case report simultaneous primary mucosal …abstract: we report one case of combining primary...

Int J Clin Exp Med 2017;10(10):14961-14971www.ijcem.com /ISSN:1940-5901/IJCEM0061099

Case ReportSimultaneous primary mucosal malignant melanoma of the oral cavity and squamous cell carcinoma of scalp: a case report and literature review

Qionglan Tang1,2*, Shaozheng Lin3*, Yuqin He3*, Qiquan Wu3*, Xuemei Ma3*, Xiaoping Yuan4, Xiaohua Wu5, Tingzhen Zhang1, Junyi Xie1, Jinsong Li6

1Department of Pathology, 2Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, 4Department of Radiology, 5Laboratory of Biotherapy, 6Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; 3Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. *Equal contributors.

Received July 9, 2017; Accepted October 11, 2017; Epub October 15, 2017; Published October 30, 2017

Abstract: We report one case of combining primary malignant melanoma (MM) in gingival mucosa and scalp squa-mous cell carcinoma (SCC) and review the literature. The patient was a 31-year-old man who had a 120-day history of one nodule in the left gingiva with three gradually enlarging masses in the left lower jaw and a mass in the scalp of the right occiput. Magnetic Resonance Imaging (MRI) revealed a well-defined borderline nodule in the left gingi-val and a mass in the scalp of the right occiput with enlargement of lymph nodes in bilateral lower jaw and cervix. The diagnosis was primary MM in gingival and primary cutaneous SCC with metastasized lesions in submandibular and cervical lymph nodes. The patient adopted combined treatment consisting of operations, chemotherapy and cellular therapy. He has been alive for 29 months from the date of diagnosis. Simultaneous occurrence of non-cutaneous primary MM and SCC is extremely rare, especially simultaneous primary oral mucosal MM and scalp SCC in our case. The biological behavior of such simultaneous double tumors is still uncertain and needed further investigation.

Keywords: Oral mucosal malignant melanoma, cutaneous squamous cell carcinoma, simultaneous double tumors

Introduction

Squamous cell carcinoma (SCC) and malignant melanoma (MM) are very prevalent and rapidly increasing malignancies [1-3]. Two or more kinds of tumors with different biological behav-iors and histopathologic entities could be seen in one patient [4]. Previous studies showed the simultaneity of primary non-cutaneous SCC and MM is extremely rare [5-8]. Herein, we present one case of combining primary malig-nant melanoma (MM) in gingival mucosa and scalp squamous cell carcinoma (SCC) and reviewed the literature.

Materials and methods

Patient selection

Ninety-three cases of malignant melanoma (MM) and 8406 cases of squamous cell carci-nomas (SCC) were collected from the De-

partment of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China, between January 2012 and July 2016. All cases were histologically and immunophe-notypically reviewed, and the diagnosis was based on the World Health Organization (WHO) classification of Pathology and Genetics of Head and Neck Tumors [2], Pathology and Genetics of Skin Tumors [1] and tumors of the Digestive System [3]. In total, one case of pri-mary oral malignant melanoma with primary cutaneous squamous cell carcinoma was iden-tified. The clinical and laboratory data of this patient was collected and tumor staging evalu-ated according to the TNM classification [1-3].

Hematoxylin and eosin (HE) and immunohisto-chemical staining

Four micrometer-thick sections from formalin fixed paraffin embedded blocks were cut for routine hematoxylin and eosin staining. The

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Concurrent oral melanoma and squamous carcinoma

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EnVision method was used for immunostaining with diaminobenzidine (DAB) as a substrate. A broad panel of antibodies included: Vimentin (V9), Melan-A (A103), HMB45 (HMB45), S-100 Protein (4C4.9), cytokeratin (CK; AE1/AE3), CK5&6 (D5/16B4), CK8&18 (5D3), Desmin (D33), MyoD1 (5.8A), CD34 (QBEnd/10) and Ki-67 Antigen (MIB-1). All antibodies were pur-chased in Beijing Zhongshan Biotechnology Co (Beijing; China). The slides were treated by pressure-cooking in citric acid buffer (10 mM, Ph 7.4) for 3 min before staining for Vimentin, Melan-A, HMB45, S-100, CK, CK8&18 and CD34, and in ethylenediaminetetraacetic acid (EDTA; 1 mM, Ph 9.0) for 8 min before staining for CK5&6, MyoD1 and Ki-67. HE and immuno-histochemical staining was evaluated by two independent observers who were blinded to clinical data. All of the experiments were repeated three times. Differences were dis-cussed to reach consensus.

