Multiple hematogenous metastasis after curative surgery in a patient with pT1a-LPM pN0 primary...

CASE REPORT

Multiple hematogenous metastasis after curative surgeryin a patient with pT1a-LPM pN0 primary malignant melanomaof the esophagus

Tomoyuki Okumura • Yutaka Shimada • Shin Ishizawa •

Isaya Hashimoto • Tomoko Watanabe • Koshi Matsui •

Isaku Yoshioka • Takuya Nagata • Kazuhiro Tsukada

Received: 10 January 2013 / Accepted: 11 March 2013 / Published online: 3 April 2013

� The Japan Esophageal Society and Springer Japan 2013

Abstract Primary malignant melanoma of the esopha-

gus (PMME) is a rare disease. Here, we describe a case of

PMME that was identified at a very early stage. A

65-year-old man underwent upper gastrointestinal endos-

copy and was found to have a pigmented small nodule in

the lower esophagus. A biopsy was taken and diagnosed

as malignant melanoma, so the patient then received

radical esophagectomy. Histopathological examination

showed atypical cell infiltrate in the lamina propria

mucosae without lymph-node metastasis. The patient was

followed up without adjuvant chemotherapy. Multiple

liver and lung metastases were found at 19 months after

surgery, and the patient received DAV-feron (DTIC/

ACNU/VCR/IFN-b) therapy. However, the tumors pro-

gressed and the patient died of the disease at 27 months

after surgery. More detailed surveys after surgery with

diagnostic imaging and tumor markers are recommended.

Adjuvant chemotherapy is worth considering, even in

patients with early-stage PMME.

Keywords Early-stage primary malignant melanoma of

the esophagus � Melanocytosis � Hematogenous

metastasis

Introduction

Primary malignant melanoma of the esophagus (PMME) is

a rare disease representing 0.1–0.5 % of all primary

esophageal neoplasms [1]. It is a very aggressive disease

with high metastatic potential, and the prognosis is very

poor. Because most of patients with PMME are diagnosed

at an advanced stage, little is known about the malignant

features of PMME in its early stages. In this report, we

describe a case of PMME in which the depth of the tumor

in the lamina propria mucosae was limited. The patient

underwent radical esophagectomy and no lymph-node

metastasis was seen, but multiple hematogenous metastases

were detected after surgery.

Case report

In December 2009, a 65-year-old Japanese man without

any symptoms underwent upper gastrointestinal (GI)

endoscopy during a periodic medical checkup and was

found to have a pigmented small nodule in the lower tho-

racic esophagus. Histological examination of biopsy sam-

ples confirmed the diagnosis of malignant melanoma, and

the patient was subsequently referred to our hospital in

January 2010. The patient had a medical history of distal

gastrectomy with Billroth 1 reconstruction due to gastric

cancer at the age of 41. He received upper GI endoscopy

annually and no lesion was detected at the previous

checkup, which was performed in November 2008

S. Ishizawa previously worked for the Department of Pathology,

Graduate School of Medicine and Pharmaceutical Sciences,

University of Toyama.

T. Okumura (&) � Y. Shimada � I. Hashimoto � T. Watanabe �K. Matsui � I. Yoshioka � T. Nagata � K. Tsukada

Department of Surgery and Science, Graduate School

of Medicine and Pharmaceutical Sciences, University

of Toyama, Sugitani 2630, Toyama City 930-0194, Japan

e-mail: okumura@med.u-toyama.ac.jp

S. Ishizawa

Department of Pathology,

Toyama Prefectural Central Hospital, Toyama City, Japan

123

Esophagus (2013) 10:184–191

DOI 10.1007/s10388-013-0373-9

(Fig. 1a, b). The patient had a smoking history of 24 packs

per year until he received the gastrectomy. Both of his

parents died of gastric cancer, and his elder brother died of

colon cancer. Physical examination was normal without

any suspicious pigmented skin lesions. The results of lab-

oratory tests, including tumor markers such as carcino-

embryonic antigen (CEA), squamous cell carcinoma-

related antigen (SCC), and neuron-specific enolase (NSE),

were all within the normal ranges.

