Two patients, with non-small cell lung carcinoma treated with pembrolizumab, developed bilateral diffuse uveal melanocytic proliferation (BDUMP) with interesting histopathological features. The first patient developed a right ciliary body mass concurrently with BDUMP. The globe was enucleated. The ciliary body mass was a mitotically active epithelioid uveal melanoma, invading the trabecular meshwork and peripheral corneal stroma, with over 90% of the cells expressing Cyclin D1 protein. The melanoma showed no chromosome 3 or 8 changes. The background uvea showed diffuse, bland spindle cell melanocytic proliferation with much lower Cyclin D1 expression (around 10%). In the choroid, this population was punctuated by islands of pigmented epithelioid cells, some of which were necrotic. All these islands expressed a high level of Cyclin D1, and some islands expressed nuclear preferentially expressed antigen in melanoma (PRAME). The ciliary body mass, epithelioid cell islands, and the BDUMP all expressed c-Met (the receptor for hepatocyte growth factor [HGF]). The features were those of ciliary body melanoma and choroidal melanoma “tumorlets,” developing on a background of BDUMP. The second patient developed bilateral periocular skin pigmentation following a diagnosis of BDUMP, which when biopsied, showed dermal islands of paraneoplastic perivascular melanocytic cell proliferation. These cells also expressed c-Met protein. These observations implicate the HGF/c-Met axis in the pathogenesis of BDUMP, the uveal melanomas in the ciliary body and choroid in the first patient and the paraneoplastic dermal melanocytic proliferation in the second patient.

Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a paraneoplastic syndrome characterized by hyperplasia of uveal melanocytes, believed to be secondary to a circulating factor, associated with systemic malignancies, the commonest of which are ovarian and lung carcinomas [1-4]. Some of the earlier publications on BDUMP documented that the uveal melanocytes appeared benign [2], but there were several publications that reported cases of BDUMP displaying cytological atypia. These studies postulated a spectrum of histological appearances, judging some as low-grade uveal melanomas [5, 6]. Mucous membrane and skin pigmentation have been described in up to a quarter of cases of BDUMP [7, 8], which can be Peutz-Jeghers-like where the dermal lesions resemble blue-nevi [7-9]. We report 2 cases of BDUMP with unusual intraocular and cutaneous histopathology that suggest a potentially fascinating pathogenic mechanism implicating the hepatocyte growth factor/c-Met axis.

This is a descriptive diagnostic histopathological study of 2 retrospective clinical cases of BDUMP. Consent was obtained from both patients for publication. The study was conducted in line with the World Medical Association Declaration of Helsinki. No specific consent was required from the Sheffield Teaching Hospitals Research Office to undertake this descriptive diagnostic study.

Case 1

A 50-year-old man with a recent diagnosis of lung adenocarcinoma with mediastinal and neck lymphadenopathy was referred to the ocular oncology service with photopsia, loss of peripheral vision, and a right inferior ciliary body mass. The best-corrected visual acuity was 20/30 in each eye. An inferior ciliochoroidal lesion in the right eye was seen, associated with multiple flat pigmented choroidal lesions scattered throughout the right fundus (Fig. 1a). The left eye examination revealed 2 small similar lesions initially thought to be choroidal nevi. On B-scan ultrasonography, the base of the ciliochoroidal lesion was 12 × 10 mm with a thickness of 6.23 mm (Fig. 1b). Trans-scleral incisional biopsy of the lesion was performed, and the histopathology showed atypical epithelioid melanocytes consistent with a uveal melanoma (cytology not shown) and he was offered treatment with enucleation but opted to defer treatment until he completed immunotherapy with pembrolizumab for the advanced lung carcinoma (adenocarcinoma, positive for PD-L1). After 3 months, the visual acuity deteriorated to hand movements (HM) in the right eye and 20/120 in the left eye. He had developed bilateral cataracts and the right ciliochoroidal mass lesion had grown with associated retinal detachment. The left eye had developed multiple new flat pigmented choroidal lesions, scattered throughout the fundus (Fig. 1c, d), resembling to the right eye at presentation. A diagnosis of BDUMP was made with biopsy-suggested uveal melanoma of the right eye. He underwent cataract surgery on the left eye and enucleation of the right eye. Plasmapheresis was considered in an effort to halt the progression of the BDUMP and prevent further vision loss. However, it was deemed not feasible as it would have washed out the pembrolizumab, impairing the efficacy against the systemic disease burden. Unfortunately, the patient passed away 14 months following his initial presentation to the eye clinic. No post-mortem was performed.

