ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Pathologic evaluation of regional lymph nodes in melanoma

Pathologic evaluation of regional lymph nodes in melanoma
Literature review current through: Jan 2024.
This topic last updated: May 03, 2022.

INTRODUCTION — Cutaneous melanoma characteristically spreads via the lymphatic system from its primary site to the locoregional lymph nodes. Knowledge of lymph node status is important for prognosis and the potential role of adjuvant systemic therapy.

The pathologic evaluation of regional lymph nodes is discussed in this topic. The role of sentinel lymph node (SLN) biopsy and the management of patients with a positive SLN biopsy are discussed separately, as is the pathology of the primary lesion. (See "Evaluation and management of regional nodes in primary cutaneous melanoma" and "Pathologic characteristics of melanoma".)

LYMPH NODE EVALUATION — Although the identification of patients with subclinical nodal metastases has evolved over time, interrogation of lymph node status remains the standard of care [1]. Alternative methods for risk classification, including gene expression profiling of primary melanoma [2], are discussed separately. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma", section on 'Gene expression profiling and proteomics'.)

Lymphatic mapping with sentinel lymph node (SLN) biopsy is a key component to the standard staging approach in patients at reasonable risk of subclinical regional lymph node metastasis. Patients at risk include those with nondesmoplastic melanomas >0.8 mm in thickness or certain thinner melanomas, particularly those with ulceration, lymphovascular invasion, and/or >1 mitosis/mm2 in the setting of younger age [3,4]. (See "Evaluation and management of regional nodes in primary cutaneous melanoma".)

For patients with clinically apparent regional lymph nodes, the role of therapeutic lymphadenectomy is discussed separately. (See "Evaluation and management of regional nodes in primary cutaneous melanoma".)

For patients with surgically resected primary tumors who have completed pathologic evaluation of regional lymph nodes, the choice of adjuvant systemic therapy (algorithm 1) is discussed separately. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

TECHNIQUE — Specimen preparation with hematoxylin and eosin (H&E) staining remains the gold standard for histologic interpretation of nodal material (picture 1) [5]. Detailed evaluation of the sentinel lymph node (SLN) for microscopic tumor burden is critical, and accordingly, sectioning of the SLN is more exhaustive than that of complete lymph node dissection.

The combination of both serial sectioning and immunohistochemical staining for melanoma-associated tumor markers (eg, the highly sensitive S100 and the highly specific melanoma antigen recognized by T cells 1 [MART-1]) facilitate the detection of metastatic melanoma cells (picture 2). In one retrospective study of 235 histologically negative SLNs from 94 patients with cutaneous melanoma, deeper serial sections and immunohistochemical stains detected microscopic metastases in approximately 12 percent of cases that would otherwise have been reported as negative for metastasis [6].

Protocols for pathologic evaluation of SLNs vary among different hospitals, though fundamentally represent variations on a theme, balancing sensitivity, specificity, and laboratory logistical issues [7,8]. Generally, the formalin-fixed SLN is bisected through its hilum and the entire node is sectioned into slices that are 1 to 2 mm thick (figure 1). Serial tissue sections are then sampled from each node in groups, with each group separated by a distance of approximately 100 microns. Periodic levels are immunostained (eg, SOX10, MART-1, S-100, etc); intervening levels are stained with H&E. With the 2017 American Joint Committee on Cancer (AJCC) tumor, node, metastasis 8th edition (TNM) staging system for cutaneous melanoma (table 1A-B) [1], the detection of a single melanoma cell by either H&E or immunohistochemical staining is sufficient to classify the lymph node as positive for metastasis. While some advocate for less exhaustive pathologic workup of melanoma SLNs [9], others emphasize the importance of thin sectioning and immunohistochemical analysis in optimizing detection of metastases [10].

HISTOLOGY — A normal lymph node contains innumerable lymphocytes admixed with histiocytes. Although benign capsular nevi may occasionally be present, the detection of intranodal deposits of melanocytic cells usually indicates metastasis [11]. Nevic rests are nests of benign melanocytes that typically reside within the nodal fibrous capsule and nodal trabeculae but are occasionally found in the subcapsular area of lymph nodes. These nevic rests have no malignant potential but are often mistaken for melanoma cells because they stain similarly to melanoma cells. They are "nevic" because they form nests in the lymph nodes and resemble either benign dermal nevus cells, Spitz nevus cells, or blue nevus cells. Intriguingly, a recent study has raised the possibility that detection of the BRAF V600E mutation in capsular nevi of a sentinel lymph node (SLN) may be correlated with negative prognosis [12].

