Collision nodal metastasis of bladder cancer and melanoma: The first reported case and literature review.

Collision metastasis is a rare phenomenon of concomitant localization of 2 or more different tumors in the same lymph node. In most cases, primary malignancies are synchronous carcinomas arising in the same organ or area of the body. A 82-year-old man presented with hematuria and acute renal failure; he had undergone dermatological consultation ten months ago because of a large deep brown skin lesion in his dorso-lumbar region, which was not excised upon patient's request. He underwent radical cystectomy with extended pelvic lymphadenectomy due to nonpapillary high-grade urothelial carcinoma, with focal squamous features, infiltrating the bladder wall and prostate gland. In one left iliac lymph node, small foci of metastatic urothelial carcinoma (positive for P63 and CK34betaE12) were close to melanoma cells (positive for HMB45). The patient refused further treatment and died of metastatic disease 12 months after cystectomy. There is no specific clinical feature for nodal collision metastasis. A polymorphic histologic appearance poses the suspect, but immunohistochemical stains are needed to define the primary tumors. Collision metastases are thought to carry a poor prognosis. Their clinical relevance is linked to the fact that the patient faces 2 different metastatic tumors that may require specific multidisciplinary approach once diagnosed as metastatic. We present, to the best of our knowledge, the first case of collision nodal metastasis from bladder cancer and melanoma, and describe its clinical and histopathological characteristics to raise awareness on this rare occurrence, which portends a poorer prognosis than each single tumor.

1. Introduction

A collision metastasis is defined as the concomitant localization of 2 or more different tumors in the same lymph node.[ This is a rare phenomenon, with only a few dozen cases having been reported in literature so far.[ In most cases, primary malignancies are both carcinomas arising in the same organ or area of the body, with 1 of the 2 primary tumors being often a thyroid carcinoma or adenocarcinoma of the prostate. Conversely, collision metastases from a primary bladder cancer are rare,[ and those involving melanoma cells are even rarer.[ To the best of our knowledge, herein, we describe the first case of collision nodal metastasis from bladder cancer and melanoma to a single lymph node, along with a brief literature review.

2. Case report

A 82-year-old man presented in October 2015 with hematuria and acute renal failure (serum creatinine 11.8mg/dL). His past medical history revealed only a previous coronary artery bypass graft in 2000.

Abdominal ultrasound pointed out a 4.5 cm lesion involving the bladder trigone, probably occluding both ureteral orifices given a grade II bilateral hydro-uretero-nephrosis. He was therefore scheduled for transurethral resection of the bladder tumor. A single large mass occluding both ureteral orifices was completely resected; by the end of the procedure, both ureteral orifices were widely open. Pathology revealed a high-grade muscle-invasive urothelial carcinoma. Twenty days after transurethral resection of the bladder tumor, serum creatinine had dropped down to 1.62mg/dL and he underwent staging thoraco-abdominal computed tomography, which revealed thickening of bladder wall at the level of the left ureteral trigone and multiple enlarged lymphnodes in the left iliac-obturator region, the larger measuring 14 mm in diameter (Fig. 1A). There was no evidence of distant metastases in the explored areas. Therefore, in November 2015, he underwent radical cystectomy, extended pelvic lymphadenectomy, and bilateral ureterocutaneostomy. Postoperative course was uneventful and the patient was discharged on 10th postoperative day with a serum creatinine of 1.88mg/dL.

Figure 1

(A) Abdominal computed tomography scanning showing thickening of bladder wall at the level of the left ureteral trigone and multiple enlarged lymphnodes in the left iliac-obturator region, the larger measuring 14 mm in diameter. (B) Immunohistochemistry: Massive nodal metastasis from melanoma (red signal, Fast Red chromogen) (×100 magnification). (C) Immunohistochemistry: Concomitant metastasis in the same lymph node, featuring melanoma cells (red signal, Fast Red chromogen) along with bladder cancer cells (brown signal, DAB chromogen) (×100 magnification).

