biochemotherapy and ipilimumab (anti-CTLA4 antibody), respectively. Adjuvant radiation to the regional nodal basin has been shown in a randomized trial to significantly decrease the likelihood of in-field relapse, but not improve relapse-free survival or overall survival, in high-risk patients after radical lymphadenectomy.11 Many patients who present with stage III melanoma from an unknown primary meet the study’s criteria for high-risk disease: Extranodal extension of tumor present, multiple (1 parotid, 2 cervical or axillary, or 3 inguinal) tumor-containing nodes, or maximum size of any one involved node >3 cm for a cervical node or >4 cm for an axillary or inguinal node. Indeed, 18.1% of patients in this trial had an unknown primary site. For all patients in this study, the risk of lymph node basin relapse was reduced from 20.6% to 6.6%,11 but at the expense of increased short- and long-term toxicity. What remains unknown at this time is whether and how often patients who suffered lymph node basin relapse on the control arm could be salvaged by re-resection, radiation, or both, restricting the morbidity of nodal basin irradiation only to those who actually recurred regionally. Until more data become available, decision making about adjuvant radiation should be personalized to reflect the risk of an in-basin relapse, the salvage options available and the relative risk of long-term complications from radiating that nodal basin (eg, there is a greater risk of lymphedema from radiating inguinal than axillary nodes). Some patients with unknown primary melanoma in the lymph nodes present at a very advanced stage, with the resectability of the disease either questionable or unequivocally not feasible without unacceptable morbidity. In those cases, neoadjuvant therapy should be strongly considered based on BRAF mutation status: Patients with BRAF V600 mutations are potentially good candidates for neoadjuvant targeted therapy with BRAF plus or minus MEK inhibitors. The objective response rate to targeted therapy in unresectable stage III disease is >50%,12,13 and possibly as high as 75% to 80% for combination therapy,14 so many patients would be expected to be converted to a clearly resectable state after only a few months of treatment. Although the situation is not quite as favorable for patients lacking a targetable BRAF mutation, recent trials of anti-PD1 antibodies alone15 or with ipilimumab16 have shown response rates nearly as high and hence hold promise to offer another form of neoadjuvant therapy for converting borderline resectable or unresectable disease to a resectable state. UNKNOWN PRIMARY MELANOMA IN THE DERMIS AND SUBCUTANEOUS TISSUE
Not infrequently, although the precise incidence is poorly defined, patients present with a single dermal or subcutaneous nodule of melanoma and the pathologist is unable to identify an epidermal component to establish the diagnosis of primary cutaneous melanoma.17 The American Joint Committee on Cancer staging guidelines for melanoma indicate that, “when there are localized metastases to the skin or subcutaneous tissues, these should. be presumed to be regional (ie, stage III instead of stage IV) if an appropriate staging workup does not reveal any other sites of
Unusual Presentations of Melanoma
metastases.”18 However, the basis for considering such a lesion to represent stage III disease is unclear. In fact, available evidence suggests that these dermal or subcutaneous tumors are usually primary melanomas where the epidermal component has regressed or been lost, such as by prior biopsy, trauma (such as repeated scratching), or cryoablation. Traumatic removal of the epidermal component of a melanoma is not infrequent in areas groomed by shaving, such as the legs in women and face in men. For tumors centered in the deep dermis or subcutaneous tissue, a diagnosis of clear cell sarcoma should be entertained, and the specimen referred for analysis for the t(12;22)(q13;q12) translocation when appropriate. Melanomas located in the dermis and subcutaneous tissue behave more like thick primary melanomas or local recurrences than regional metastases, and it is generally our practice to treat them as such. In at least some cases, this type of melanoma may have arisen as a primary tumor within the dermis (“primary dermal melanoma”), and hence does not represent a truly unknown primary.17,19 Management of these cases benefits greatly