Benign pigment-laden histiocytes, which are normally scattered throughout the node, can resemble melanoma cells, further adding to the difficulty in identifying a single malignant melanoma cell within a lymph node. These challenges to the accurate and precise identification of melanoma metastasis to the SLN are further exaggerated on frozen section analysis [13]. (See "Pathologic characteristics of melanoma", section on 'Growth phases of melanoma'.)

The subcapsular region is an important area for microscopic examination. Benign nevic cell rests are sometimes located in subcapsular areas and can be difficult to distinguish from metastatic melanoma cells. The lymphatic drainage, and therefore metastatic cells, enter the node at the level of the subcapsular sinus, and the majority of nodal metastases involve the subcapsular area. In one study of 281 SLN biopsies, 86 percent of nodal metastases involved at least the subcapsular region (32 percent were purely restricted to this region), while 11 percent were purely restricted to the parenchyma [14].

The prognostic significance of the location of nodal metastases is unclear. However, the location of the metastasis within an SLN may predict the likelihood of involvement of other lymph nodes. In a report of 146 patients with melanoma and at least one positive SLN, those with isolated subcapsular micrometastases had a significantly lower rate of non-SLN nodal metastases than those with a different microanatomic location pattern (0 of 38 [0 percent] compared with 24 of 108 [22 percent]) [15]. In part based upon these data, the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group recommends explicit documentation in the pathology report of the microanatomic location of the metastasis, the SLN tumor burden according to the Rotterdam Criteria for the maximum diameter of the largest metastasis expressed as an absolute number, and the SLN tumor burden stratified per category (<0.1, 0.1 to 1, or >1 mm) [16].

Assessment of the size and extracapsular extension of melanoma in SLNs may provide useful prognostic information. In a study of 1539 SLN-positive melanoma patients, the subcapsular micrometastases <0.1 mm in maximum diameter had the least non-SLN metastases. On the other hand, tumor dimension of >1 mm had the highest rate of non-SLN positivity and diminished disease-free survival [17]. A similar relationship was observed in an earlier study [18]. The "sentinel node invasion level" has also been proposed as a potential prognostic tool, reflecting anatomic extent of infiltration by melanoma through lymph node architecture (capsular/sinus region versus cortex/paracortex versus medulla/capsule) [7,19].

Extrapolating from the prognostic import of tumor-infiltrating lymphocytes of primary melanoma, the significance of the lymphocytic milieu associated with metastatic melanoma deposits within an SLN is also being investigated. Positive correlations between recurrence-free and/or overall survival and the number of CD3+ tumor-infiltrating lymphocytes, the number of CD4+ tumor-infiltrating lymphocytes, and the number of CD8+ tumor-infiltrating lymphocytes were observed [20]. There was a negative correlation with the number of peritumoral programmed cell death receptor 1 (PD-1)+ lymphocytes, but not with programmed cell death ligand 1 (PD-L1) expression. Higher survival rates may be related to lymph node PD-1 expression [21].

IMMUNOHISTOCHEMISTRY — Examination of nodal metastases by hematoxylin and eosin (H&E) staining alone can lead to overdiagnosis or underdiagnosis of metastatic disease, due to hypercellularity of the lymph node and similar staining of melanoma cells with normal lymph node constituent cells. Immunohistochemical staining in conjunction with H&E analysis is used to improve sensitivity and specificity [22-25]. Several antigens have been identified on melanoma cells that are used for diagnostic immunohistochemistry. Because no one single antigen has yet been isolated with 100 percent sensitivity and 100 percent specificity to serve as the ideal "melanoma marker," combinations of immunohistochemical stains are typically employed to balance sensitivity and specificity.

