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Figure 1.
Left, Section of parotid gland (patient 1) showing a portion of serous salivary gland (asterisk), and an intraparotid lymph node containing tumor cells (arrow) (hematoxylin-eosin, original magnification ×180). Right, High magnification of squamoid epithelioid tumor cells (arrow) from the same patient (hematoxylin-eosin, original magnification ×400).

Left, Section of parotid gland (patient 1) showing a portion of serous salivary gland (asterisk), and an intraparotid lymph node containing tumor cells (arrow) (hematoxylin-eosin, original magnification ×180). Right, High magnification of squamoid epithelioid tumor cells (arrow) from the same patient (hematoxylin-eosin, original magnification ×400).

Figure 2.
Section of parotid gland (patient 3) containing a duct of salivary gland (bottom arrow), a portion of salivary gland (asterisk), and a tumor with unknown primary site. The tumor cells appear fusiform and anaplastic (top arrow) (hematoxylin-eosin, original magnification ×250).

Section of parotid gland (patient 3) containing a duct of salivary gland (bottom arrow), a portion of salivary gland (asterisk), and a tumor with unknown primary site. The tumor cells appear fusiform and anaplastic (top arrow) (hematoxylin-eosin, original magnification ×250).

Figure 3.
Disease-free survival for patients with and without known primary melanomas.

Disease-free survival for patients with and without known primary melanomas.

Table 1. 
Patients With Malignant Melanomas of the Parotid Gland*
Patients With Malignant Melanomas of the Parotid Gland*
Table 2. 
Primary Sites of 785 Metastases to the Parotid Gland*
Primary Sites of 785 Metastases to the Parotid Gland*
1.
Nasri  SNamazie  ADulguerov  PMickel  P Malignant melanoma of cervical and parotid lymph nodes with an unknown primary site. Laryngoscope. 1994;1041194- 1198
2.
Panagopoulos  EMarray  D Metastatic malignant melanoma of unknown primary origin: a study of 30 cases. J Surg Oncol. 1983;238- 10Article
3.
Conley  JHamaker  RC Melanoma of the head and neck. Laryngoscope. 1977;87460- 464
4.
Bahar  MAnavi  YAbraham  ABen-Bassat  M Primary malignant melanoma in the parotid gland. Oral Surg Oral Med Oral Pathol. 1990;70627- 630Article
5.
Santinni  HByers  RMWolf  PF Melanoma metastatic to cervical and parotid nodes from an unknown primary site. Am J Surg. 1985;150510- 512Article
6.
Robert  CJayaramachandran  S Malignant melanoma of the parotid gland. Br J Clin Pathol. 1992;46217- 218
7.
Conley  JArena  S Parotid gland as a focus of metastasis. Arch Surg. 1963;876- 11Article
8.
Gnepp  DR Metastatic disease to the major salivary glands. Ellis  GLAnclair  PLGnepp  DRedsSurgical Pathology of the Salivary Glands Philadelphia, Pa WB Saunders Co1991;560- 569
9.
Jecker  PHartwein  J Metastasis to the parotid gland: is a radical surgical approach justified? Am J Otolaryngol. 1996;17102- 105Article
10.
Greene  GWBernier  JL Primary malignant melanomas of the parotid gland. Oral Surg. 1961;14108- 116Article
11.
Takeda  Y Melanocytes in the human parotid gland. Pathol Int. 1997;47581- 583Article
12.
Smith  LJStehlin  JS Spontaneous regression of primary malignant melanoma with regional metastasis. Cancer. 1965;181399- 1415Article
13.
Woodward  RTShepherd  NAHensher  SR Malignant melanoma of the parotid gland: a case report and literature review. Br J Oral Maxillofac Surg. 1993;31313- 315Article
14.
Brocheriou  CVaillant  JMSzpirglas  HTereau  Y Melanome malin primitif de la parotide: une observation. Rev Stomatol. 1978;7961- 68
15.
Vuong  PNCassembon  FHouissa-Vuong  S  et al.  Melanome malin primitif de la parotide-etude anatomoclinique. Ann Otol Laryngol. 1986;10345- 55
16.
Travis  LMRice  DLMcClatchy  KDWallace  SW Malignant melanoma of conjunctiva metastatic to parotid gland: reports of cases and discussion of surgical management. Laryngoscope. 1977;872000- 2007Article
17.
Buenechea  RGarrote  JCastro-Forns  MBassas  C Parotid gland metastases from orbital tumors: report of two cases. J Oral Maxillofac Surg. 1993;51570- 574Article
18.
Chang  PKnapper  WH Metastatic melanoma of unknown primary. Cancer. 1982;151106- 1111Article
19.
Klausner  JMInbar  MRozin  RR Unknown primary melanoma. J Surg Oncol. 1983;24129- 131Article
20.
Ball  ABSThomas  JM Management of parotid metastases from cutaneous melanoma of the head and neck. J Laryngol Otol. 1990;104350- 351Article
Original Article
June 1999