Fig. 1.

a–d Case 1. a A wide-field fundus photograph of the right eye at the initial presentation showing a ciliochoroidal mass lesion inferiorly and multiple flat choroidal lesions. b A longitudinal B-scan at 6 o’clock at the initial presentation showing the choroidal lesion with choroidal excavation. The anterior edge of the tumour is not visualized on the B-scan. c A transverse UBM of the left ciliary body at 6 o’clock on the follow-up visit showing multiple ciliary body nodules, in a diffusely thickened ciliary body that was not present on the initial visit. d A wide-field fundus photograph of the left eye showing multiple flat choroidal lesions the majority of which were not present at the initial visit. e–g Case 2. e Anterior segment photograph of the right eye showing a pigmented ciliary body mass lesion extruding through the iris root and a dense cataract. f A wide-field fundus photograph of the left eye at the initial presentation showing multiple flat choroidal lesions. g An external photo of the left eye showing lower eyelid and infraorbital greyish discolouration of the skin. UBM, ultrasound biomicroscopy.

Fig. 1.

a–d Case 1. a A wide-field fundus photograph of the right eye at the initial presentation showing a ciliochoroidal mass lesion inferiorly and multiple flat choroidal lesions. b A longitudinal B-scan at 6 o’clock at the initial presentation showing the choroidal lesion with choroidal excavation. The anterior edge of the tumour is not visualized on the B-scan. c A transverse UBM of the left ciliary body at 6 o’clock on the follow-up visit showing multiple ciliary body nodules, in a diffusely thickened ciliary body that was not present on the initial visit. d A wide-field fundus photograph of the left eye showing multiple flat choroidal lesions the majority of which were not present at the initial visit. e–g Case 2. e Anterior segment photograph of the right eye showing a pigmented ciliary body mass lesion extruding through the iris root and a dense cataract. f A wide-field fundus photograph of the left eye at the initial presentation showing multiple flat choroidal lesions. g An external photo of the left eye showing lower eyelid and infraorbital greyish discolouration of the skin. UBM, ultrasound biomicroscopy.

Close modal

Case 2

A 78-year-old woman was referred to the eye clinic with a 4-year history of reduced vision in the right eye, attributed to cataract. Systemic review revealed a history of chronic productive cough and non-resolving lower respiratory tract infections. She was an ex-smoker. On examination, the acuity was HM on the right and 20/30 on the left. A ciliary body lesion was seen, extruding temporally through the iris root of the right eye (Fig. 1e). There was a dense right cataract preventing fundal examination. Ophthalmoscopy of the left eye revealed multiple flat pigmented choroidal lesions (Fig. 1f). A trans-corneal incisional biopsy of the right ciliary body lesion showed a bland melanocytic spindle cell lesion in which the differential diagnosis offered was BDUMP or uveal melanoma. A computed tomography scan of the chest, abdomen, and pelvis showed a right upper lobe lung mass with distant metastasis (Staging: T4N3M1c). Biopsy of the lung mass confirmed invasive squamous carcinoma (positive for PD-L1), and the ocular diagnosis was revised to BDUMP. The patient received systemic chemotherapy and pembrolizumab. The ciliary body mass was stable over 6 months of close observation. In this time, she developed bilateral periocular greyish skin pigmentation (Fig. 1g). She underwent cataract extraction and incisional punch biopsy of the pigmented periocular skin (left lower eyelid).