from close collaboration with the pathologist as well as a careful history to seek evidence for an initial cutaneous component of the tumor versus a history of a primary melanoma at another site that could have potentially been the source of metastasis. A full metastatic workup may or may not be ordered depending on the level of uncertainty about the possibility that the lesion might represent a primary tumor and the size of the nodule itself, and regional nodal ultrasonography is frequently employed as well. Most cases are managed as if they were a known cutaneous melanoma of equal thickness, that is, by wide excision and sentinel lymph node biopsy, if not otherwise contraindicated. Not infrequently, the presence of an epidermal component is noted in the wide excision specimen, in retrospect establishing these lesions as primary cutaneous melanoma after all. UNKNOWN PRIMARY MELANOMA IN VISCERAL ORGANS
The most challenging scenarios are presented by cases of melanoma developing in visceral sites without a known cutaneous primary. All of the considerations regarding a regressed, traumatized, or misdiagnosed primary tumor mentioned for stage III unknown primary must be considered when evaluating a case of presumed stage IV unknown primary melanoma. Just as the location of the nodal disease can point toward possible primary sites in stage III unknown primary cases, the pattern of metastatic disease can point toward possible primary sites in stage IV cases. For example, because uveal melanoma metastasizes so frequently to the liver, when a patient presents with widespread metastatic melanoma in the liver without a known primary, an appropriate ophthalmologic evaluation should be undertaken. When the visceral melanoma is found in a single site, such as the gastrointestinal tract, the possibility of a visceral primary rather than metastatic disease from an unknown primary must be entertained seriously. Recently, genetic characterization of tumors felt to represent unknown primary metastatic melanoma in the small intestine and other sites have revealed some of these tumors to have the characteristic chromosomal translocation of clear cell sarcoma,20 suggesting that they were in fact primary sarcomas and not melanoma metastases. Currently, when faced with a patient with an isolated lesion consistent with metastatic melanoma but no known cutaneous or ocular primary site, we use standard molecular testing for BRAF mutations and also send the tumor for analysis for the t(12;22)(q13;q12) translocation, resulting in the fusion protein EWSR1/ATF1, to evaluate for the possibility the tumor is actually a primary clear cell sarcoma. At present, however, the management is the same whether or not the translocation is found: A full metastatic workup including cross-sectional body and brain imaging, with resection of an
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isolated lesion whenever possible. Unlike stage III melanoma of unknown primary origin, the role of adjuvant therapy is less clear for stage IV unknown primary melanoma (and completely unknown for primary clear cell sarcoma of the gastrointestinal tract). Overall, however, the outcome for patients with unknown primary stage IV melanoma seems to be more favorable than for patients with a known primary, even in matched-pair analysis compared with otherwise similar known primary cases.21 CUTANEOUS MELANOMA ARISING IN CHILDHOOD
Incidence rates for melanoma in children
MD
a,b,c,
*, Jane L. Messina,
MD
a,d,e,f
KEYWORDS Melanoma Unknown primary Pediatric melanoma Mucosal melanoma Uveal melanoma Immunotherapy Targeted therapy Adjuvant therapy KEY POINTS Major advances have occurred in our understanding of cutaneous melanoma in adults, but these have not yet translated into significant breakthroughs for the management of melanomas arising in noncutaneous locations such as the eye and mucosal surfaces. Management of melanoma arising in children remains controversial. Melanoma presenting in regional lymph nodes without a known cutaneous primary site behaves in a manner entirely consistent with recurrence after removal of a known primary, and should therefore be managed in an analogous fashion. New molecular tests, including gene expression profiling and comparative genomic hybridization, have been introduced for evaluation of uveal and pediatric melanomas, but their optimal role in patient management remains to be defined.