A 31-year-old man was referred to Sun Yat-sen Memorial Hospital in October 2014, with a 120-day history of one nodule in the left gingi-va with three gradually enlarging masses in the left lower jaw and a mass in the scalp of the right occiput. The mass in gum had a well-defined borderline with ulceration. His physical examination on admission was unremarkable and revealed no evidence of any pigmented lesions on his skin. The patient had no history of alcohol and tobacco abuse. Magnetic Resonance Imaging (MRI) revealed a well-defined borderline nodule in the left gingival and a mass in the scalp of the right occiput with enlargement of lymph nodes in bilateral lower jaw and cervix (Figure 1). Chest radiograph showed no evidence of metastasis in the lung and the liver scan was negative. The patient underwent an extended resection for the mass in the left gingiva and a partly resection for the left jawbone with a left neck dissection. The

Figure 1. MRI imaging features of oral primary malignant melanoma with cutaneous primary squamous cell carcinoma in this series. L, left; A-D. MRI imaging, A. Primary malignant melanoma of gingiva (black arrow). B. Me-tastasized lesion of malignant melanoma in lymph node (white arrow). C. Primary squamous cell carcinoma of scalp (white arrow). D. Metastasized lesion of squamous cell carcinoma in lymph node (white arrow).

Review of literature and sta-tistical analysis

Articles from 1953 to 2016 that contain the keywords “squamous cell carcinoma” and “malignant melanoma” in the PubMed and MEDLINE databases were reviewed. All statistical analyses were per-formed using the SPSS WIN program package 13.0 (SPSS, Inc, Chicago, IL, USA). Survival time was measured from pri-mary diagnosis until their cen-soring date. Survival analysis was carried out using the log-rank test in association with Kaplan-Meier analysis. Differ- ences were statistically signifi-cant when P-value < 0.05.

Ethical approval

Each institution obtained approval to participate in the study as required by the local district research ethics com-mittee. Informed consent was obtained from each patient and/or his or her legal guar- dian.

Results

Clinical features of the patient


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diagnosis was primary malignant melanoma (MM) in gingival. Metastasized lesions of MM were found in the left anterior deep cervical and submandibular lymph nodes, respectively. The TNM stage was T4bN2bM0 (IIIc). A month later, the patient was managed with CVD (cis-platin, DDP; vindesine sulfate, VDS; dacarba-zine, DTIC) chemotherapy (cisplatin 30 mg/m2 on days 1-3, vindesine 2.5 mg/m2 on day 1 and dacarbazine 250 mg/m2 on days 1-3). After one

course of chemotherapy, a resection for the mass in the scalp was taken and the diagnosis was primary cutaneous squamous cell carcino-ma (SCC). The day after the operation, cellular therapy (dendritic cells, DC; cytokine induced killer, CIK) at the amount of 2.5×1010) was given. A month later, the patient came back for the second course of CVD chemotherapy and cellular therapy (at the amount of 1.5×1010). One and a half months later, a gradually enlarg-

Figure 2. Pathological characteristics of oral primary malignant melanoma with cutaneous primary squamous cell carcinoma in this series. A-D. Primary malignant melanoma, A. Histopathology of malignant melanoma (HE, original magnificent ×100). B. Tumor cells positive for Vimentin (EnVision method, original magnificent ×100). C. Tumor cells positive for HMB45 (EnVision method, original magnificent ×100). D. Tumor cells negative for CK5/6 (EnVision method, original magnificent ×100). E-I. Primary squamous cell carcinoma, E and F. Histopathology of squamous cell carcinoma (HE, original magnificent ×40). G. Tumor cells positive for CK5/6 (EnVision method, original mag-nificent ×100). H. Tumor cells negative for Vimentin (EnVision method, original magnificent ×100). I. Tumor cells negative for HMB45 (EnVision method, original magnificent ×100).


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ing mass was found in the right of cervix. The patient was managed with a right neck dissec-tion and the third course of cellular therapy (at the amount of 1.5×1010). Metastasized lesions of SCC were found in one lymph node of the right posterior cervix and one in the right sub-maxillary, respectively. However, a recurrent nodule was found in the scalp of the right occiput. The patient underwent the second resection for the scalp mass and was diag-nosed recurrent SCC. Then, the fourth and fifth course of cellular therapy (at the amount of 1.0×1010) was performed. However, nodules were found in the scalp of the right occiput and the right of cervix after one month. Then, a nod-ule excision of scalp and cervix was conducted and diagnosed as recurrent and metastasized SCC. The patient was discharged in June 2015.