S100 — S100 (100 percent soluble in ammonium sulfate at neutral pH), a calcium-binding protein, is a sensitive marker of melanocyte differentiation [26]. The monoclonal antibody directed against S100 was derived from human melanoma cells, and it targets a 10-kDa cytoplasmic glycoprotein portion of the transmembrane complex [27]. Although highly sensitive, the monoclonal antibody targeting S100 is not specific for melanoma cells, as it stains a variety of other cell types, including benign nevic cells, macrophages, Langerhans cells, adipocytes, chondrocytes, myoepithelial cells, sweat gland cells, and neural-crest-derived cells (eg, Schwann cells, glial cells). Within the lymph node, S100-positive-staining nevic rests and dendritic cells complicate the assessment for melanoma.

MART-1 and Melan-A — Melanoma antigen recognized by T cells 1 (MART-1) and Melan-A antibodies target the product of the MART-1/Melan-A complex, which is a small protein that is expressed in melanomas as well as normal adult melanocytes; it was initially identified as the target for cytotoxic T lymphocytes [28]. Antibodies against Melan-A are immunoreactive against both benign and malignant melanocytic lesions [29]. Anti-Melan-A also reacts with the perivascular smooth muscle cells of lymphangiomyomatosis, the so-called clear cell "sugar" tumor of the lung (a rare, benign perivascular epithelioid cell tumor), renal angiomyolipoma, adrenocortical tumors, as well as sex-cord stromal tumors of the ovary. Because melanomas of spindle cell morphology do not stain with HMB45 (human melanoma black), immunoreactivity with anti-Melan-A is particularly helpful in diagnosing these lesions. While MART-1 positivity within the lymph node is valuable for its high specificity, it should be noted that occasional histiocytes presenting melanocyte antigens may also react to MART-1 antibodies. Although MART-1 expression is not specific for malignant transformation, its expression by micrometastasis in sentinel lymph nodes (SLNs) has been correlated with poorer survival in some studies [30].

HMB45 — The antibody HMB45 reacts with a 10-kDa cytoplasmic glycoprotein that is part of the glycoprotein 100 (gp100) premelanosome complex. In addition to reacting with most melanomas, it is immunoreactive with fetal and neonatal melanocytes, intraepidermal and superficial dermal components of benign nevi, blue nevi, and deep-penetrating nevi. Although HMB45 does not differentiate between benign and malignant melanocytic lesions, staining with HMB45 provides strong evidence of melanocytic histogenesis. In addition, diffuse staining of the deeper dermal components of borderline melanocytic neoplasms is suggestive of melanoma. However, the lack of reactivity with spindle cell melanomas limits its usefulness as an immunohistochemical marker for melanoma.

SOX10 — The nuclear transcription factor Sry-related HMg-Box gene 10 (SOX10) is a useful diagnostic marker for melanoma [31,32]. SOX10 is involved in the generation, survival, and maintenance of the pluripotency of neural crest cells and is commonly expressed in melanomas, including desmoplastic melanomas; SOX10 may also be seen in tumors with Schwann cell differentiation and in some salivary gland neoplasms, particularly those with myoepithelial differentiation [31,33]. The nuclear pattern of its immunostaining facilitates its distinction from cytoplasmic melanin of histiocytes.

Mitf — Microphthalmia transcription factor (Mitf) is another melanoma marker that can be applied to immunohistochemical analysis. Mitf is a transcription regulator of the tyrosinase gene that exhibits highly sensitive and specific immunoreactivity for melanocytic lesions [34], with the exception of desmoplastic melanomas [35]. Although Mitf expression is present in both benign and malignant melanocytic lesions, anti-Mitf immunostaining is often positive in melanomas that fail to react with HMB45 or anti-S100 [36].

The utility of Mitf as a component of a panel of immunostains was shown in a study comparing five antibody markers in 40 patients with melanoma and 32 with nonmelanocytic malignant neoplasms [37]. The sensitivity and specificity of combined testing for Mitf and Melan-A (95 and 100 percent, respectively) were better than that of combined S-100 and HMB45 (80 and 100 percent, respectively).

Tyrosinase — Tyrosinase is a key enzyme in melanin biosynthesis, catalyzing the conversion of tyrosine to dihydroxyphenylalanine (DOPA), and DOPA to dopaquinone. The monoclonal antibody developed against tyrosinase is immunoreactive against normal melanocytes, nevus cells, and melanoma cells. Tyrosinase expression diminishes in higher-stage melanomas, with 100 percent staining in stage I and II lesions but only 86 percent in stage III and IV tumors (table 1A-B) [38].