Malignant Melanomas of the ParotidComparison of Survival for Patients With Metastases From Known vs Unknown Primary Tumor Sites

Author Affiliations

From the Lillian and Henry M. Stratton–Hans Popper Department of Pathology (Drs Wang and Brandwein) and the Department of Otolaryngology–Head and Neck Surgery (Drs Lawson and Brandwein), Mount Sinai Medical Center, New York, NY; the Department of Pathology, University of Iowa Hospital and Clinics, Iowa City (Dr Robinson); and the Division of Anatomic Pathology, Sunnybrook Health Science Centre, University of Toronto, Toronto, Ontario (Dr Perez-Ordonez).

Arch Otolaryngol Head Neck Surg. 1999;125(6):635-639. doi:10.1001/archotol.125.6.635
Abstract

Background  Malignant melanoma (MM) rarely affects the parotid, and usually this diagnosis will herald a search for a primary skin neoplasm. Occasionally, no primary tumor is ever found, raising questions regarding prognosis and the issue of primary melanoma of the parotid.

Objective  To evaluate retrospectively the clinical and histological features of MM involving the parotid in 19 patients.

Data Sources  Pathology and hospital files at 3 tertiary care university hospitals.

Study Selection  Patients with MM within the parotid with adequate histopathologic and immunohistochemical documentation, as well as clinical information regarding patient outcome.

Data Extraction  In 6 patients, no extraparotid MM was ever identified. After parotidectomy, 5 patients (including 1 patient who died of other causes) were melanoma free at a mean of 4.2 years (range, 14 months to 7.5 years). Only 1 patient died of disease after 17 months. An extraparotid primary tumor was present in 13 patients, 10 with dermal and 3 with mucosal sites. At follow-up, only 1 of these patients was disease free after 2 years. Nine patients died of melanoma after a mean of 2.6 years (range, 10 months to 5 years); the other 3 had evidence of metastatic disease at a mean of 4.3 years (range, 3-6 years). Nondermal sites of primary tumors were the nasal cavity, sclera, and conjunctiva.

Data Synthesis  Patients with metastatic MM from unknown primary tumors have a longer disease-free survival than those with metastases from known primary disease.

Conclusions  Although rare, MM should be considered in the differential diagnosis of parotid tumors. Unusual mucosal or ocular sites should be considered in the search for possible primary tumor sites to avoid treatment delay. These data support the idea that patients with metastatic MM from unknown primary tumors may follow a more improved course than that of patients with metastases from known primary disease.

MALIGNANT melanoma (MM) constitutes 15% of all malignant neoplasms, and 20% of MM occurs in the head and neck region.13 Malignant melanoma will rarely affect the parotid gland, presenting as progressively enlarging, asymptomatic, firm, fixed parotid tumors. Malignant melanoma of the parotid is presumed to be of metastatic origin, but occasionally the primary tumor site may never be identified,4,5 thus raising the issue of regressed dermal primary tumors or primary parotid melanoma. From a pathology viewpoint, the lack of suspicion of MM may lead to erroneous histological diagnoses and delay appropriate management.6 A recent case of parotid MM initially diagnosed as an undifferentiated carcinoma prompted us to search our files and review this issue.