Pathological features of the patient

Based on partial resection of the left mandible, radical left cervical lymph node dissection and scalp tumor resection, this case was diagnosed as primary MM in gingiva and cutaneous pri-mary SCC. As for MM, grossly, there was a white or tan, solid mass on the cut surface, measur-ing approximately 1.5 cm×1.5 cm×1 cm in the gum, which infiltrated epidermis, striated mus-cle and mandibular. Histopathologically, a spin-dle cell proliferation in the lamina propria with a solid, sheet and groove-like pattern of growth, which marked cytologic atypia, nuclear grooves, folds, large eosinophilic nucleoli and abundant mitotic figures, some of them atypical (Figure 2A). Melanin pigmentation was found some-where. Immunohistochemically, the atypical melanocytes were reactive for vimentin (Figure 2B), Melan-A and HMB-45 (Figure 2C), while negative for S-100, CK, CK5/6 (Figure 2D), CK8/18, desmin, MyoD1 and CD34. Reactive expression of Ki-67 which is an accurate mark-er of the proliferative index of cells was 50%. Metastasized lesions of MM were found in one lymph node in the left of superior cervix and eight lymph nodes in the left of submaxillary, respectively. As for SCC, grossly, there was a white solid nodular in the right occipital scalp with hyperkeratosis and ulcerate, measuring approximately 2.5 cm×2 cm×1.5 cm in epider-mis, infiltrated subcutaneous tissue. Histo- pathologically, SCC in situ was characterized by highly atypical cells at all levels of the epider-mis (Figure 2E). Invasive SCC exhibited variable differentiation, ranging from tumors formed by

polygonal squamous cells arranged in orderly lobules that exhibited numerous large zone of keratinization to neoplasms formed by highly anaplastic, rounded cells with foci of necrosis, abortive single-cell keratinization and abun-dant mitotic figures (Figure 2F). Immuno- histochemically, the atypical squamous cells were reactive for CK and CK5/6 (Figure 2G), while negative for Vimentin (Figure 2H), Melan-A, HMB45 (Figure 2I), S-100 and CK8/18. Reactive expression of Ki-67 was 70%. Metastasized lesions of SCC were found in one lymph node of the right of occipitalis and one in the right of submaxillary, respectively.

Review of literatures

From what we searched, there were 58 articles in English about combining MM and SCC, including 928 cases combining cutaneous MM and cutaneous SCC and 4 cases combining mucosal MM and mucosal SCC [5-61]. Considering our case combining mucosal MM and cutaneous SCC, 5 selected cases from 1988 to 2016 were summarized (Table 1). The study group comprised 5 patients, of whom 4 were men and 1 was women. The mean age of the study group was about 53.4 years old and the follow-up was about 18.75 months average-ly (range from 14 to 29 months). Their physical examination on admission was unremarkable and revealed no evidence of any pigmented lesions on their skin. In the study group, the combination of mucosal MM and mucosal SCC that occurred separately but simultaneously in the same organ was diagnosed in three cases, including 2 in the oral cavity [5-6] and one in the esophagus [8].

The first oral case had a chronic, draining oro-antral fistula in the right posterior maxillary mucobuccal fold that had been present for 13 years, a 2 cm lesion of MM in the right buccal mucosa and multiple plaques of SCC through-out the floor of his mouth extending to the right anterior tonsillar pillar, and a large, white exo-phytic lesion was attached to the uvula [5]. The second oral case was found a gradually enlarg-ing dark-brown and pigmented nodule measur-ing approximately 3.5 cm×4.3 cm, some sepa-rate dark, pigmented spots on the hard palate, maxillary gingival, and the left side of the buc-cal mucosa and an ulcerative lesion measuring 1.2 cm in diameter. Incisional biopsies of both the dark-brown tumor and ulcerative lesion


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Table 1. Summary of simultaneous primary squamous cell carcinoma and mucosal malignant melanoma

NO. AuthorAge

(years)/Gender

RaceHistory of alcohol and tobacco abuse

Mucosal MM SCCTherapy

Relationship between MM and SCC

Follow-up (months

and status)Site Depth of infiltration Stage Site Size Stage

1 Kippax JB [5]

50, male Caucasiam-American

Tobacco abuse (positive) alcohol abuse (positive)