Other potentially helpful immunohistochemical stains — Other immunohistochemical stains under investigation for their potential value in melanoma detection within SLNs include the neural progenitor cell transcription factor SOX2 and the neural stem/progenitor cell marker nestin [39].

MOLECULAR ANALYSIS — Reverse transcription polymerase chain reaction (RT-PCR) assay for molecular detection of melanoma-specific tumor markers, such as tyrosinase messenger RNA in lymph node tissue, is more sensitive for the detection of occult metastases than routine histology [40-45]. However, the prognostic significance of a positive RT-PCR remains uncertain [46]. Risk stratification may be aided by the expression pattern of two particular genes, with high expression of PIGR (polymeric immunoglobulin receptor) and loss of TFAP2A (transcription factor AP-2 alpha) associated with higher risk [47].

SUMMARY

Lymph node evaluation – Cutaneous melanoma characteristically spreads via the lymphatic system from its primary site to the locoregional lymph nodes. Knowledge of lymph node status provides important information for prognosis and the potential role of adjuvant systemic therapy. (See 'Lymph node evaluation' above and "Evaluation and management of regional nodes in primary cutaneous melanoma", section on 'SLNB timing and technique' and "Evaluation and management of regional nodes in primary cutaneous melanoma".)

Technique – Routine histology with hematoxylin and eosin (H&E) staining remains the gold standard for lymph node analysis. (See 'Technique' above.)

Immunohistochemistry – Immunohistochemistry is an important adjunct to routine histology and can minimize both overdiagnosis and underdiagnosis of metastatic disease in regional lymph nodes. Antibodies directed against S100, melanoma antigen recognized by T cells 1 (MART-1)/Melan-A, HMB45, and SOX10 have proven to be the most useful to date, although newer candidates are currently being evaluated. (See 'Immunohistochemistry' above.)

Molecular analysis – Reverse transcriptase polymerase chain reaction (RT-PCR) for the molecular detection of melanoma-specific tumor markers, such as tyrosinase messenger RNA in lymph node tissue, is even more sensitive for the detection of occult metastases, although its prognostic significance remains uncertain. (See 'Molecular analysis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Martin C Mihm, Jr, MD (deceased), who contributed to earlier versions of this topic review.