All biopsy material was fixed in 10% buffered formalin for at least 24 h, processed to paraffin wax blocks and 4-micron sections cut and stained with haematoxylin and eosin. The following antibodies were used to stain the sections in this study: Cyclin D1 (Dako, Copenhagen, Denmark; Clone EPU2., ready to use antibody, OMNIS-Dako platform); BAP1 (Santa Cruz InSite Biotechnology, Dallas, TX, USA, clone C4; 1:400, Dako AS48 Link platform); Melan A (Dako, Clone A103, ready to use antibody OMNIS-Dako platform); HMB45 (Dako, clone HMB45, ready to use antibody, OMNIS-Dako platform); CD117 (Dako, clone CD117, diluted 1:50, Dako AS48 Link platform); Ki67 (Dako, clone MIB1, ready to use antibody, OMNIS-Dako platform); Beta-catenin (Dako , Clone beta-catenin 1, ready to use antibody ONMIS-Dako platform); Preferentially expressed antigen in melanoma (PRAME) (Abcam, Cambridge, MA, USA, clone EPR20330, 1:50 dilution, Leica-Bond III automated immunostainer [Leica Microsystems, Bannockburn, IL, USA]); and c-Met (prediluted antibody, clone SP44 Ventana #790-Leica-Bond III Autostainer platform). Fluorescence in situ hybridization was carried out using probes to chromosome 3 and 8 as previously described [10].

Case 1 Histopathology

The ciliary body lesion comprised atypical amelanotic epithelioid melanocytic cells with prominent nucleoli, arranged as clones, around which were periodic acid Schiff positive matrix patterns. There were 6 mitotic figures per 40 high power fields (×40 lens Olympus BX51). Focal necrosis was seen and there was invasion of the trabecular meshwork and peripheral corneal stroma (Fig. 2a–d) The rest of the uveal tract contained amelanotic, bland, spindle melanocytic cells, in which mitotic figures were absent (Fig. 2e–h). This latter proliferation respected the iris and choroidal vasculature. Amongst the bland, spindle melanocytic proliferation, were well-defined islands of pigmented atypical epithelioid cells in the posterior choroid, some of which were necrotic (Fig. 3a, b). Immunohistochemistry showed that over 90% of the cells in the ciliary body lesion and the pigmented choroidal epithelioid islands expressed Cyclin D1 (Fig. 3c–e). This was in sharp contrast to the very low expression in the uveal bland spindle melanocytic cells (up to 10% of cell positive) (Fig. 3f). BAP1 nuclear expression was retained in all of the uveal melanocytic cells (not shown). Fluorescence in situ hybridization showed no changes in chromosome 3 and 8 in the ciliary body mass, the pigmented choroidal epithelioid islands or the bland uveal amelanotic spindle cell proliferation. PRAME immunohistochemistry showed no expression in the ciliary body lesion or in the bland uveal spindle cell proliferation but was expressed by some of the pigmented choroidal epithelioid cell islands. When present, all the epithelioid cells in the island expressed PRAME (Fig. 3g). Immunohistochemistry for c-Met showed expression in the cytoplasm of the melanocytic cells of the ciliary body lesion, the posterior pigmented choroidal epithelioid islands and the bland uveal spindle cell proliferation (Fig. 3h). Staining of a normal eye control showed faint positivity of normal choroidal melanocytes and staining of another uveal melanoma showed positive staining (not shown). The ciliary body tumour was sampled fresh at the time of enucleation for whole-genome sequencing (as part of the UK 100,000 genome project), but, the DNA was of suboptimal quality so whole-genome sequencing was not performed. In summary, the histological and immunohistochemical features weighed heavily in favour of a ciliary body melanoma of epithelioid type, occurring on a background of BDUMP (the bilateral designation is based on the clinical picture which showed identical bilateral lesions in the uveal tract). Furthermore, we propose that the BDUMP was punctuated by multifocal pigmented epithelioid uveal melanoma “tumorlets,” based on their atypical epithelioid cytology, high expression of Cyclin D1, necrosis and some expressing PRAME protein.