Endoscopically, flat, pigmented mucosal lesions were

seen in the middle and lower thoracic esophagus (Fig. 2a,

b), and a small pigmented nodule surrounded by flat pig-

mentation was found in the lower thoracic esophagus

(Fig. 2b, c). Histological examination of a biopsy specimen

revealed atypical melanocytic infiltration with junctional

activity, confirming the diagnosis of malignant melanoma.

Esophagography demonstrated a small, elevated, nodular

lesion in the lower esophagus (Fig. 2d).

A computed tomograpy (CT) scan detected no tumor in

the esophagus, no lymph node swelling in the mediastinum

and abdomen, and no distant metastasis to the liver and

lungs. Positron emission tomography (PET) using F-18-

fluorodeoxyglucose (FDG) showed no abnormal accumu-

lation, even in the primary lesion.

Because the nodular lesion diagnosed as PMME was

accompanied by widely spreading flat lesions with pig-

mentation and it was difficult to differentially diagnose

melanocytosis and melanoma, endoscopic mucosal resec-

tion (EMR) was not carried out.

The patient received video-assisted thoracoscopic

esophagectomy with extensive lymph-node dissection

reconstructed with colonic interposition in February 2010.

The resected specimen showed weak, spotted pigmentation

throughout the esophagus. There were 2 flat lesions

(30 mm in diameter at the middle thoracic esophagus and

10 mm at the abdominal esophagus, respectively) with

strong pigmentation and an elevated lesion (8 mm in

diameter) with strong pigmentation (Fig. 3a). Histopa-

thological examination with whole tissue sections (Fig. 3b)

showed melanocytosis at the spotted pigmentation (lesion 1

in Fig. 3b), melanoma in situ at the 2 flat lesions (lesions 2

and 3 in Fig. 3b), and invasive melanoma at the elevated

lesion (lesion 4 in Fig. 2b).

No atypical change was seen in HE-stained sections

(Fig. 4a) of the weak, spotted pigmentation (Lesion 1 in

Fig. 2b), while Melan-A was strongly expressed in the

whole basal layer of the esophageal epithelium (Fig. 4b),

leading to a diagnosis of melanocytosis. In the flat lesions

with strong pigmentation (lesions 2 and 3 in Fig. 2b),

atypical cells infiltrated from the basal layer towards the

epithelial surface in HE-stained sections (Fig. 4c), and

immunohistochemistry revealed that the cells were positive

for Melan-A (Fig. 4d). Melan-A is recognized as an anti-

gen on melanoma cells by cytotoxic T-lymphocytes. The

antibody against Melan-A is reactive with cells and tumors

of the melanocytic lineage, and has been commonly used

as a melanocyte differentiation marker [2]. No invasion

across the basement membrane was seen, leading to a

diagnosis of melanoma in situ. According to the classifi-

cation of the Japan Esophageal Society [3, 4], the 2 lesions

of the disease were diagnosed as Mt, 30 9 3 mm, p0-IIb,

pT1a-EP, INFb, ly0, v0, pStage0, and Ae, 10 9 4 mm, p0-

IIb, pT1a-EP, INFb, ly0, v0, pStage0. In the nodular lesion

in the lower thoracic portion (lesion 4 in Fig. 2b), undif-

ferentiated round cells infiltrated into the lamina propria

mucosae with junctional activity (Fig. 3e). The depth of the

Fig. 1 Upper GI endoscopy at the previous medical checkup

performed in November 2008 showed a normal appearance without

any pigmentation or lesion in the upper-middle esophagus (a) and

lower esophagus (b)

Esophagus (2013) 10:184–191 185

123

invasion from the surface of the epithelium was 1–1.5 mm.