  1. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma of the skin. In: AJCC Cancer Staging Manual, 8th ed, Amin MB (Ed), Springer, Chicago 2017. p.563.
  2. Gerami P, Cook RW, Russell MC, et al. Gene expression profiling for molecular staging of cutaneous melanoma in patients undergoing sentinel lymph node biopsy. J Am Acad Dermatol 2015; 72:780.
  3. Swetter SM, Tsao H, Bichakjian CK, et al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol 2019; 80:208.
  4. Stebbins WG, Garibyan L, Sober AJ. Sentinel lymph node biopsy and melanoma: 2010 update Part I. J Am Acad Dermatol 2010; 62:723.
  5. http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2012/SkinMelanoma_12protocol.pdf (Accessed on November 06, 2014).
  6. Yu LL, Flotte TJ, Tanabe KK, et al. Detection of microscopic melanoma metastases in sentinel lymph nodes. Cancer 1999; 86:617.
  7. Cook MG, Massi D, Szumera-Ciećkiewicz A, et al. An updated European Organisation for Research and Treatment of Cancer (EORTC) protocol for pathological evaluation of sentinel lymph nodes for melanoma. Eur J Cancer 2019; 114:1.
  8. Mitteldorf C, Bertsch HP, Zapf A, et al. Cutting a sentinel lymph node into slices is the optimal first step for examination of sentinel lymph nodes in melanoma patients. Mod Pathol 2009; 22:1622.
  9. Lino-Silva LS, Castillo-Medina AL, Salcedo-Hernández RA, García-Pérez L. Exhaustive pathologic work-up in sentinel lymph node biopsy for melanoma: is it necessary? Melanoma Res 2017; 27:116.
  10. Stowman AM, Hickman AW, Gru AA, Slingluff CL Jr. Histopathologic review of negative sentinel lymph node biopsies in thin melanomas: an argument for the routine use of immunohistochemistry. Melanoma Res 2017; 27:369.
  11. Carson KF, Wen DR, Li PX, et al. Nodal nevi and cutaneous melanomas. Am J Surg Pathol 1996; 20:834.
  12. Siroy AE, Aung PP, Torres-Cabala CA, et al. Clinical significance of BRAF V600E mutational status in capsular nevi of sentinel lymph nodes in patients with primary cutaneous melanoma. Hum Pathol 2017; 59:48.
  13. Scolyer RA, Thompson JF, McCarthy SW, et al. Intraoperative frozen-section evaluation can reduce accuracy of pathologic assessment of sentinel nodes in melanoma patients. J Am Coll Surg 2005; 201:821.
  14. Murray CA, Leong WL, McCready DR, Ghazarian DM. Histopathological patterns of melanoma metastases in sentinel lymph nodes. J Clin Pathol 2004; 57:64.
  15. Dewar DJ, Newell B, Green MA, et al. The microanatomic location of metastatic melanoma in sentinel lymph nodes predicts nonsentinel lymph node involvement. J Clin Oncol 2004; 22:3345.
  16. van Akkooi AC, Spatz A, Eggermont AM, et al. Expert opinion in melanoma: the sentinel node; EORTC Melanoma Group recommendations on practical methodology of the measurement of the microanatomic location of metastases and metastatic tumour burden. Eur J Cancer 2009; 45:2736.
  17. van der Ploeg AP, van Akkooi AC, Haydu LE, et al. The prognostic significance of sentinel node tumour burden in melanoma patients: an international, multicenter study of 1539 sentinel node-positive melanoma patients. Eur J Cancer 2014; 50:111.
  18. Debarbieux S, Duru G, Dalle S, et al. Sentinel lymph node biopsy in melanoma: a micromorphometric study relating to prognosis and completion lymph node dissection. Br J Dermatol 2007; 157:58.
  19. Kretschmer L, Mitteldorf C, Hellriegel S, et al. The sentinel node invasion level (SNIL) as a prognostic parameter in melanoma. Mod Pathol 2021; 34:1839.
  20. Kakavand H, Vilain RE, Wilmott JS, et al. Tumor PD-L1 expression, immune cell correlates and PD-1+ lymphocytes in sentinel lymph node melanoma metastases. Mod Pathol 2015; 28:1535.
  21. Alessi C, Scapulatempo Neto C, Viana CR, Vazquez VL. PD-1/PD-L1 and VEGF-A/VEGF-C expression in lymph node microenvironment and association with melanoma metastasis and survival. Melanoma Res 2017; 27:565.
  22. Gibbs JF, Huang PP, Zhang PJ, et al. Accuracy of pathologic techniques for the diagnosis of metastatic melanoma in sentinel lymph nodes. Ann Surg Oncol 1999; 6:699.
  23. Messina JL, Glass LF, Cruse CW, et al. Pathologic examination of the sentinel lymph node in malignant melanoma. Am J Surg Pathol 1999; 23:686.
  24. Prieto VG. Sentinel lymph nodes in cutaneous melanoma: handling, examination, and clinical repercussion. Arch Pathol Lab Med 2010; 134:1764.
