Bilateral diffuse melanocytic uveal proliferation (B-DUMP) with multifocal diffuse integumentary and mucosal melanocytic proliferation (DIMP) paraneoplastic syndrome: A case report

Abstract

Bilateral diffuse uveal melanocytic proliferation (B-DUMP) is a rare paraneoplastic syndrome typically presenting with bilateral visual loss. B-DUMP is associated with extraocular systemic malignancies with the most common being lung cancer in males, and uro-gynecological cancer in females (mainly ovarian cancer). Cutaneous and/or mucosal involvement in patients with B-DUMP has been reported but it is not well characterized. Herein we present a female in her 70s with diagnosis of stage IV vaginal clear cell carcinoma and unknown primary cutaneous and non-cutaneous melanoma that developed progressive bilateral loss of visual acuity compatible with ‘B-DUMP’. Simultaneously, she developed multifocal bilateral bluish-greyish patches on the skin that were shown to have a proliferation of dermal melanocytes. We propose that the clinical and histopathologic cutaneous findings seen in patients with B-DUMP termed ‘diffuse integumentary melanocytic proliferation (DIMP)’.

Introduction:

Bilateral diffuse uveal melanocytic proliferation (B-DUMP) is a rare paraneoplastic syndrome typically presenting with bilateral visual loss. Less than 100 cases have been described in the literature.¹ This paraneoplastic syndrome is associated with extraocular systemic malignancies with the most common being lung cancer in males, and uro-gynecological cancers in females (mainly ovarian cancer).^1,2 The median age at presentation is 65 years and the histopathology of B-DUMP is unrelated to the primary systemic neoplasia.¹ In the B-DUMP syndrome, the uvea becomes thickened due to hyperplastic proliferation of benign uveal melanocytes.

Cutaneous and/or mucosal involvement in patients with B-DUMP has been reported;^2,3 but this is not typical or not well recognized. Herein we report a patient with history of vaginal clear cell carcinoma and multiple metastatic melanomas with an unknown primary who presented with both B-DUMP and multifocal bilateral acquired bluish cutaneous patches composed of melanocytes. We suggest the term ‘diffuse integumentary melanocytic proliferation’ (DIMP) to characterize the skin findings and propose the term B-DUMP-DIMP to characterize this systemic oculo-cutaneous paraneoplastic syndrome.

Main text:

A female in her early 70s presented with vaginal clear cell carcinoma and was treated with chemoradiation (interstitial radiation and cisplatin). Two years after treatment, she developed pulmonary and nodal recurrence and was treated with paclitaxel and carboplatin. Four years after vaginal carcinoma diagnosis, she was diagnosed with a dermal metastatic melanoma of unknown primary and this was treated surgically. Simultaneously, she started to develop progressive bilateral loss of visual acuity and was referred for ophthalmologic evaluation, which revealed the presence of multiple pigmented round or oval choroidal elevations, diffusely thickened choroid, outer retinal and retinal pigment epithelium disturbance (Figure 1). These findings were compatible with the diagnosis of ‘B-DUMP’. She started systemic steroids but due to progression of visual symptoms and visual loss in the right eye, the patient was also started on biweekly plasmapheresis. She has been maintained on plasmapheresis for 6 years: the right eye vision did not improve, and the progression of B-DUMP slowed in the left eye with vision declining from 20/70 to 20/150. In the past year, she developed visual hallucinations (Charles Bonnet syndrome), which were treated with methotrexate and have recently been controlled with oral steroids.

Figure 1:

Bilateral diffuse uveal melanocytic proliferation (‘B-DUMP’). A. Fundus photography of the left eye showing multiple round/oval melanocytic choroidal lesions B. Fundus autofluorescence demonstrating areas of hypoautofluorescence with scattered intrinsic hyperautofluorescence speckling C. Optical coherence tomography showing diffuse choroidal thickening with outer retinal and retinal pigment epithelial disturbance and cystoid macula changes

While undergoing therapy for her B-DUMP, she was noted to have developed multifocal bilateral bluish-greyish patches on the supraclavicular skin, the upper back, the dorsum of the hands and ankles (Figure 2A–B). These were non-palpable and did not blanch. Aside from bluish patches, she also developed a solitary bluish nodule on her supraclavicular skin (Figure 2 B–C). Patient denied intake of any systemic drug that can cause skin hyperpigmentation. A series of 4-mm punch biopsies were performed; the background bluish areas revealed a dermal biphasic benign melanocytic proliferation composed of a nodule of pigmented spindle and epithelioid melanocytes and melanophages flanked by fascicular aggregates and small individual units of pauci- or amelanotic fusiform melanocytes (Figure 2D). The solitary bluish nodule showed features of a blue nevus, or benign melanocytoma (Figure 2E–F). The findings were interpreted histopathologically as most in keeping with a pigmented blue nevus or melanocytoma nodule in midst of a diffuse plaque type spindle cell nevus. The pigmented nodule and fascicles of fusiform melanocytes in the cutaneous bluish background were found to be negative for GNAQ or GNA11 mutations. We proposed that this clinical and histopathologic findings be termed ‘diffuse integumentary melanocytic proliferation (DIMP)’.