Fig. 2.

a H&E stained enucleation showing the dome-shaped ciliary body melanoma. The posterior part was sampled prior to fixation. b H&E: higher power of the ciliary body mass showing mitotic figures (arrow), amongst atypical epithelioid melanoma cells. c PAS stain showing the networks and loops pattern of extracellular matrix deposition around the tumour clones of the ciliary body mass. d H&E showing invasion of the peripheral corneal stroma by the ciliary body melanoma. e H&E showing BDUMP involving the iris. f H&E showing BDUMP involving the choroid with some central pigmentation. g H&E: higher power of the iris BDUMP showing the bland melanocytic cells respecting the iris vasculature. h H&E: higher power of the choroidal BDUMP showing the bland spindle melanocytic cells. BDUMP, bilateral diffuse uveal melanocytic proliferation; H&E, haematoxylin and eosin; PAS, periodic acid Schiff.

Fig. 2.

a H&E stained enucleation showing the dome-shaped ciliary body melanoma. The posterior part was sampled prior to fixation. b H&E: higher power of the ciliary body mass showing mitotic figures (arrow), amongst atypical epithelioid melanoma cells. c PAS stain showing the networks and loops pattern of extracellular matrix deposition around the tumour clones of the ciliary body mass. d H&E showing invasion of the peripheral corneal stroma by the ciliary body melanoma. e H&E showing BDUMP involving the iris. f H&E showing BDUMP involving the choroid with some central pigmentation. g H&E: higher power of the iris BDUMP showing the bland melanocytic cells respecting the iris vasculature. h H&E: higher power of the choroidal BDUMP showing the bland spindle melanocytic cells. BDUMP, bilateral diffuse uveal melanocytic proliferation; H&E, haematoxylin and eosin; PAS, periodic acid Schiff.

Close modal
Fig. 3.

a H&E showing one of the pigmented epithelioid islands amongst the choroidal BDUMP. The atypical pigmented epithelioid melanoma cells lie above the bland BDUMP melanocytic cells (BDUMP = asterisk). b H&E showing central necrosis amongst the pigmented epithelioid melanoma cells. c Cyclin D1 immunohistochemistry showing 2 distinct zones. The ciliary body melanoma is to the left and the iris BDUMP to the right. d, e Are at the same magnification and show Cyclin D1 immunohistochemistry for the ciliary body melanoma (d) and the adjacent BDUMP (e). Note the much higher expression in the ciliary body melanoma compared to the BDUMP (brown = positive). f Cyclin D1 immunohistochemistry on the pigmented epithelioid islands showing high expression compared to the BDUMP present bottom right (brown = positive). g PRAME immunohistochemistry showing expression in the pigmented epithelioid islands (red = positive). The BDUMP towards the bottom right does not stain. h c-Met immunohistochemistry of the BDUMP showing positive cytoplasmic staining (brown = positive). BDUMP, bilateral diffuse uveal melanocytic proliferation; H&E, haematoxylin and eosin.

Fig. 3.

a H&E showing one of the pigmented epithelioid islands amongst the choroidal BDUMP. The atypical pigmented epithelioid melanoma cells lie above the bland BDUMP melanocytic cells (BDUMP = asterisk). b H&E showing central necrosis amongst the pigmented epithelioid melanoma cells. c Cyclin D1 immunohistochemistry showing 2 distinct zones. The ciliary body melanoma is to the left and the iris BDUMP to the right. d, e Are at the same magnification and show Cyclin D1 immunohistochemistry for the ciliary body melanoma (d) and the adjacent BDUMP (e). Note the much higher expression in the ciliary body melanoma compared to the BDUMP (brown = positive). f Cyclin D1 immunohistochemistry on the pigmented epithelioid islands showing high expression compared to the BDUMP present bottom right (brown = positive). g PRAME immunohistochemistry showing expression in the pigmented epithelioid islands (red = positive). The BDUMP towards the bottom right does not stain. h c-Met immunohistochemistry of the BDUMP showing positive cytoplasmic staining (brown = positive). BDUMP, bilateral diffuse uveal melanocytic proliferation; H&E, haematoxylin and eosin.