Financial Disclosures: Dr V.K. Sondak is a compensated consultant for Bristol-Myers Squibb, GlaxoSmithKline, Merck, Navidea, Novartis and Provectus. a Department of Cutaneous Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; b Department of Oncologic Sciences, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA; c Department of Surgery, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA; d Department of Anatomic Pathology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; e Department of Pathology & Cell Biology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA; f Department of Dermatology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA * Corresponding author. Department of Cutaneous Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612. E-mail address: [email protected] Surg Clin N Am 94 (2014) 1059–1073 http://dx.doi.org/10.1016/j.suc.2014.07.010 surgical.theclinics.com 0039-6109/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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Sondak & Messina
INTRODUCTION
More than 90% of all melanomas present as primary tumors on the skin surface, and most are diagnosed during adulthood. About 5% of all melanomas arise in the eye, and 1% to 2% arise on the mucosal surfaces or present as apparently metastatic disease somewhere other than on the skin without any known history of a cutaneous primary melanoma.1 Melanoma is being diagnosed in pediatric age patients more frequently than ever before.2 Surgeons need to be aware of these unusual presentations of melanoma, and in particular to understand the important site-specific differences in biology and management compared with the ‘typical’ adult patient presenting with a cutaneous primary melanoma. UNKNOWN PRIMARY MELANOMA IN REGIONAL NODES
A review of the National Cancer Data Base found that 2.2% of all melanoma patients presented without a known primary site.1 The same review found that 23.1% of cutaneous melanoma patients presented with stage III disease (nodal or intralymphatic involvement). Among melanoma patients presenting with palpable lymph nodes, however, between 13% and 17% have no known primary site.3,4 Potential explanations for this unusual presentation include removal of the original primary on the skin without recognizing it as malignant (eg, cryoablation of a presumed nonmelanoma skin cancer, misdiagnosis of a biopsy specimen as a benign nevus, unrecognized accidental or traumatic amputation of the primary), regression of the original primary with persistence of a clone of metastatic cells in the regional node, and primary malignant degeneration of intranodal melanocytes (nodal nevus cells). However, it is not unusual for a careful physical examination to turn up an occult primary site in a patient referred in with “an unknown primary.” Initial Evaluation
Initial evaluation of the patient includes evaluating these various potential explanations, as well as the typical evaluation of the stage III melanoma patient for resectability and the possibility of occult distant metastatic disease. A thorough history includes detailed questioning about traumatized, regressed, ablated, or removed pigmented or amelanotic lesions located anywhere in the draining field of the involved nodal basin. For the inguinal nodes, the questioning should also encompass any history of hemorrhoids and lesions on the genitalia, as well as on the toes and soles of the feet. If the patient relates a history of a benign nevus having been removed from the relevant anatomic region, efforts to secure the pathology report and/or the slides for secondary review can be helpful. If the patient relates a history of a regressed pigmented skin lesion, they may have old photographs that document the lesion’s original appearance. Physical examination should follow up on any areas identified during the history, and look for unrecognized pigmented or amelanotic lesions and unexplained scars or hypopigmented areas. The physical can be supplemented by examination using a Wood’s lamp (“black light”) to highlight areas of hypopigmentation for further evaluation. Direct ophthalmoscopy can be carried out, but the likelihood that a nodal metastasis is arising from a uveal primary site is extremely remote, and routine referral to an ophthalmologist is not required in the absence of visual symptoms or suspected abnormalities seen on ophthalmoscopy. For inguinal lymphadenopathy, rectal and (for females) pelvic examinations are appropriate, with more detailed evaluation or referral for gynecologic examination or endoscopy if findings warrant. For cervical lymphadenopathy, the possibility of a nasal or oropharyngeal mucosal primary should be entertained, and referral for endoscopy considered.
Unusual Presentations of Melanoma
The staging workup is similar to that for palpable stage III melanoma from a known primary, and includes cross-sectional imaging (whole body positron emission tomography (PET)/computed tomography (CT) or CT of the chest and abdomen, with inclusion of the pelvis or neck depending on the site of nodal disease) and evaluation of the central nervous system (contrast-enhanced brain magnetic resonance imaging, with CT if magnetic resonance imaging is contraindicated or the patient is severely claustrophobic). We often add ultrasound evaluation of other nodal basins, particularly if we suspect that the original primary lesion might have arisen on an area of skin with ambiguous lymphatic drainage. Relevant Biology