MATERIALS AND METHODS

One hundred eight parotidectomies were identified from January 1, 1975, through December 31, 1997, at The Mount Sinai Medical Hospital, New York, NY. Eight of these were for MM. An additional 6 cases from The University of Iowa Hospital and Clinics, Iowa City, and 5 from Sunnybrook Hospital of Toronto, Toronto, Ontario, were identified. Hematoxylin-eosin–stained slides were reviewed, and standard immunohistochemical studies were performed on formalin-fixed, paraffin-embedded sections using the avidin-biotin-peroxidase complex methods. The following antibodies were evaluated for confirmation: S100 protein (1:300; Dako, Carpinteria, Calif), HMB-45 (1:800; Dako), cytokeratin 5.2 (1:2; Becton Dickinson, San Jose, Calif), and vimentin (1:40; BioGenex, San Ramon, Calif). Medical records were reviewed, and patients were contacted for follow-up.

RESULTS

The 19 patients identified are described in Table 1. Three patients originally received misdiagnoses of poorly differentiated squamous cell carcinoma, adenocarcinoma, and anaplastic carcinoma. (Figure 1 and Figure 2). These patients had no clinical history of MM. The primary site for MM was identified in 13 patients. Ten sites were facial, usually on the forehead or around the ear. The remaining 3 were unusual, nondermal primary sites (sinonasal, scleral, and conjunctival). Of the 6 patients with no identifiable extraparotid MM, 5 (including 1 patient who died of other causes) were melanoma free at a mean of 4.2 years (range, 14 months to 7.5 years). Of the 13 patients with known extraparotid MM, only 1 patient was disease free at 2-year follow-up. Nine patients died of MM after a mean of 2.6 years (range, 10 months to 5 years); the other 3 had evidence of metastatic disease at a mean of 4.3 years (range, 3-6 years).

COMMENT

Since the publication of the series by Conley and Arena,7 there have been many articles on the subject of metastatic disease to the parotid gland.4,5,8,9 Most parotid metastases arise from cutaneous cancers of the upper face and scalp, usually MM (46%) or squamous cell carcinoma (37%).7 The Armed Forces Institute of Pathology files, reporting on 490 cases, reveal that MMs are the second most common metastatic tumor of the parotid gland, after squamous cell carcinoma. Table 2 represents a compilation of all primary tumor sites that may result in parotid metastases.8

What are possible sources of parotid MM with unknown primary tumor sites? Several possibilities exist. The primary melanoma may regress, or the parotid gland may be the primary source of MM.5 The issue of origin of a primary parotid MM is unsettled, yet it is a moot point, as any parotid melanoma obligates the clinician to investigate dermal and nondermal sites. Greene and Bernier10 reasoned that melanoblasts may be present within the parotid, as this gland develops from invaginating buccal epithelium, which is known to have the potential of containing melanoblasts. They demonstrated melanin within ductal and acinar cells. We could not confirm any definite ductal or acinar melanin or the presence of melanocytes in our histological review. Takeda,11 however, recently documented the existence of benign melanocytes in the basal and suprabasal layers of a parotid interlobular duct in an autopsy case. Greene and Bernier10 also noted that primary parotid melanomas were not located in lymph nodes but were infiltrative and poorly demarcated tumors. However, many of our "primary" cases of parotid MM revealed the MM within an intraparotid lymph node. Regression of a primary cutaneous melanoma by autoimmune surveillance is known to occur. Smith and Stehlin12 reported spontaneous regression of primary MM with regional metastases; in 8 of 456 cases of metastatic MM (1.7%), no dermal primary lesion was ever found. Spontaneous regression of the dermal primary tumor was observed to develop in another patient.12

Woodward et al13 proposed the following criteria for the diagnosis of a primary parotid MM: (1) the tumor epicenter is within the parotid; (2) there is no identifiable lymph node tissue present in the mass; (3) there is no evidence of MM elsewhere after diligent search of eyes, skin, nose, pharynx, mouth, esophagus, anogenital region, and meninges; and (4) there is no evidence of previous excisions of an MM or progression of a pigmented lesion. By these standards, they identified 1 case of primary parotid MM and reviewed 8 other cases.4,10,14,15 We disagree, however, that the presence of MM within an intraparotid lymph node is inconsistent with the possibility of a primary parotid MM, as melanocytes can be present within lymph nodes.