Close modal

Case 2 Histopathology

The intraocular biopsy showed a bland population of spindle cells with no mitotic activity and with some faint melanin pigment. The population was positive for Melan A (Fig. 4a, b). The periocular skin biopsy showed superficial and deep dermal, variably sized, well-defined nests of bland amelanotic nevoid-like melanocytes, with eosinophilic cytoplasm and non-atypical ovoid/ellipsoid nuclei, with some variation in nuclear size. No mitotic figures were identified (Fig. 4c, d). All the nests were concentrated around blood vessels (Fig. 4e). The nests were positive for Melan A (Fig. 4f) and negative for HMB45, CD117, Ki67, Cyclin D1, and beta-catenin. c-Met was expressed in the cytoplasm of these cells (Fig. 4g). The background epidermal melanocytes were negative. The features were those of paraneoplastic dermal melanocytic hyperplasia, in the context of BDUMP, in a highly unusual bilateral periocular distribution.

Fig. 4.

a H&E of the intraocular biopsy showing bland spindle cells suggestive of BDUMP. b Melan A immunohistochemistry of the intraocular biopsy showing positivity (red = positive). c Low power H&E showing well-defined nodules in the dermis (arrows). d H&E: higher power of plate c showing bland melanocytic cells. e H&E: the bland melanocytic cells (asterisk) are centred around blood vessels (arrows). f The bland melanocytic nests are immunohistochemically positive for Melan A (brown = positive). Note the blood vessel toward the left in negative profile. g c-Met immunohistochemistry showing staining of the melanocytic nests (brown = positive). BDUMP, bilateral diffuse uveal melanocytic proliferation; H&E, haematoxylin and eosin.

Fig. 4.

a H&E of the intraocular biopsy showing bland spindle cells suggestive of BDUMP. b Melan A immunohistochemistry of the intraocular biopsy showing positivity (red = positive). c Low power H&E showing well-defined nodules in the dermis (arrows). d H&E: higher power of plate c showing bland melanocytic cells. e H&E: the bland melanocytic cells (asterisk) are centred around blood vessels (arrows). f The bland melanocytic nests are immunohistochemically positive for Melan A (brown = positive). Note the blood vessel toward the left in negative profile. g c-Met immunohistochemistry showing staining of the melanocytic nests (brown = positive). BDUMP, bilateral diffuse uveal melanocytic proliferation; H&E, haematoxylin and eosin.

Close modal

The original histological description of BDUMP by Barr et al. [2] documented bilateral uveal benign spindle cell melanocytic proliferations, secondary to a variety of systemic carcinomas. However, re-examination of the figures in the paper, demonstrate islands of cytologically atypical epithelioid cells, with associated necrosis. Subsequently, Mullaney et al. [5] and Margo et al. [6] also recorded bilateral cases where the histology was indistinguishable from mixed cell uveal melanomas.

Despite the lack of genetic changes in the ciliary body lesion and the choroidal tumourlets, the expression of PRAME in some of the tumourlets, taken with the cytology, would support their malignant designation. PRAME mRNA is expressed in uveal melanoma [11], is a marker for metastatic risk in uveal melanoma [12, 13] and is also part of a 12-gene prognostic assay for uveal melanoma [12]. It is also very useful in distinguishing benign skin melanocytic lesions (absent PRAME staining) from malignant melanoma (positive nuclear PRAME staining) [14]. An alternative interpretation is that the enucleation specimen simply contained a diffuse mixed cell uveal melanoma with spindle and epithelioid areas. However, the bland spindle cells, with a non-destructive/non-invasive pattern and the clinical bilateral presentation support BDUMP being present.