Emerging data suggest that the mutational status of unknown primary melanomas within the regional nodes closely mirrors the pattern seen with known cutaneous primaries, with approximately half of cases harboring BRAF V600 mutations.5 This finding lends support to the notion that most, if not all, cases of nodal unknown primary melanoma represent metastases from an original cutaneous primary. Overall, the outcome for patients with unknown primary melanomas within the regional nodes is slightly better than that for all patients with macroscopic stage III melanoma from a known primary site. In one series, the 5-year survival rates were 55% for patients with an unknown primary compared with 42% for those with a known primary (P 5 .04),3 whereas in another the rates were 55% versus 44% (P 5 .002).4 This has led to speculation that an antitumor immune response led to regression of the primary site and potentially a favorable systemic response as well. However, available evidence suggests that in fact the prognosis for unknown primary patients is identical to known primary patients presenting with metachronous nodal metastasis, and that both groups have a more favorable survival than patients presenting with synchronous nodal metastasis at the time of diagnosis of the primary cutaneous melanoma.6,7 Moreover, in our experience with cases where a previous lesion has been biopsied on the skin and misdiagnosed as benign, subsequent pathology re-review generally has shown the lesion to be a relatively thin melanoma with nevus-like features and few or absent mitoses. If so, it would not be surprising that, when such lesions eventually metastasize, the outcome might be slightly more favorable than average. Surgical Management
Overall, we believe the prognosis of unknown primary melanoma presenting in the lymph nodes is identical to that for patients with known cutaneous primaries and metachronous lymph node metastases, and hence the surgical management is almost exactly the same, namely, radical lymphadenectomy. We are slightly less inclined to perform a pelvic lymphadenectomy for unknown primary patients presenting with inguinal nodal involvement and radiographically negative pelvic nodes than would be the case for known primary patients, because of the possibility that the original primary might have lymphatic drainage to both groins or to the groin and the axilla. If the preoperative evaluation uncovered any areas of hypopigmentation or other suspect skin lesions, these are removed at the time of radical lymphadenectomy for histopathologic evaluation. Adjuvant Therapy
Postoperatively, identical criteria are used for decision making about adjuvant systemic therapy and adjuvant radiation as would be employed for patients with a known cutaneous primary. Adjuvant interferon (IFN) alfa-2b has been repeatedly shown in multiple clinical trials to improve relapse-free survival8,9 and, in metaanalyses, to
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have a small but statistically significant impact on overall survival.10 Its use should be considered in appropriately selected patients. Most important, patients with unknown primary melanoma in regional nodes should be considered appropriate candidates for participation in clinical trials testing new forms of adjuvant therapy, and not excluded from these trials because of an anticipated difference in prognosis and natural history from other types of stage III melanoma patients. Examples of recent adjuvant therapy trials that successfully included unknown primary stage III melanoma patients are the Southwest Oncology Group trial S0008 (NCT00006237) and the Eastern Cooperative Oncology Group trial E1609 (NCT01274338), which compare high-dose IFN with biochemotherapy and ipilimumab (anti-CTLA4 antibody), respectively. Adjuvant radiation to the regional nodal basin has been shown in a randomized trial to significantly decrease the likelihood of in-field relapse, but not improve relapse-free survival or overall survival, in high-risk patients after radical lymphadenectomy.11 Many patients who present with stage III melanoma from an unknown primary meet the study’s criteria for high-risk disease: Extranodal extension of tumor present, multiple (1 parotid, 2 cervical or axillary, or 3 inguinal) tumor-containing nodes, or maximum size of any one involved node >3 cm for a cervical node or >4 cm for an axillary or inguinal node. Indeed, 18.1% of patients in this trial had an unknown primary site. For all patients in this study, the risk of lymph node basin relapse was reduced from 20.6% to 6.6%,11 but at the expense of increased short- and long-term toxicity. What remains unknown at this time is whether and how often patients who suffered lymph node basin relapse on the control arm could be salvaged by re-resection, radiation, or both, restricting the morbidity of nodal basin irradiation only to those who actually recurred regionally. Until more data become available, decision making about adjuvant radiation should be personalized to reflect the risk of an in-basin relapse, the salvage options available and the relative risk of long-term complications from radiating that nodal basin (eg, there is a greater risk of lymphedema from radiating inguinal than axillary nodes). Some patients with unknown primary melanoma in the lymph nodes present at a very advanced stage, with the resectability of the disease either questionable or unequivocally not feasible without unacceptable morbidity. In those cases, neoadjuvant therapy should be strongly considered based on BRAF mutation status: Patients with BRAF V600 mutations are potentially good candidates for neoadjuvant targeted therapy with BRAF plus or minus MEK inhibitors. The objective response rate to targeted therapy in unresectable stage III disease is >50%,12,13 and possibly as high as 75% to 80% for combination therapy,14 so many patients would be expected to be converted to a clearly resectable state after only a few months of treatment. Although the situation is not quite as favorable for patients lacking a targetable BRAF mutation, recent trials of anti-PD1 antibodies alone15 or with ipilimumab16 have shown response rates nearly as high and hence hold promise to offer another form of neoadjuvant therapy for converting borderline resectable or unresectable disease to a resectable state. UNKNOWN PRIMARY MELANOMA IN THE DERMIS AND SUBCUTANEOUS TISSUE