The right buccal mucosa

3.5 mm IIB The floor of the mouth and u

vula (multiple)

NC NC Limited radiation regi-men

Simultaneously but separately in the same organ

NC, alive, NC

2 Nakahara H [6]

72, female Asian-Japanese

Tobacco abuse (NC) alcohol abuse (NC)

Oral NC NC oral NC NC Cryosurgery, immuno-therapy, chemotherapy


14, alive, CR

3 Sirikan-janapong S [7]

53, male NC Tobacco abuse (positive) alcohol abuse (NC)

Larynx 2.8 mm IIB Larynx NC NC Total laryngectomy, left selective neck dissec-tion, radiation therapy

Simultaneously and admixed

15, alive, CR

4 Hikage M [8]

61, male Asian-Japanese

Tobacco abuse (NC) alcohol abuse (NC)

The upper tho-racic esophagus at 22 cm from the incisors

NC 0 The abdominal esophagus at

43 cm from the incisors

3 cm×1.3 cm 0 Thoracoscopic subtotal esophagectomy, lymph-adenectomy


17, alive, CR

5 This report 31, male Asian-Chinese

Tobacco abuse (negative) alcohol abuse (negative)

Oral 10 mm IIIc Scalp 2.5 cm×2 cm×1.5 cm

III Resection, left neck and right dissection, chemo-therapy, radiotherapy, cellular therapy

Simultaneously but separately in different organ

29, alive, CR

MM, malignant melanoma; SCC, squamous cell carcinoma; NC, not clear; CR, complete remission; PR, partial remission.


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were performed. The histologic diagnosis of the dark-brown nodule was MM and the ulcerative lesion showed SCC. The patient adopted com-bined treatment consisting of cryosurgery, immunotherapy, and chemotherapy. Initially, interferon-γ at a dose of 3×106 IU per day and intratumoral injection of a streptococcal prepa-ration, OK-432, at a dose of 10 KE per day (total 240×106 IU doses of interferon-γ, 220 KE doses of OK-432) were used. Cryosurgery and intratumoral injection of interferon-β at a dose of 40×106 IU per course were performed alter-nately (total 120×106 IU doses of interferon-β). Furthermore, chemotherapy consisting of intra-arterial infusion of 10 mg cisplatin (CDDP) and 250 mg 5-fluorouracil (5-FU) and of intramus-cular injections of 5 mg peplomycin (PEP) per day (total 200 mg CDDP, 5,000 mg 5-FU, and 60 mg PEP) was performed [6].

The case of esophagus was revealed several flat and black pigmented mucosal lesions (2 cm in diameter) in the upper thoracic esopha-gus at 22 cm from the incisors which was histo-logically diagnosed as MM. At the same time, a slightly pitted ulcerous lesion (2 cm in diame-ter) was detected in the abdominal esophagus at 43 cm from the incisors, which was histologi-cally diagnosed as SCC [8].

The case of larynx is the first report recording the combination of mucosal MM and mucosal SCC that not only occurred simultaneously but also admixed consistently with each other,

The patient adopted combined treatment con-sisting of operations, chemotherapy and cellu-lar therapy. The patient has been alive for 29 months from the date of diagnosis.

21 articles about the combination and simulta-neity of cutaneous MM and cutaneous SCC were reviewed [9-30]. These patients were 22 men and seven women, ranging in age from 22 to 72 years at the time of presentation. Most patients were Caucasian. 27 were alive and three died, and the mean time of follow-up was 30.8 months (range, 0.5 to 167 months).

Overall survival time of combination and simul-taneity of MM and SCC for one-year, three-year, and five-year were 94.1%, 91.2%, and 91.2%, respectively. Divided into two groups, one group contains cases combining and simultaneous cutaneous MM and cutaneous SCC and the other contains cases combining and simultane-ous non-cutaneous MM and SCC. 1-year, 3-year, 5-year overall survival rate of the former group were 93.3.0%, 90.0%, 90.0%, respec-tively. The survival time between the two groups has no significant difference (Figure 3, P = 0.486).