The development of multifocal uveal melanoma in BDUMP is not surprising. Hyperplasia is fertile territory for neoplasia development and in this example, may be via an alternative genetic pathway, as opposed to the well-established GNAQ/GNA11 pathway that causes the transformation of uveal nevi to uveal melanoma. Niffenegger et al. [15] recently noted that a case of BDUMP was associated with raised serum HGF levels and the authors proposed that the high levels were attributable to production by the lung carcinoma and by the patient being on tyrosine-kinase inhibitors and immune checkpoint inhibitors. HGF is an important mitogen for melanocytes and exerts its effects via the c-Met receptor [16, 17]. With this in mind, we stained our case with c-Met and found expression within the cytoplasm of the BDUMP melanocytes, the ciliary body melanoma and the choroidal tumourlets, raising the possibility that the normal uveal melanocyte to BDUMP to melanoma transition may be driven by HGF. This could either be autocrine (HGF being produced by the melanocytic cells) or a paracrine effect (HGF produced by the lung carcinoma) possibly enhanced by the pembrolizumab immune checkpoint therapy [13]. The HGF/c-Met axis is a key tumour-promoting factor in the tumour microenvironment [18]. HGF, synthesized and secreted by tumour cells and stromal fibroblasts and acting via c-Met receptor, promotes epithelial-to-mesenchymal transition, proliferation, migration, invasion, and survival of tumour cells [18]. Non-small cell lung carcinoma is known to produce HGF [19, 20], with high serum HGF levels thought to confer a worse prognosis [21].

Recently, it has been shown that resistance to immune checkpoint inhibition therapy (in this case pembrolizumab) is associated with elevated serum cytokines, including HGF levels [22]. Clinically, the patient’s non-small cell lung carcinoma did not respond favourably to pembrolizumab; this was associated with BDUMP development in the contralateral eye and an increase in the ciliary body melanoma size. The clinical course of the disease could suggest a possible role of HGF acting in a paracrine manner via c-Met receptors to trigger BDUMP and subsequent melanoma development, through chronic c-Met signalling. These tie in with the observations of the previous case report implicating this mechanism [15].

In the second case, the clinical scenario was similar, with the patient receiving pembrolizumab for advanced non-small cell lung carcinoma. The histology from the right intraocular biopsy showed a bland spindle cell melanocytic lesion which was consistent with BDUMP, in the clinical context, although uveal melanoma could not be excluded. The periocular skin biopsy showed dermal perivascular melanocyte hyperplastic nodules. These melanocytes showed expression of c-Met, implicating the HGF/c-Met axis in the hyperplasia of these melanocytes. Their distribution around dermal blood vessels strongly implies response to a circulating factor and also suggests possible nests of perivascular dermal melanocytes. Non-ocular BDUMP-associated melanocytic proliferations have been well documented in the literature [7-9]. Up to 25% of cases may be associated with non-ocular lesions that can affect oral and genital mucosa and the skin [7]. Their nomenclature has attracted a variety of acronyms such as bilateral diffuse uveal and focal dermal melanocytic proliferation [9] and diffuse integumentary melanocytic proliferation. It appears that previous workers may have missed the observation that we have noted of the melanocytic hyperplastic nests centred on small blood vessels. It is possible that the early phase of the dermal melanocytic proliferation was captured in our case, as this patient was biopsied promptly, after the appearance of the periocular skin pigmentation. Given this, we would like to propose a mechanistic acronym of “PPDeMP”-standing for “paraneoplastic perivascular dermal melanocytic proliferation,” which incorporates the physiological significance of the distribution of the melanocytic proliferation (i.e., as a possible response to circulating HGF).

This study has some limitations. We were unable to assay the levels of HGF in the serum of both patients as this highly specialized assay was not available locally. Secondly, we were unable to stain the lung tumours from both cases with HGF as this antibody was not available locally. Thirdly, the intraocular biopsy from Case 2 that showed the suspected BDUMP we were unable to stain with antibodies to c-Met and perform genetic analysis on because the material was very sparse and had been exhausted from the paraffin block.

Despite the above limitations, this study has demonstrated, in summary:

•That multifocal uveal melanomas can develop in the setting of BDUMP and that this may develop via a hyperplasia-to-neoplasia pathway, via a mechanism that could be independent of the nevus-to-melanoma pathway.

•That the above progression may be due to the chronic activation of the HGF/c-Met pathway, as demonstrated by the expression of c-Met on the BDUMP and multifocal melanomas.