Not infrequently, although the precise incidence is poorly defined, patients present with a single dermal or subcutaneous nodule of melanoma and the pathologist is unable to identify an epidermal component to establish the diagnosis of primary cutaneous melanoma.17 The American Joint Committee on Cancer staging guidelines for melanoma indicate that, “when there are localized metastases to the skin or subcutaneous tissues, these should. be presumed to be regional (ie, stage III instead of stage IV) if an appropriate staging workup does not reveal any other sites of
Unusual Presentations of Melanoma
metastases.”18 However, the basis for considering such a lesion to represent stage III disease is unclear. In fact, available evidence suggests that these dermal or subcutaneous tumors are usually primary melanomas where the epidermal component has regressed or been lost, such as by prior biopsy, trauma (such as repeated scratching), or cryoablation. Traumatic removal of the epidermal component of a melanoma is not infrequent in areas groomed by shaving, such as the legs in women and face in men. For tumors centered in the deep dermis or subcutaneous tissue, a diagnosis of clear cell sarcoma should be entertained, and the specimen referred for analysis for the t(12;22)(q13;q12) translocation when appropriate. Melanomas located in the dermis and subcutaneous tissue behave more like thick primary melanomas or local recurrences than regional metastases, and it is generally our practice to treat them as such. In at least some cases, this type of melanoma may have arisen as a primary tumor within the dermis (“primary dermal melanoma”), and hence does not represent a truly unknown primary.17,19 Management of these cases benefits greatly from close collaboration with the pathologist as well as a careful history to seek evidence for an initial cutaneous component of the tumor versus a history of a primary melanoma at another site that could have potentially been the source of metastasis. A full metastatic workup may or may not be ordered depending on the level of uncertainty about the possibility that the lesion might represent a primary tumor and the size of the nodule itself, and regional nodal ultrasonography is frequently employed as well. Most cases are managed as if they were a known cutaneous melanoma of equal thickness, that is, by wide excision and sentinel lymph node biopsy, if not otherwise contraindicated. Not infrequently, the presence of an epidermal component is noted in the wide excision specimen, in retrospect establishing these lesions as primary cutaneous melanoma after all. UNKNOWN PRIMARY MELANOMA IN VISCERAL ORGANS
The most challenging scenarios are presented by cases of melanoma developing in visceral sites without a known cutaneous primary. All of the considerations regarding a regressed, traumatized, or misdiagnosed primary tumor mentioned for stage III unknown primary must be considered when evaluating a case of presumed stage IV unknown primary melanoma. Just as the location of the nodal disease can point toward possible primary sites in stage III unknown primary cases, the pattern of metastatic disease can point toward possible primary sites in stage IV cases. For example, because uveal melanoma metastasizes so frequently to the liver, when a patient presents with widespread metastatic melanoma in the liver without a known primary, an appropriate ophthalmologic evaluation should be undertaken. When the visceral melanoma is found in a single site, such as the gastrointestinal tract, the possibility of a visceral primary rather than metastatic disease from an unknown primary must be entertained seriously. Recently, genetic characterization of tumors felt to represent unknown primary metastatic melanoma in the small intestine and other sites have revealed some of these tumors to have the characteristic chromosomal translocation of clear cell sarcoma,20 suggesting that they were in fact primary sarcomas and not melanoma metastases. Currently, when faced with a patient with an isolated lesion consistent with metastatic melanoma but no known cutaneous or ocular primary site, we use standard molecular testing for BRAF mutations and also send the tumor for analysis for the t(12;22)(q13;q12) translocation, resulting in the fusion protein EWSR1/ATF1, to evaluate for the possibility the tumor is actually a primary clear cell sarcoma. At present, however, the management is the same whether or not the translocation is found: A full metastatic workup including cross-sectional body and brain imaging, with resection of an
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isolated lesion whenever possible. Unlike stage III melanoma of unknown primary origin, the role of adjuvant therapy is less clear for stage IV unknown primary melanoma (and completely unknown for primary clear cell sarcoma of the gastrointestinal tract). Overall, however, the outcome for patients with unknown primary stage IV melanoma seems to be more favorable than for patients with a known primary, even in matched-pair analysis compared with otherwise similar known primary cases.21 CUTANEOUS MELANOMA ARISING IN CHILDHOOD
Incidence rates for melanoma in children