Immunohistochemistry revealed that the lesion was posi-

tive for Melan-A (Fig. 3f) and S100, leading to a diagnosis

of invasive melanoma. According to the classification of

the Japan Esophageal Society, the disease was diagnosed as

Lt, 8 9 3 mm, p0-Is ? IIb, pT1a-LPM, INFb, ly0, v0,

pIM0, pPM0, pDM0, pStage0.

Detailed observation revealed that the margin of the

melanoma in situ adjoined the melanocytosis (Fig. 3g) and

the margin of the invasive melanoma adjoined the mela-

noma in situ (Fig. 3h).

The patient was discharged at 26 days after surgery and

closely observed at an outpatient service without adjuvant

chemotherapy. A CT scan was taken at 6 months after

surgery and showed no metastatic lesions, but multiple

hematogenous metastases were found in CT scans of lung

(Fig. 5a) and liver (Fig. 5b) taken at 19 months after sur-

gery. Laboratory examination revealed high levels of NSE

(14.4 ng/ml) and 5-S-cysteinyldopa (41.8 nmol/L).

The patient received combined chemotherapy with

dacarbazine (DTIC), nimustine (ACNU), vincristine

(VCR), and interferon-b (IFN-b), i.e., DAV-feron therapy

[5, 6]. However, the tumors progressed very rapidly and the

patient died of the disease at 27 months after surgery.

Discussion

PMME is a very aggressive disease with high metastatic

potential, and the prognosis is very poor. In earlier reports,

the average overall survival in cases of PMME was

10–13 months and the 5-year survival rate was\5 % [1, 7,

Fig. 2 Upper GI endoscopy showed flat, pigmented mucosal lesions

in the middle (a) and lower (b) thoracic esophagus. A small

pigmented nodule surrounded by flat pigmentation was found in the

lower thoracic esophagus (b, c). Esophagography demonstrated a

small, elevated, nodular lesion in the lower esophagus (d)

186 Esophagus (2013) 10:184–191

123

8], largely because the disease tends to be identified at an

advanced stage. It has been reported that about 50 % of

patients present distant metastases to the liver (31 %), the

mediastinum (29 %), the lungs (18 %), and the brain

(13 %) at initial diagnosis [7]. On the other hand, a recent

report showed an improved 5-year survival rate of 37 %

[9], reflecting improvements in early endoscopic detection

[10]. This is compatible with previous reports which indi-

cated that the depth of the primary tumor, lymph node

metastasis, distant metastasis, and disease stage were pre-

dictive factors for the prognosis in cases of PMME [11,

12]. However, PMME still shows high metastatic potential,

even during its early stages, as it is reported that lymph

node metastasis is usually seen even when the depth of the

tumor is limited to the submucosal layer [13, 14].

The incidence of metastasis has not yet been established

for early-stage PMME limited to the mucosal layer

(pT1aPMME). There have been 10 previously reported

cases with pT1a PMME, as summarized in Table 1 [13,

15–22]. No lymph-node metastasis was seen in any of the

cases, and liver metastasis was seen in 1 case with a pT1a-

LPM primary tumor during repeated endoscopic mucosal

resection and ablation. In our case, the tumor was patho-

logically diagnosed as pT1a-LPM pN0M0, but liver and

lung metastases developed after curative surgery, present-

ing very high metastatic potential. Considering the rela-

tively short observiation periods in the cases summarized

in Table 1, at least 2 (18.2 %) of the 11 pT1aPMME cases

developed hematogenous metastasis.

In our case, multiple hematogenous metastases devel-

oped during the 13-month interval between the first (at

6 months) and second (at 19 months) CT scans performed

after surgery, suggesting that more detailed imaging sur-

veys should be done at shorter intervals (i.e., every

6 months), even in cases with early-stage PMME.