A third consideration, as we illustrate, is metastasis from unusual, noncutaneous sites (eg, paranasal sinuses or sclera). Travis and colleagues16 detailed unusual primary sites for MM that metastasized to the parotid. They reported 5 invasive conjunctival melanomas, 2 of which had intraglandular parotid metastases. Buenechea et al17 also reported 2 orbital MMs with parotid metastases. In fact, the original sclera lesion in 1 of our patients was diagnosed as an atypical melanocytic proliferation before discovery of a metastatic melanoma. Therefore, we invoke the time-honored admonition that it is necessary to obtain a detailed history of lesions that have undergone biopsy and to perform a thorough physical examination on any patient with a parotid melanoma.

In this series, 3 patients (among the 6 without extraparotid MM) originally received the misdiagnosis of poorly differentiated squamous cell carcinoma, adenocarcinoma, and anaplastic carcinoma (Figure 1 and Figure 2). This fact highlights how difficult the diagnosis of MM may be at times, especially when one is not suspecting this diagnosis. Malignant melanoma may have epithelioid, spindled, plasmacytoid, or clear cell features. Intranuclear holes, amphophilic nucleoli, eccentric nuclei, cytoplasmic pigment that may be finely granular and stippled, and pigment within adjacent histiocytes all point toward the possibility of MM. The immunohistochemical profile (vimentin and S100 positivity for all cases, HMB-45 positivity for most cases, and cytokeratin negativity) is characteristic and diagnostic.

In general, the course of MM from an unknown primary lesion is difficult to predict, but there is some dogma that these patients may in fact have an improved prognosis despite tumor discovery at a metastatic stage. The Memorial Sloan Kettering Cancer Center staging of MM,1 which is pertinent to parotid MM, is shown in the following tabulation:

Chang and Knapper18 reviewed 3805 patients with MM and found that 166 (4.4%) of them had unknown primary tumor sites; Klausner and colleagues19 found a similar incidence of unknown primary tumor sites (5.2%) among 230 patients with melanoma reviewed. Chang and Knapper found that patients with MM of unknown primary tumor site followed a similar clinical course to that of patients with overt primary tumors and stages II and III metastases. Klausner et al19 also concluded that the prognoses for MM of unknown primary tumor site seems to be no worse than for typical melanoma at the same stage. Santinni and colleagues5 studied 96 patients with MM metastatic to the parotid gland, the cervical nodes, or both, in whom primary MM was never documented pathologically or was documented by results of physical examination and subsequent close observation. They showed that the survival rate for patients with unknown primary tumor sites was better than that for patients with known primary tumor sites. For the former group, the survival rate was 51.0% for 2 years, 38.5% for 5 years, and 18.8% for 10 years, compared with 32.5% for 2 years, 22.6% for 5 years and 14.2% for 10 years for the latter group.5 Our data also support this contention, as only 1 of 13 patients with known primary MM was disease free at follow-up; 9 patients died after a mean of 2.6 years, and 3 had evidence of metastatic disease at a mean of 4.3 years. By comparison, only 1 of 6 patients without known primary MM died of disease, and the remaining 5 patients were disease free after a mean of 4.2 years (Figure 3).

The recommended treatment plan for parotid MM includes an assiduous search for a dermal, mucosal, or ocular primary MM. Superficial parotidectomy with neck dissection (plus treatment of the primary tumor if present) is recommended. There is no added survival advantage associated with radical parotidectomy.9,20 Malignant melanoma should be considered in the differential diagnosis of parotid tumors. Unusual mucosal or ocular sites should be considered in the search for possible primary tumor sites to avoid treatment delay. Our data support the idea that patients with metastatic MM from unknown primary tumor sites may follow a more improved course than those with metastases from known primary tumor sites.