The opened bladder contained a fungated and ulcerated mass involving the bladder trigone, not extending into the prostate, measuring 2.5 × 4 cm. Cut sections of the prostate demonstrated bilateral, symmetrical enlargement. Pathology showed a non-papillary high-grade urothelial carcinoma, with focal squamous features, infiltrating the detrusor muscle and extending into the prostate gland (pT4 according to the 2010 7th edition of the TNM staging system). Lymphovascular invasion was not identified. In one left iliac lymph node, the architecture was largely replaced with metastatic tumor composed of large sheets of pleomorphic cells with eosinophilic cytoplasm, thus suggestive of melanoma origin (Fig. 1B). The same cells were identified in another lymph node, whereby we identified also small foci of metastatic urothelial carcinoma, some of them close to the melanoma cells. Upon suspicion of a collision metastasis in the above-mentioned lymph node, immunohistochemistry was carried out. Urothelial cancer cells exhibited strong staining for P63 and CK34betaE12, while melanoma cells were positive for HMB45 (Fig. 1C). On further anamnestic investigation the patient revealed that on January 2015, he had undergone dermatological consultation because of a deep brown skin lesion in his dorso-lumbar region, approximately 8.2 cm in width, with irregular borders (Fig. 2). Though complete surgical excision was recommended, he had chosen not to undergo such procedure, claiming a slight reduction in lesion size over the following few months.

Figure 2

A deep brown skin lesion of the dorso-lumbar region, approximately 8.2 cm in width, with irregular borders, strongly suggestive for melanoma.

The patient refused further treatment for his 2 metastatic tumors; he died of metastatic disease 12 months after cystectomy.

3. Discussion

The collision phenomenon in a metastatic site has been described as the presence of coexistent but histologically distinct neoplasms from topographically separate primaries, in the absence of any area showing a transitional pattern that suggests a structure intermediate between the 2 tumor types.[ Such definition was subsequently refined by Spagnolo and Heenan,[ who highlighted the presence of 2 distinct, topographically separate, sites of origin for the 2 components, but allowed some transitional patterns to be seen in the area of collision. Actual criteria for collision tumors are: different cell origin and phenotype, independent topographical site of origin, lack of transitional morphological features between neoplasms,[ which are fulfilled in our case.

Gohji et al.[ stated they were able to delineate the different morphologies using hematoxylin-eosin alone; however, they could compare the histology of metastases to the primaries, as they were both known at the time of diagnosis, and the metastatic foci of the 2 primaries were clearly demarcated. Subsequent reports pointed out that the diagnosis of colliding tumor in a lymph node could be suspected on a morphologic basis in a patient known to have 2 synchronous tumors.[ However, as in our case, a clear diagnosis can be achieved only by proper immunohistochemical staining.[

Possible explanations for collision metastases include: 1) involvement of carcinomas which are indolent and common (such as prostate cancer),[ their frequency and long clinical course without any overt clinical symptoms may allow time for second malignancies to develop and metastasize to the same node; 2) an “accidental meeting” of two primary tumors[; 3) a common tumorigenic stimulus triggering neoplastic transformation of both types of cells.[ In case of tumor-to-tumor metastasis, which is a form of collision tumor, it has been hypothesized that the presence of the first tumor alters the microenvironment, thus facilitating the development of the second adjacent tumor.[ This mechanism could apply to collision metastases as well. A novel interesting hypothesis involves the expression of chemokines by neoplastic cells; in their report of secondary breast carcinoma and neuroendocrine rectal carcinoma colliding in the same lymph node, Gasparinho et al.[ suggest that tumors featuring similar chemokines receptor profiles may migrate to specific lymph nodes or organs.

We performed a review of the 22 cases of nodal collision metastases described so far; articles reporting the concomitant presence of a metastatic tumor and lymphoproliferative disease in the same lymph node have been excluded, since this occurrence should rather be regarded as tumor-to-tumor metastasis. As shown in Table 1, most cases involve cervical or abdominal lymph nodes (9 out of 22 cases each), and at least one malignancy is a thyroid carcinoma or a prostate adenocarcinoma, respectively. According to Miyauchi et al.,[ a possible explanation is the slow growth and indolent clinical behavior of these 2 neoplasms, which are often diagnosed as occult or incidental/latent disease. There have been described only 4 cases of colliding secondary bladder cancer; all 4 patients underwent cystoprostatectomy for muscle-invasive bladder cancer, and in all cases one pelvic node contained neoplastic cells from both bladder and prostatic carcinoma. Interestingly, in 3 out of 4 cases, patients were unaware of the prostate cancer before surgery.

