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Melanoma

Melanoma Summary

Epidemiology:

Malignant melanoma is recognized as one of the most aggressive forms of skin cancer, with an estimated 99,780 new cases projected in the United States for 2022 1. It poses a significant challenge not only due to its rapid metastatic potential but also because it accounts for a large proportion of skin cancer deaths, making effective treatment a pressing concern 2. Despite the concerning statistics associated with melanoma, spontaneous remission (SR) has been documented, albeit infrequently, in this malignancy 3. Reports indicate that complete spontaneous regression can occur in a range of 10-35% of cases characterized by primary melanoma; however, this phenomenon becomes exceedingly uncommon in metastatic scenarios 4.

Clinical Characteristics:

To date, there have been 30 reported cases of SR of either primary or metastatic melanoma. Several clinical trends can be observed among these cases. The patients’ ages at the time of remission ranged from 22 to 83 years, with a peak incidence between 50 and 70 years of age. Males exhibited slightly higher rates of SR than females (approximately 1.3:1). Most remissions occurred in cutaneous melanomas, although cases involving ocular (choroidal) and mucosal sites were also documented. See table 1 below for further information.

Histological Characteristics:

Patients who experienced SR of melanoma typically presented with advanced or metastatic disease, often involving cutaneous, ocular, or visceral sites such as the liver, lungs, and lymph nodes. The diagnosis was established through histopathological confirmation of malignant melanocytic cells in primary or metastatic lesions. In most cases, the primary sites were cutaneous regions of the extremities or trunk, with occasional involvement of the choroid, conjunctiva, and mucosal surfaces. Remission was characterized by partial or complete disappearance of measurable lesions, as verified by clinical examination, imaging, or histologic regression of tumor tissue. Several patients exhibited durable remission or prolonged disease stability without therapeutic intervention, far exceeding the expected prognosis for untreated malignant melanoma.

Proposed Contributing Mechanisms:

Various mechanisms have been proposed to explain SR in melanoma. The most frequently reported involve immune-mediated activation, often triggered by infection, surgical intervention, or tissue injury such as biopsy or trauma. Additional contributing factors included postoperative inflammation, autoimmune responses, and immune modulation following systemic stress or emotional events. In some instances, local factors such as tumor necrosis or ischemia were suggested to contribute to tumor regression. In contrast, others proposed an abscopal or immunologic “bystander” effect induced by immune recognition of melanoma antigens. These observations suggest that spontaneous remission in melanoma likely results from a combination of host immune reactivity and localized tumor-destructive processes rather than a single causative event.

Site and extent of regressions:

Most (28/30) SR events represented complete remissions, with only a few cases showing partial or site-specific tumor resolution. In several patients, remission occurred concurrently in primary and metastatic lesions, including cutaneous, lymphatic, and visceral sites such as the liver and lungs. Remission of metastatic deposits alone was documented in a subset of cases, most frequently involving lymph nodes or hepatic tissue. The duration of follow-up among reported cases ranged widely from a few weeks to over 16 years, with many patients maintaining long-term disease stability or survival exceeding typical prognostic expectations for metastatic melanoma.

Table 1: Melanoma SR Cases and Clinical Characteristics

Author–year

Age/sex

Primary site

Remission site

Proposed mechanisms

Follow-up

Chong et al., 198920

66/M

Choroid

Right eye

Not reported

8 years

Daland et al., 19395

43/M

Skin (toe)

Thigh

Not reported

6 years

Malleson, 19556

22/M

Not reported

Lymph nodes

Not reported

6 years

Pelner, 19607

Not reported

Skin

Not specified

Immune stimulation

Not reported

Baker, 19648

46/M

Ear

Neck

Host immune response

6 years

Reese et al., 19709

Not reported

Choroid

Not reported

Immunological response

Not reported

Doyle et al., 197310

65/M

Skin (cheek)

Skin (cheek)

Not reported

3 years

Scheffer et al., 197311

68/F

Choroid

Not reported

Not reported

Not reported

Scheffer et al., 197311

46/M

Choroid

Not reported

Not reported

Not reported

Bulkley et al., 197512

58/F

Skin

Liver

Host immunity

12 years

Sindelar et al., 197613

38/F

Skin

Right thigh and liver

Postoperative infection

16 years

Bodurtha et al., 197614

74/M

Skin (chest wall)

Skin (chest wall)

Immunologic response

Not reported

Nathanson, 197615

Not reported

Skin

Cutaneous, lymphatic, pulmonary, hepatic

Immunologic factors

Not reported

McCarthy et al., 197816

62/F

Skin

Left groin, thigh

Immune-stimulating event

3 months

Mikhail & Gorsulowsky, 198617

77/F

Face

lymph nodes, lungs

Not reported

6 years

Hogan et al., 198818

25/F

Skin

Skin

Immune response

Not reported

Miller et al., 201419

75/F

Conjunctiva (left lower fornix)

Conjunctiva (left lower fornix)

Immunologic reaction to biopsy

6 years

Bramhall et al., 201420

Not reported

Skin (left leg)

Skin (left leg)

Not reported

9 years

Bramhall et al., 201420

Not reported

Occult

Liver, spleen, and peritoneal metastases

Not reported

3 months

Bramhall et al., 201420

Not reported

Skin (dorsum of foot)

Lymph nodes

Not reported

5 years

Bramhall et al., 201420

Not reported

Right thigh (skin)