•Paraneoplastic perivascular dermal melanocytic proliferations are centred on blood vessels suggesting that a circulating factor is responsible for the melanocyte hyperplasia.

•Paraneoplastic perivascular dermal melanocytic proliferations, like BDUMP, express c-Met receptors implicating the HGF/c-Met axis in its pathogenesis.

The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. No specific ethical approval was required from our Sheffield Teaching Hospitals NHS Research Office as they deemed this paper as a retrospective description of routine diagnostically worked up cases and not research. Written consent was obtained from the patient or their next of kin if the patient had deceased.

The authors have no conflicts of interest to declare.

No specific funding was required for this study.

Dr. Hardeep Singh Mudhar wrote the manuscript and did the diagnostic histopathology on both cases with all histopathology image preparation. Dr. Bashar M. Bata wrote the clinical aspects of the paper and edited the text. Ms. Hibba Quhill contributed clinical data and edited the manuscript. Dr. Tatyana Milman performed the c-Met immunohistochemistry and provided interpretation of this data and edited the manuscript. Dr. Sachin M. Salvi contributed clinical data and edited the text.

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.

1.
Machemer
R
.
[On the pathogenesis of the flat malignant melanoma]
.
Klin Monbl Augenheilkd
.
1966
;
148
(
5
):
641
52
.
2.
Barr
CC
,
Zimmerman
LE
,
Curtin
VT
,
Font
RL
.
Bilateral diffuse melanocytic uveal tumors associated with systemic malignant neoplasms. A recently recognized syndrome
.
Arch Ophthalmol
.
1982 Feb
;
100
(
2
):
249
55
.
3.
Miles
SL
,
Niles
RM
,
Pittock
S
,
Vile
R
,
Davies
J
,
Winters
JL
,
A factor found in the IgG fraction of serum of patients with paraneoplastic bilateral diffuse uveal melanocytic proliferation causes proliferation of cultured human melanocytes
.
Retina
.
2012
;
32
(
9
):
1959
66
. .
4.
Jansen
JC
,
Van Calster
J
,
Pulido
JS
,
Miles
SL
,
Vile
RG
,
Van Bergen
T
,
Early diagnosis and successful treatment of paraneoplastic melanocytic proliferation
.
Br J Ophthalmol
.
2015
;
99
(
7
):
943
8
. .
5.
Mullaney
J
,
Mooney
D
,
O’Connor
M
,
McDonald
GS
.
Bilateral ovarian carcinoma with bilateral uveal melanoma
.
Br J Ophthalmol
.
1984
;
68
:
261
7
. .
6.
Margo
CE
,
Pavan
PR
,
Gendelman
D
,
Gragoudas
E
.
Bilateral melanocytic uveal tumors associated with systemic non-ocular malignancy. Malignant melanomas or benign paraneoplastic syndrome?
Retina
.
1987
;
7
(
3
):
137
41
. .
7.
Gass
JD
,
Glatzer
RJ
.
Acquired pigmentation simulating Peutz-Jeghers syndrome: initial manifestation of diffuse uveal melanocytic proliferation
.
Br J Ophthalmol
.
1991
;
75
(
11
):
693
5
. .
8.
O’Neal
KD
,
Butnor
KJ
,
Perkinson
KR
,
Proia
AD
.
Bilateral diffuse uveal melanocytic proliferation associated with pancreatic carcinoma: a case report and literature review of this paraneoplastic syndrome
.
Surv Ophthalmol
.
2003 Nov–Dec
;
48
(
6
):
613
25
.
9.
Pulido
JS
,
Flotte
TJ
,
Raja
H
,
Miles
S
,
Winters
JL
,
Niles
R
,