Surgical resection with radical lymph-node dissection is

the most common treatment for PMME [1, 7, 14, 23] and

long-term survival has occasionally been reported after

surgery [8, 24]. In the present case, the patient underwent

subtotal esophagectomy with lymph-node dissection.

Metastasis was not seen in any of the 25 dissected nodes,

and lymphovascular invasion was not observed, but the

patient died of multiple hematogenous metastasis. Because

the incidence of lymph-node metastasis in pT1a PMME is

still unclear, one proposed treatment is adjuvant chemo-

therapy with extended radical surgery [16]. The combina-

tion of radical surgery and DAV or DAV-feron therapy was

reported to be effective for PMME [6, 25–28].

In some cases, EMR has reported to be a curative

treatment [18, 19] in early-stage PMME. On the other

hand, local recurrence after EMR was also reported [20].

The combination of EMR and adjuvant chemotherapy is a

possible alternative strategy in T1a PMME without lymph-

node metastasis. However, the development of accurate

preoperative diagnostic strategies, such as endoscopic

ultrasound, is necessary.

Endoscopic biopsy was carried out in the present case to

achieve a definitive diagnosis. In malignant melanoma of

Fig. 3 Resected specimen (a) showed weak, spotted pigmentation

throughout the esophagus. There were several flat lesions with strong

pigmentation and an elevated nodular lesion with strong pigmentation

in the lower esophagus. Histopathological examination with whole

tissue sections (b) showed melanocytosis at the spotted pigmentation

(lesion 1), melanoma in situ at the 2 flat lesions (lesions 2 and 3), and

invasive melanoma at the elevated lesion (lesion 4)

Fig. 4 No atypical change was seen in HE-stained sections of lesion

1 (a), while Melan-A was strongly expressed in the whole basal layer

of the epithelium (b). In lesions 2 and 3, atypical cells infiltrated from

the basal layer towards the epithelial surface in HE-stained sections

(c). Immunohistochemistry revealed that the cells were positive for

Melan-A (d), leading to a diagnosis of melanoma in situ. In lesion 4,

undifferentiated round cells infiltrated into the lamina propria

mucosae with junctional activity in HE-stained sections (e). The

depth of the invasion from the surface of the epithelium was

1–1.5 mm. Immunohistochemistry revealed that the lesion was

positive for Melan-A (f), leading to a diagnosis of invasive

melanoma. The margin of the melanoma in situ adjoined the

melanocytosis (g) and the margin of the invasive melanoma adjoined

the melanoma in situ (h)

c

Esophagus (2013) 10:184–191 187

123

188 Esophagus (2013) 10:184–191

123

the skin, biopsy is generally considered to be contraindi-

cated in order to avoid triggering hematogenous metastasis

[29]. However, it is difficult to perform radical esopha-

gectomy without a definitive diagnosis. Especially in early-

stage cases, a pathological diagnosis is necessary because

performing a differential diagnosis between melanocytosis

and melanoma in situ by endoscopy is difficult [12]. In the

pT1aPMME cases summarized in Table 1, hematogenous

metastasis was not established in 9 of the 11 cases, even

though all 11 patients underwent biopsy prior to curative

treatment.

In the present case, a malignant melanoma and 2 mel-

anoma in situ lesions were accompanied by widely

spreading melanocytosis. This is compatible with a previ-

ous report that 25–30 % of PMMEs are accompanied by

melanocytosis [30]. More detailed observations revealed

that the margin of the melanoma in situ adjoined the

melanocytosis, and the margin of the invasive melanoma

adjoined the melanoma in situ, suggesting a possible

melanocytosis–melanoma sequence in this case. A case has

been reported in which a melanoma arose from a previ-

ously detected melanotic lesion [31]. In addition, in the

present case, all of the mixed lesions developed within

1 year, indicating very rapid progression after initiation.

Although the patient did not suffer from reflux esophagitis,

it is possible that long-term stimulation by reflux after

gastrectomy influenced the development of melanocytosis

and melanoma.