  25. Chopra A, Sharma R, Rao UNM. Pathology of Melanoma. Surg Clin North Am 2020; 100:43.
  26. Blessing K, Sanders DS, Grant JJ. Comparison of immunohistochemical staining of the novel antibody melan-A with S100 protein and HMB-45 in malignant melanoma and melanoma variants. Histopathology 1998; 32:139.
  27. Donato R. Functional roles of S100 proteins, calcium-binding proteins of the EF-hand type. Biochim Biophys Acta 1999; 1450:191.
  28. Coulie PG, Brichard V, Van Pel A, et al. A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med 1994; 180:35.
  29. Busam KJ, Chen YT, Old LJ, et al. Expression of melan-A (MART1) in benign melanocytic nevi and primary cutaneous malignant melanoma. Am J Surg Pathol 1998; 22:976.
  30. Hochberg M, Lotem M, Gimon Z, et al. Expression of tyrosinase, MIA and MART-1 in sentinel lymph nodes of patients with malignant melanoma. Br J Dermatol 2002; 146:244.
  31. Willis BC, Johnson G, Wang J, Cohen C. SOX10: a useful marker for identifying metastatic melanoma in sentinel lymph nodes. Appl Immunohistochem Mol Morphol 2015; 23:109.
  32. Tacha D, Qi W, Ra S, et al. A newly developed mouse monoclonal SOX10 antibody is a highly sensitive and specific marker for malignant melanoma, including spindle cell and desmoplastic melanomas. Arch Pathol Lab Med 2015; 139:530.
  33. Ordóñez NG. Value of SOX10 immunostaining in tumor diagnosis. Adv Anat Pathol 2013; 20:275.
  34. King R, Googe PB, Weilbaecher KN, et al. Microphthalmia transcription factor expression in cutaneous benign, malignant melanocytic, and nonmelanocytic tumors. Am J Surg Pathol 2001; 25:51.
  35. Busam KJ, Iversen K, Coplan KC, Jungbluth AA. Analysis of microphthalmia transcription factor expression in normal tissues and tumors, and comparison of its expression with S-100 protein, gp100, and tyrosinase in desmoplastic malignant melanoma. Am J Surg Pathol 2001; 25:197.
  36. King R, Weilbaecher KN, McGill G, et al. Microphthalmia transcription factor. A sensitive and specific melanocyte marker for MelanomaDiagnosis. Am J Pathol 1999; 155:731.
  37. Sheffield MV, Yee H, Dorvault CC, et al. Comparison of five antibodies as markers in the diagnosis of melanoma in cytologic preparations. Am J Clin Pathol 2002; 118:930.
  38. Hofbauer GF, Kamarashev J, Geertsen R, et al. Tyrosinase immunoreactivity in formalin-fixed, paraffin-embedded primary and metastatic melanoma: frequency and distribution. J Cutan Pathol 1998; 25:204.
  39. Chen PL, Chen WS, Li J, et al. Diagnostic utility of neural stem and progenitor cell markers nestin and SOX2 in distinguishing nodal melanocytic nevi from metastatic melanomas. Mod Pathol 2013; 26:44.
  40. Reintgen, DS, Rapaport, et al. Lymphatic mapping and sentinel lymphadenectomy. In: Cutaneous Melanoma, 3rd, Balch, CM, Houghton, AN, Sober, AJ, Soong, SJ (Eds), Quality Medical Publishing, St. Louis 1997.
  41. Bostick PJ, Morton DL, Turner RR, et al. Prognostic significance of occult metastases detected by sentinel lymphadenectomy and reverse transcriptase-polymerase chain reaction in early-stage melanoma patients. J Clin Oncol 1999; 17:3238.
  42. Shivers SC, Wang X, Li W, et al. Molecular staging of malignant melanoma: correlation with clinical outcome. JAMA 1998; 280:1410.
  43. Goydos JS, Ravikumar TS, Germino FJ, et al. Minimally invasive staging of patients with melanoma: sentinel lymphadenectomy and detection of the melanoma-specific proteins MART-1 and tyrosinase by reverse transcriptase polymerase chain reaction. J Am Coll Surg 1998; 187:182.
  44. Li W, Stall A, Shivers SC, et al. Clinical relevance of molecular staging for melanoma: comparison of RT-PCR and immunohistochemistry staining in sentinel lymph nodes of patients with melanoma. Ann Surg 2000; 231:795.
  45. Blaheta HJ, Ellwanger U, Schittek B, et al. Examination of regional lymph nodes by sentinel node biopsy and molecular analysis provides new staging facilities in primary cutaneous melanoma. J Invest Dermatol 2000; 114:637.
  46. Scoggins CR, Ross MI, Reintgen DS, et al. Prospective multi-institutional study of reverse transcriptase polymerase chain reaction for molecular staging of melanoma. J Clin Oncol 2006; 24:2849.
  47. Hao H, Xiao D, Pan J, et al. Sentinel Lymph Node Genes to Predict Prognosis in Node-Positive Melanoma Patients. Ann Surg Oncol 2017; 24:108.
Topic 15868 Version 28.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