Discussion

Oral squamous cell carcinoma (OSCC) is the most frequent of head and neck malignancies [58]. Although malignant melanoma (MM) is a common cutaneous lesion [62], mucosal mela-noma is infrequent [63]. In all of the previously

Figure 3. Kaplan-Meier analysis of overall survival of patients in different groups.

which is called a collision tumor, representing the coexis-tence of two morphologically distinct tumors [7]. The patient underwent the total lar-yngectomy and was found a 2.5 cm ulcerated, black, nodu-lar area located on the left laryngeal mucosa, extending from the false vocal cord to the true vocal cord. Micro- scopic examination revealed in situ and invasive SCC admixed with MM.

To our knowledge, the case of this study is the first case that the combination of mucosal MM and cutaneous SCC occurred separately and simul-taneously in different organs.


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reported cases, it is common that these two tumors occur simultaneously in skin [9-61]. However, non-cutaneous MM combined with SCC is very rare [5-8]. According to what we searched in English literatures, the combina-tion of non-cutaneous MM and SCC occurred only in 5 cases (including our case), which has a higher incidence in middle aged people. It may be more common in men. These kind of double tumors appear more often separately and simultaneously in the same organ. The case of this study is the first case that the com-bination of mucosal MM and cutaneous SCC occurred separately and simultaneously, but in different organs.

In most of the cases, mucosal MM is originated from melanocytes in the basal/deeper layers of the epithelium [8]. History of tobacco and alco-hol abuse, sunlight, radiation, burning of skin, immunodepression, immunodeficiency and some cancerigenic material like hydrocarbons or arsenic, were the most important factors in the pathogenesis of both MM and SCC [10-12, 16, 30-32, 35, 36, 39, 40, 46-51, 53, 55, 56, 61-64]. Another major cause of their simultane-ous or successive appearance in one person is the abnormal expression of signaling molecules during cell proliferation and cell differentiation, such as the expression of p53, cyclinD1, Bcl-2 and proliferating cell nuclear antigen [65, 66]. In the report of Sirikanjanapong S et al [7], it was suggested that both laryngeal mucosal MM and invasive laryngeal mucosal SCC had an overexpression of IL-17A and CD70, eliciting a strong immune response against the tumor resulting in a favorable prognosis. Ile105Val polymorphism of the GSTP1 gene may have genetic contribution to the development of MM [67]. To sum up, genes’ abnormality involved in the mechanisms may play a significant role in progression and prognosis of such malignant tumors.

Like laryngeal SCC, the mainstay treatment for primary mucosal melanoma in the head and neck region is radical surgery with or without adjuvant therapy including radiation and che-motherapy [6]. Generally, radical surgery is the preferred treatment for a localized primary malignant tumor in the oral cavity. However, the second oral case, radical surgery was consid-ered to be impossible because of the extensive involvement by the tumor [6]. In dealing with neoplasms in this region, anatomic consider-

ations often make surgery difficult or impossi-ble. Furthermore, Immunotherapy was incorpo-rated into the treatment of the malignant melanoma, although the patient’s immune response could significantly alter the clinical course of the neoplasm, for which many attempts to therapeutically modulate immune response would be conducted [68-70]. CD24 may be used as a new drug target for malignant melanoma [71].

The depth of invasion of MM and the diameter and infiltrated extension of primary lesion and metastasis of lymph nodes of SCC are the most important prognostic factors [72, 73]. It is gen-erally agreed that the prognosis of oral malig-nant melanoma remains quite poor when com-pared with cutaneous melanoma [6]. Many reports showed that simultaneous evaluation of tumor thickness and stage of invasion was of greater value in assessing prognosis of MM than either method alone [72, 73]. The pattern of tumor invasion was more significant than positive surgical margin in predicting local recurrence and overall survival in patients with oral SCC [73]. Therefore, it may be highly pos-sible that the prognosis of combining MM and SCC have an association with the stages of MM and SCC, surgical margin and treatments.

The biological behavior of such unique cases is still uncertain. Thus, future identification of more of such cases and longer follow-up evalu-ations is still needed to define their biological behaviors.

Acknowledgements

This work was supported in part by grants from the Guangdong Natural Science Foundation (2015A030313177), a research grant from the Guangdong Science and Technology Foundation (2013B021800104) and National College Students Innovation and Entrepreneurship Training Program (201710558010).

Disclosure of conflict of interest

None.

Address correspondence to: Qionglan Tang, De- partment of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan-jiang Road, Guangzhou 510120, China. Tel: 86-20-81332590; Fax: 86-20-81332781; E-mail: [email protected]

mailto:[email protected]

mailto:[email protected]


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case report simultaneous primary mucosal …abstract: we report one case of combining primary...

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