Several genes, such as MC1R and CDKN2A, are repor-

ted to be involved in the development of malignant mela-

noma of the skin, but their role in PMME is unknown.

Exposure to ultraviolet (UV) radiation is widely recognized

as a carcinogen for malignant melanoma of the skin. UVB

has been shown to enhance cyclooxygenase 2 (COX-2)

protein levels in skin, indicating its role in the development

of UVB-related malignant melanoma [32, 33]. On the other

hand, COX-2 has been reported to play a role in the

development of reflux esophagitis as well as esophageal

carcinoma. Reports have also shown a relationship between

bile reflux and induced COX-2 expression [34]. Taken

together, it is possible that long-term stimulation by reflux

after gastrectomy affected the development of melanocy-

tosis through COX-2 induction, and then additional

molecular events accelerated the transformation to malig-

nant melanoma. Further investigations of the biological

process involved in the development of melanocytosis and

melanoma in esophagus may provide us with a better

understanding of and treatment for the disease.

In conclusion, the present case demonstrated very rapid

development and progression of PMME from normal

mucosa to melanocytosis, to malignant melanoma, and

then to multiple hematogenous micrometastases, all within

1 year. Based on the extremely malignant characteristics of

PMME, we suggest that melanocytosis of the esophagus

should be considered a high-risk precancerous lesion.

Although the overall outcomes of therapies for this extre-

mely rare disease are unclear, radical esophagectomy with

adjuvant chemotherapy is worth considering, even for

patients with early-stage PMME. In addition, more detailed

surveys after surgery, utilizing diagnostic imaging and

tumor markers such as NSE and 5-S-cysteinyldopa, are

strongly recommended.

Fig. 5 Multiple hematogenous metastases were found in CT scans of

lung (a) and liver (b) at 19 months after surgery

Esophagus (2013) 10:184–191 189

123

Conflict of interest The authors declare that they have no conflict

of interest.

References

1. Sabanthan S, Eng J, Pradhan GN. Primary malignant melanoma

of the esophagus. Am J Gastroenterol. 1989;12:1475–81.

2. Jungbluth AA. Serological reagents for the immunohistochemical

analysis of melanoma metastases in sentinel lymph nodes. Semin

Diagn Pathol. 2008;25(2):120–5.

3. Japan Esophageal Society. Japanese classification of esophageal

cancer, 10th edn: part I. Esophagus. 2009;6:1–25.

4. Japan Esophageal Society. Japanese classification of esophageal

cancer, tenth edition: parts II and III. Esophagus. 2009;6:71–94.

5. Yamashita Y, Hirai T, Mukaida H, Kawano K, Toge T, Niimoto

M, et al. Primary malignant melanoma of the esophagus—a case

report. Jpn J Surg. 1989;19:498–501.

6. Kawada K, Kawano T, Nagai K, Nishikage T, Nakajima Y,

Tokairin Y, et al. Local injection of interferon beta in malignant

melanoma of the esophagus as adjuvant of systemic pre- and

postoperative DAV chemotherapy: case report with 7 years of

long-term survival. Gastrointest Endosc. 2007;66:408–10.

7. Calhkiadakis G, Wihlm JM, Morand G, Weill-Bousson M, Witz

JP. Primary malignant melanoma of the esophagus. Ann Thorac

Surg. 1985;39:472–5.

8. Joob AW, Haines GK, Kies MS, Shields TW. Primary malignant

melanoma of the esophagus. Ann Thorac Surg. 1995;60(1):

217–22.

9. Volpin F, Sauvanet A, Couvelard A, Belghiti J. Primary malig-

nant melanoma of the esophagus: a case report and review of the

literature. Dis Esophagus. 2002;15:244–9.

10. Miyatani H, Yoshida Y, Ushimaru S, Sagihara N, Yamada S.

Slow growing flat-type primary malignant melanoma of the

esophagus treated with cap-assisted EMR. Dig Endosc.