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Article Information

Accepted for publication December 18, 1998.

Presented in part at the International Academy of Pathology, Boston, Mass, March 1998, and at the International Academy of Oral Pathology, Capetown, South Africa, August 1998.

The authors thank Micha Zeffren and Norman Katz for their photographic assistance.

Corresponding author: Margaret Brandwein, MD, Departments of Pathology and Otolaryngology, Box 1189, The Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029 (e-mail: m_brandwein@smtplink.mssm.edu).

References
1.
Nasri  SNamazie  ADulguerov  PMickel  P Malignant melanoma of cervical and parotid lymph nodes with an unknown primary site. Laryngoscope. 1994;1041194- 1198
2.
Panagopoulos  EMarray  D Metastatic malignant melanoma of unknown primary origin: a study of 30 cases. J Surg Oncol. 1983;238- 10Article
3.
Conley  JHamaker  RC Melanoma of the head and neck. Laryngoscope. 1977;87460- 464
4.
Bahar  MAnavi  YAbraham  ABen-Bassat  M Primary malignant melanoma in the parotid gland. Oral Surg Oral Med Oral Pathol. 1990;70627- 630Article
5.
Santinni  HByers  RMWolf  PF Melanoma metastatic to cervical and parotid nodes from an unknown primary site. Am J Surg. 1985;150510- 512Article
6.
Robert  CJayaramachandran  S Malignant melanoma of the parotid gland. Br J Clin Pathol. 1992;46217- 218
7.
Conley  JArena  S Parotid gland as a focus of metastasis. Arch Surg. 1963;876- 11Article
8.
Gnepp  DR Metastatic disease to the major salivary glands. Ellis  GLAnclair  PLGnepp  DRedsSurgical Pathology of the Salivary Glands Philadelphia, Pa WB Saunders Co1991;560- 569
9.
Jecker  PHartwein  J Metastasis to the parotid gland: is a radical surgical approach justified? Am J Otolaryngol. 1996;17102- 105Article
10.
Greene  GWBernier  JL Primary malignant melanomas of the parotid gland. Oral Surg. 1961;14108- 116Article
11.
Takeda  Y Melanocytes in the human parotid gland. Pathol Int. 1997;47581- 583Article
12.
Smith  LJStehlin  JS Spontaneous regression of primary malignant melanoma with regional metastasis. Cancer. 1965;181399- 1415Article
13.
Woodward  RTShepherd  NAHensher  SR Malignant melanoma of the parotid gland: a case report and literature review. Br J Oral Maxillofac Surg. 1993;31313- 315Article
14.
Brocheriou  CVaillant  JMSzpirglas  HTereau  Y Melanome malin primitif de la parotide: une observation. Rev Stomatol. 1978;7961- 68
15.
Vuong  PNCassembon  FHouissa-Vuong  S  et al.  Melanome malin primitif de la parotide-etude anatomoclinique. Ann Otol Laryngol. 1986;10345- 55
16.
Travis  LMRice  DLMcClatchy  KDWallace  SW Malignant melanoma of conjunctiva metastatic to parotid gland: reports of cases and discussion of surgical management. Laryngoscope. 1977;872000- 2007Article
17.
Buenechea  RGarrote  JCastro-Forns  MBassas  C Parotid gland metastases from orbital tumors: report of two cases. J Oral Maxillofac Surg. 1993;51570- 574Article
18.
Chang  PKnapper  WH Metastatic melanoma of unknown primary. Cancer. 1982;151106- 1111Article
19.
Klausner  JMInbar  MRozin  RR Unknown primary melanoma. J Surg Oncol. 1983;24129- 131Article
20.
Ball  ABSThomas  JM Management of parotid metastases from cutaneous melanoma of the head and neck. J Laryngol Otol. 1990;104350- 351Article
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