Table 1

Literature reports of collision metastases occurring in the same lymph node.

Author, year [Reference]	Age	Sex	Nodal site	Primary tumors
Sughayer, 2009[8]	63	F	Axillary	Serous papillary ovarian carcinoma	Ductal breast carcinoma
Saco, 2018[10]	71	M	Axillary	Prostate adenocarcinoma	Melanoma
Pastolero, 1996[4]	41	M	Cervical	Papillary thyroid carcinoma	Medullary thyroid carcinoma
Guelfucci, 2004[11]	51	M	Cervical	Papillary thyroid carcinoma	Squamous tongue carcinoma
Elias da Cruz Perez, 2008[12]	57	M	Cervical	Thyroid carcinoma	Squamous oral carcinoma
Lim, 2008[13]	47	M	Cervical	Papillary thyroid carcinoma	Squamous tongue carcinoma
Mattioli, 2009[14]	50	F	Cervical	Papillary thyroid carcinoma	Squamous cell carcinoma (unknown origin)
Sadat Alavi, 2011[15]	32	M	Cervical	Papillary thyroid carcinoma	Medullary thyroid carcinoma
Zeng, 2012[16]	49	F	Cervical	Papillary thyroid carcinoma	Ductal breast carcinoma
Alhanafy, 2016[17]	73	F	Cervical	Papillary thyroid carcinoma	Squamous thyroid carcinoma
Xu, 2018[18]	63	M	Cervical	Papillary thyroid carcinoma	Squamous tongue carcinoma
Gasparinho, 2011[19]	55	F	Hylar	Neuroendocrine rectal carcinoma	Ductal breast carcinoma
Wade, 2004[5] (1)	80	M	Mesenteric	Prostate adenocarcinoma	Colonic adenocarcinoma
Mourra, 2005[6]	70	M	Mesorectal	Prostate adenocarcinoma	Rectal adenocarcinoma
Terada, 1993[7]	83	M	Para-aortic	Prostate adenocarcinoma	Stomach adenocarcinoma
Ergen, 1995[2]	67	M	Pelvic	Prostate adenocarcinoma	Urothelial bladder carcinoma
Gohji, 1997[3]	78	M	Pelvic	Prostate adenocarcinoma	Squamous bladder carcinoma
Overstreet, 2001[1]	67	M	Pelvic	Prostate adenocarcinoma	Urothelial bladder carcinoma
Bhavsar, 2012[9]	83	M	Pelvic	Prostate adenocarcinoma	Urothelial bladder carcinoma
Wade, 2004[5] (2)	61	M	Perirectal	Prostate adenocarcinoma	Colonic adenocarcinoma
Miyauchi, 2013[20]	82	M	Perirectal	Prostate adenocarcinoma	Rectal adenocarcinoma
El-Gendy, 2008[21]	51	F	Thoracic	Oesophageal adenocarcinoma	Ductal breast carcinoma

In the vast majority of cases, collision between solid tumors occurring in the same lymph node involves only epithelial tumors; one case of both metastatic melanoma and prostate adenocarci-noma detected has been reported so far.[ The collision metastasis was detected in an axillary sentinel lymph node biopsied for cutaneous melanoma, and the patient had a history of metastatic prostate adenocarcinoma. Conversely, in our case a clear diagnosis of melanoma was lacking before the detection of nodal metastases.

Independently of biological behavior and pathogenetic mechanism, collision metastases are thought to carry a poor prognosis probably due to the fact that patients face 2 different metastatic tumors.[As a matter of fact, they are clinically relevant because the individual primary tumors may require different treatments once diagnosed as metastatic.

Our patient does not provide much information regarding prognosis as he refused further treatment for both malignancies.

Collision nodal metastasis is extremely rare and should be considered when a polymorphic histological appearance is presented in a patient suspected/known to have 2 or more malignant neoplasms. Proper immunohistochemical staining is of great aid to confirm the diagnosis. Though often considered to be merely an academic curiosity, collision metastases often involve urogenital cancers, therefore require expert multidisciplinary approach, as the patient actually faces 2 different metastatic tumors.