2009;21(4):255–7.

11. Cheung MC, Perez EA, Molina MA, Jin X, Gutierrez JC,

Franceschi D, et al. Defining the role of surgery for primary

gastrointestinal tract melanoma. J Gastrointest Surg. 2008;12(4):

731–8.

12. Iwanuma Y, Tomita N, Amano T, Isayama F, Tsurumaru M,

Hayashi T, et al. Current status of primary malignant melanoma

of the esophagus: clinical features, pathology, management and

prognosis. J Gastroenterol. 2012;47(1):21–8.

13. Suzuki H, Nakanishi Y, Taniguchi H, Shimoda T, Yamaguchi H,

Igaki H, et al. Two cases of early-stage esophageal malignant

melanoma with long-term survival. Pathol Int. 2008;58(7):432–5.

14. Ludwig ME, Shaw R, de Suto-Nagy G. Primary malignant mel-

anoma of the esophagus. Cancer. 1981;48(11):2528–34.

15. Kido T, Morishima H, Nakahara M, Nakao K, Tanimura H, Ni-

shimura R, Tsujimoto M. Early stage primary malignant mela-

noma of the esophagus. Gastrointest Endosc. 2000;51(1):90–1.

Table 1 A summary of the reported cases of early-stage primary malignant melanoma of the esophagus

No Author Age

(years)

Sex TNM

stage

Japanese

classification

Biopsy Treatment Survival

(months)

Outcome

1 Kido [15] 60 M T1N0M0 pT1a-MM N0M0

Stage0

? Surgery 1 Disease-free

Stage1

2 Mikami

[16]

41 F T1N0M0 pT1a N0M0

Stage0

? Surgery ? chemotherapy 31 Disease-free

Stage1

3 Hara [17] 52 M TisN0M0 pT1a-EP N0M0

Stage0

? Surgery 1 Disease-free

Stage0

4 Kimura

[18]

73 M T1N0M0 pT1a-LPM

N0M0 Stage0

? EMR 15 Disease-free

Stage1

5 Suzuki

[13]

62 M TisN0M0 pT1a-EP N0M0

Stage0

? Surgery 33 Disease-free

Stage0

6 Suzuki

[13]

67 M T1N0M0 pT1a-LPM

N0M0 Stage0

? Surgery 53 Disease-free

Stage1

7 Miyatani

[19]

64 M T1N0M0 pT1a-LPM

N0M0 Stage0

? EMR 20 Disease-free

Stage1

8 Morita

[20]

75 M T1N0M0 pT1a-LPM

N0M0 Stage0

? EMR 9 6,

tumor ablation 9 7,

chemotherapy,

TACE

84 Survive with liver

metastasisStage1

9 Minami

[21]

72 M TisN0M0 pT1a-EP N0M0

Stage0

? Surgery 25 Disease-free

Stage0

10 Hikage

[22]

61 M T1N0M0 pT1a-MM N0

M0 pStage0

? Surgery 17 Disease-free

Stage1

11 Our case 65 M T1N0M0 pT1a-LPM

N0M0 Stage0

? Surgery ? chemotherapy 27 Death due to liver and

lung metastasesStage1

190 Esophagus (2013) 10:184–191

123

16. Mikami T, Fukuda S, Shimoyama T, Yamagata R, Nishiya D,

Sasaki Y, et al. A case of early-stage primary malignant mela-

noma of the esophagus. Gastrointest Endosc. 2001;53(3):365–7.

17. Hara S, Noguchi M, Sugiyama K, Yamaguch M, Unakami M,

Imatani A, et al. A case of primary malignant melanoma of the

esophagus in situ. Gastroenterol Endosc. 2003;45:935–9.

18. Kimura H, Kato H, Sohda M, Nakajima M, Fukai Y, Miyazaki T,

et al. Flat-type primary malignant melanoma of the esophagus

treated by EMR: case report. Gastrointest Endosc.