Dermal and conjunctival melanocytic proliferations in diffuse uveal melanocytic proliferation
.
Eye
.
2013
;
27
:
1058
62
. .
10.
Mudhar
HS
,
Saunders
E
,
Rundle
P
,
Rennie
IG
,
Sisley
K
.
The in vivo modulatory effects of an anterior-chamber microenvironment on uveal melanoma
.
Br J Ophthalmol
.
2009
;
93
(
4
):
535
40
. .
11.
Sanchez
MI
,
Field
MG
,
Kuznetsov
JN
,
Kurtenbach
S
,
Pham
D
,
Harbour
JW
.
The role of PRAME in promoting uveal melanoma metastasis [abstract]
. Proceedings of the American association for cancer research annual meeting 2017. Washington, DC.
Philadelphia, PA
:
AACR
;
Cancer Res
.
2017
;
77
(
13 Suppl l
):
4861
.
12.
Field
MG
,
Decatur
CL
,
Kurtenbach
S
,
Gezgin
G
,
Van der Velden
PA
,
Jager
MJ
,
PRAME as an independent biomarker for metastasis in uveal melanoma
.
Clin Cancer Res
.
2016
;
22
:
1234
42
. .
13.
Field
MG
,
Durante
MA
,
Decatur
CL
,
Tarlan
B
,
Oelschlager
KM
,
Stone
JF
,
Epigenetic reprogramming and aberrant expression of PRAME are associated with increased metastatic risk in class 1 and class 2 uveal melanomas
.
Oncotarget
.
2016
;
7
:
59209
19
. .
14.
Lezcano
C
,
Jungbluth
AA
,
Nehal
KS
,
Hollmann
TJ
,
Busam
KJ
.
PRAME expression in melanocytic tumors
.
Am J Surg Pathol
.
2018
;
42
(
11
):
1456
65
. .
15.
Niffenegger
JH
,
Soltero
A
,
Niffenegger
JS
,
Yang
S
,
Adamus
G
.
Prevalence of hepatocyte growth factor and autoantibodies to α-HGF as a new etiology for bilateral diffuse uveal melanocytic proliferation masquerading as neovascular age-related macular degeneration
.
J Clin Exp Ophthalmol
.
2018
;
9
(
4
):
740
. .
16.
McGill
GG
,
Haq
R
,
Nishimura
EK
,
Fisher
DE
.
c-Met expression is regulated by Mitf in the melanocyte lineage
.
J Biol Chem
.
2006
;
281
:
10365
73
. .
17.
Kos
L
,
Aronzon
A
,
Takayama
H
,
Maina
F
,
Ponzetto
C
,
Merlino
G
,
Hepatocyte growth factor/scatter factor-MET signaling in neural crest-derived melanocyte development
.
Pigment Cell Res
.
1999
;
12
:
13
21
. .
18.
Owusu
BY
,
Galemmo
R
,
Janetka
J
,
Klampfer
L
.
Hepatocyte growth factor, a key tumor-promoting factor in the tumor microenvironment
.
Cancers
.
2017
;
9
(
4
):
35
. .
19.
Tsao
MS
,
Yang
Y
,
Marcus
A
,
Liu
N
,
Mou
L
.
Hepatocyte growth factor is predominantly expressed by the carcinoma cells in non-small-cell lung cancer
.
Hum Pathol
.
2001 Jan
;
32
(
1
):
57
65
.
20.
Kanaji
N
,
Yokohira
M
,
Nakano-Narusawa
Y
,
Watanabe
N
,
Imaida
K
,
Kadowaki
N
,
Hepatocyte growth factor produced in lung fibroblasts enhances non-small cell lung cancer cell survival and tumor progression
.
Respir Res
.
2017
;
18
(
1
):
118
. .
21.
Hosoda
H
,
Izumi
H
,
Tukada
Y
,
Takagiwa
J
,
Chiaki
T
,
Yano
M
,
Plasma hepatocyte growth factor elevation may be associated with early metastatic disease in primary lung cancer patients
.
Ann Thorac Cardiovasc Surg
.
2012
;
18
(
1
):
1
7
. .
22.
Costantini
A
,
Takam Kamga
P
,
Julie
C
,
Corjon
A
,
Dumenil
C
,
Dumoulin
J
,
Plasma biomarkers screening by multiplex ELISA assay in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors
.
Cancers
.
2020
;
13
(
1
):
97
. .
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