Figure 2:

Diffuse integumentary melanocytic proliferation (‘DIMP’). A. Subtle bluish macules on the dorsum of hands. B. Bluish macules on the shoulders and thorax. Note the dark blue nodule amidst the bluish background C. Dermoscopic image showing homogeneous blue pattern (Polarized light dermoscopy, original magnification 10X). D. Histopathology corresponding to the nodular clinical lesion of panel B: Benign pigmented nodular melanocytic proliferation with features of blue nevus associated with an amelanotic spindle cell nevus. E and F:Histopathology corresponding to the background bluish skin of panel B: Plaque-type spindle cell nevus (H&E, 4X). F: The spindle cells of the plaque-type spindle cell nevus are immunoreactive for Melan-A.

The patient is still receiving weekly plasmapheresis and oral steroids and remains under close monitoring by a multidisciplinary team. There has been a slow deterioration of her B-DUMP and a partial improvement in her DIMP component with decreasing intensity of bluish color of her skin.

Conclusion:

Herein we report a case of paraneoplastic B-DUMP and ‘DIMP’ most likely secondary to metastatic clear-cell vaginal cancer. This paraneoplastic syndrome leads to proliferation of melanocytes in the uvea (B-DUMP) but may also lead to proliferation of melanocytes in the dermis (DIMP). The dermal melanocytic proliferations in our patient manifested clinically as bluish discolored patches akin to the color seen in nevus of Ito. It is estimated that mucocutaneous involvement may be present in as many as 25% of cases presenting with B-DUMP;⁴ however, the cutaneous lesions can easily be overlooked. Their detection can assist the clinician in making the diagnosis of this rare paraneoplastic syndrome. The appearance of bluish discolored patches of skin in a person with a previous history of cancer should alert the clinician to the possibility of B-DUMP syndrome and should prompt an ophthalmology consult. Based on our case and previous reports,^2,3 cutaneous lesions are usually located on the dorsum of the hands, the upper back, extremities, and/or the mucosal surfaces. It is unclear whether the DIMP component is associated with: (1) A worse prognosis of the underlying malignancy, (2) the subtype of underlying cancer, (3) a more rapidly progressive course of the eye component, or (4) a different treatment response to the primary tumor and/or the B-DUMP component. In our case, the patient had a partial response with steroids and plasmapheresis. The rate of loss of visual acuity appeared to have slowed down and her DIMP component displayed partial improvement. Authors have previously noted the relevance of the integumentary component and have posited to unify the paraneoplastic syndrome under the term ‘bilateral diffuse uveal and focal dermal melanocytic proliferation’ (‘BDUFDMP’);³ however, since mucosal surfaces can also be involved, and the melanocytic proliferation can be diffuse, we propose the more inclusive term of ‘DIMP’ as a unifying phrase that also acts to complement the term used for uveal involvement (B-DUMP). Thus, our patient had both B-DUMP and DIMP.

It has been shown that B-DUMP patients have an associated circulating factor in the IgG-fraction of their serum and this may be the stimulus that causes melanocytes to proliferate in vitro. This factor has been termed ‘CMEP’ factor.⁵ It remains to be proven whether blocking or removing (e.g., via plasmapheresis), this CMEP factor can slow B-DUMP progression. It stands to reason that this same circulating IgG may also stimulate melanocyte proliferation in other areas of the body such as the integumentary system, hence causing DIMP, similar to the B-DUMP proliferation in uveal melanocytes.³ Dermal and uveal melanocytes respond differently to stimuli and signals when compared to epidermal melanocytes; this phenomenon is partly explained by different embryological development and maturation of melanocytes.^6,7 This, in turn, may provide an explanation as to the clinical observation that B-DUMP-DIMP only affects uveal and dermal melanocytes, sparing epidermal melanocytes. These dermal melanocytic proliferations appear clinically as diffuse bluish patches and correlate histopathologically with benign melanocytic proliferations.

B-DUMP is diagnosed based on 5 cardinal ocular signs (Table 1).⁸ It can both coexist with uveal melanoma and mimic melanoma so it must be included in the differential of uveal tumors.^9,10 Despite not yet being part of the diagnostic criteria, we believe the DIMP component is an important diagnostic feature in these patients when B-DUMP is suspected and vice versa (Table 1).

Table 1:

‘Bilateral diffuse melanocytic uveal proliferation’ (B-DUMP) diagnostic criteria as proposed by Gass et al.⁸ plus the proposed ‘diffuse integumentary melanocytic proliferation’ (DIMP) components.

B-DUMP criteria

Multiple, round or oval, subtle, red patches at the level of the RPE in the posterior fundus

Multifocal areas of early hyper-fluorescence corresponding with these patches

Development of multiple, slightly elevated, pigmented and non-pigmented uveal melanocytic tumors, as well as evidence of diffuse thickening of the uveal tract

Exudative retinal detachment

Rapid progression of cataracts

DIMP component

Diffuse bluish macules (usually bilateral) corresponding to the proliferation of dermal melanocytes without epidermal involvement

Typical location: dorsum of hands and extremities, upper back, neck and mucosal surfaces

B-DUMP is a rare paraneoplastic disorder affecting the uveal melanocytes, but it can also affect dermal and mucosal melanocytes (DIMP) in up to one quarter of patients. It is important to recognize the DIMP component since it may arise as an additional clue when suspecting an underlying B-DUMP diagnosis in patients with systemic cancer, as well as serve as a window to evaluate response/monitor treatment or progression.