2005;61(6):787–9.

19. Miyatani H, Yoshida Y, Ushimaru S, Sagihara N, Yamada S.

Slow growing flat-type primary malignant melanoma of the

esophagus treated with cap-assisted EMR. Dig Endosc.

2009;21(4):255–7.

20. Morita S, Miyamoto S, Matsumoto S, Muto M, Chiba T. Multiple

early stage malignant melanoma of the esophagus with long

follow-up period after endoscopic treatment: report of a case.

Esophagus. 2009;6:249–52.

21. Minami H, Inoue H, Satodate H, Hamatani S, Shin-Ei K. A case

of primary malignant melanoma in situ in the esophagus. Gas-

trointest Endosc. 2011;73(4):814–5.

22. Hikage M, Kamei T, Fujishima F, Miyata G, Onodera K, Ichi-

kawa H, et al. Early stage primary malignant melanoma of the

esophagus detected simultaneously with esophageal squamous

cell carcinoma. Esophagus. 2012;9:33–8.

23. Adili F, Monig SP. Surgical therapy of primary malignant mel-

anoma of the esophagus. Ann Thorac Surg. 1997;63(5):1461–3.

24. Itami A, Makino T, Shimada Y, Imamura M. A case of primary

malignant melanoma of the esophagus with long term survival.

Esophagus. 2004;1:135–7.

25. Naomoto Y, Perdomo JA, Kamikawa Y, Haisa M, Yamatsuji T,

Kenzo A, et al. Primary malignant melanoma of the esophagus:

report of a case successfully treated with pre- and post-operative

adjuvant hormone chemotherapy. Jpn J Clin Oncol.

1998;28:758–91.

26. Matsutani T, Onda M, Miyashita M, Hagiwara N, Akiya Y,

Takubo K, et al. Primary malignant melanoma of the esophagus

treated by esophagectomy and systemic chemotherapy. Dis

Esophagus. 2001;14:241–4.

27. Sunagawa H, Nishimaki T, Shimoji H, Kuninaka K, Nakachi N,

Kinjyou F. Primary malignant melanoma of the esophagus suc-

cessfully treated by an esophagectomy followed by systemic

chemotherapy. Esophagus. 2005;2:33–7.

28. Larkin J, Gore M. Malignant melanoma (metastatic). Clin Evid

(Online). 2008;Aug 22;pii:1718.

29. Shapiro RL. Surgical approaches to malignant melanoma. Prac-

tical guidelines. Dermatol Clin. 2002;20(4):681–99.

30. Lohmann CM, Hwu WJ, Iversen K, Jungbluth AA, Busam KJ.

Primary malignant melanoma of the oesophagus: a clinical and

pathological study with emphasis on the immunophenotype of the

tumours for melanocyte differentiation markers and cancer/testis

antigens. Melanoma Res. 2003;13(6):595–601.

31. Oshiro T, Shimoji H, Matsuura F, Uchima N, Kinjo F, Nakayama

T, Nishimaki T. Primary malignant melanoma of the esophagus

arising from a melanotic lesion: report of a case. Surg Today.

2007;37(8):671–5.

32. Denkert C, Kobel M, Berger S, Siegert A, Leclere A, Trefzer U,

Hauptmann S. Expression of cyclooxygenase 2 in human

malignant melanoma. Cancer Res. 2001;61(1):303–8.

33. Kim JY, Shin JY, Kim MR, Hann SK, Oh SH. siRNA-mediated

knock-down of COX-2 in melanocytes suppresses melanogene-

sis. Exp Dermatol. 2012;21(6):420–5.

34. Song S, Guha S, Liu K, Buttar NS, Bresalier RS. COX-2

induction by unconjugated bile acids involves reactive oxygen

species-mediated signalling pathways in Barrett’s oesophagus

and oesophageal adenocarcinoma. Gut. 2007;56(11):1512–21.

Esophagus (2013) 10:184–191 191

123