Right groin lymph nodes

Not reported

7 months

Bramhall et al., 201420

F

Right medial calf

Lung and subcutaneous metastases

Emotional factors

15 months

Bramhall et al., 201420

F

Right hip

lymph nodes

Immune-related abscopal effect

2 years

Ong et al., 201521

83/M

Skin

Lung

Not reported

8 months

Yamada et al., 201622

65/M

Skin (right sole of foot)

Skin (right sole of foot)

Not reported

2 years

Schlabe et al., 201823

75/M

Mandible, skin

Mandible

Immunological response

3 months

Behnia et al., 201824

55/F

Lung

Left lower lobe

Biopsy-induced inflammation

43 days

Schlabe et al., 201825

75/M

Skin

Mandible

Biopsy-induced immune response

3 months

Koibuchi et al., 202326

40/M

Skin

Subcutaneous tissue

Biopsy-induced inflammation

Not reported

Arjunan, 202127

65-year-old female

Liver

Before treatment was initiated, she showed a spontaneous decrease in serum AFP to 250 ng/mL. Magnetic resonance imaging (MRI) showed complete involution of both the primary tumor and the portal vein tumor thrombus.

specific mechanisms of immune surveillance. host immune responses can at times successfully target HCC

Before treatment was initiated, she showed a spontaneous decrease in serum AFP to 250 ng/mL. Magnetic resonance imaging (MRI) showed complete involution of both the primary tumor and the portal vein tumor thrombus.

Gaylord & Clowes et al., 190628

spontaneous recovery

immune responses that are antagonistic to cancer

spontaneous recovery

Hula, 197629

It can be supposed that in this area the skin may develop quite a normal appearance. In the histological picture there is a series of changes, none of which are necessarily typical for spontaneous regression. Some of these changes were found in all cases (obligatory), some only in several cases (facultative).

The cause of the spontaneous regression of the primary melanoblastoma of the skin is not known.

It can be supposed that in this area the skin may develop quite a normal appearance. In the histological picture there is a series of changes, none of which are necessarily typical for spontaneous regression. Some of these changes were found in all cases (obligatory), some only in several cases (facultative).

Rampen, 197930

A 37-year-old male

The patient has been free of disease for more than 15 years

The patient has been free of disease for more than 15 years

Sroujieh, 198831

55-year-old male

Alive 8 years after diagnosis without evidence of malignancy

Alive 8 years after diagnosis without evidence of malignancy

Fedoreev, 198032

Of the 2292 in the no treatment group, 95.9% of the true capillary hemangiomas of the skin disappeared. Subcutaneous hemangiomas regressed somewhat less often; in 81.3% of the cases.

Of the 2292 in the no treatment group, 95.9% of the true capillary hemangiomas of the skin disappeared. Subcutaneous hemangiomas regressed somewhat less often; in 81.3% of the cases.

Miller et al.33

Bramhall et al.34

Arpaia et al., 200635

Cecchi et al., 200836

Ducic, 200237

Dunn et al., 200838

Emanuel et al., 200839

Fontaine et al., 200340

Inoue et al., 200741

Kalialis et al., 200942

Kamino et al., 201043

Kaur et al., 200844

King et al., 200145

King et al., 200946

Liszkay et al., 200547

McKay et al., 201148

Michael et al., 200749

Muniesa et al., 200950

Ng et al., 200651

Oni et al., 200952

Pizzichetta et al., 200653

Printz, 200154

Saleh et al., 200555

Saleh et al., 200356

Satzger et al., 200657

Valenzano Menada et al., 201058

Wenzel et al., 200559

Zalaudek et al., 200460

Zoller et al., 201061

Caminal et al., 201162

Cui et al., 200463

Dissemond et al., 200364

Dissemond et al., 200364

Hu et al., 200965

Jaganjac et al., 200866

Pathak et al., 200067

Rambow et al., 200868

Rambow et al., 200868

Krebbers et al.69

Paolino et al.70

Schlabe et al.71

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  66. Jaganjac, M., Poljak-Blazi, M., Zarkovic, K., Schaur, R. J., & Zarkovic, N. (2008). The involvement of granulocytes in spontaneous regression of walker 256 carcinoma. Cancer Letters, 260(1-2), 180-186. doi:10.1016/j.canlet.2007.10.039
  67. Pathak, S., Multani, A. S., McConkey, D. J., Imam, A. S., & Amoss, M. S.,Jr. (2000). Spontaneous regression of cutaneous melanoma in sinclair swine is associated with defective telomerase activity and extensive telomere erosion. International Journal of Oncology, 17(6), 1219-1224.
  68. Rambow, F., Malek, O., Geffrotin, C., Leplat, J. J., Bouet, S., Piton, G., . . . Vincent-Naulleau, S. (2008). Identification of differentially expressed genes in spontaneously regressing melanoma using the MeLiM swine model. Pigment Cell & Melanoma Research, 21(2), 147-161. doi:10.1111/j.1755-148X.2008.00442.x
  69. Krebbers I., Kunst H., Baijens L., Hout M., & Waterval J. Spontaneous regression of a middle ear melanoma. Otology & Neurotology. 2021;42(10):e1572-e1576
  70. Paolino G , Rizzo N , Pampena R , et al. Spontaneous regression of primary melanoma and multiple melanocytic nevi in a patient with metastatic melanoma. Dermatol Pract Concept. 2020:e2020052
  71. Schlabe, J., Shah, K. A., Sheerin, F., Payne, M. J., & Fasanmade, A. A. Complete spontaneous regression of a metastatic melanoma of the mandible: a case report and follow-up recommendations. Internat
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