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Background

This carcinoma of the salivary glands accounts for 5% of all salivary gland tumors. About 2/3 arise within the parotid gland and 1/3 arise within the minor salivary glands. When these tumors arise within the oral cavity, the palate is the most common site. The tumor is slightly more common in women and peaks in the 5th decade. However, it is also the most common malignant tumor to arise in children and adolescents under 20 yrs of age. The tumor is a firm mass and usually asymptomatic. Pain is usually associated with high grade histology tumors. These tumors have a prognosis based upon the clinical stage and histologic grade.

OUTLINE

Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

CLINICAL VARIANTS CHARACTERIZATION
LACRIMAL SAC  

Mucoepidermoid carcinoma of the lacrimal sac.

Williams JD, Agrawal A, Wakely PE Jr.

Departments of Pathology and Otolaryngology, The Ohio State University College of Medicine, Columbus, OH.

Ann Diagn Pathol 2003 Feb;7(1):31-4 Abstract quote

Mucoepidermoid carcinoma of the lacrimal sac is a rare entity. We report a case of mucoepidermoid carcinoma arising in the lacrimal sac of a 30-year-old man who presented with an inner canthal mass. To our knowledge this is the first example of the cytopathology of this neoplasm in this anatomic site.

LUNG  
Pulmonary Mucoepidermoid Carcinoma With Prominent Tumor-Associated Lymphoid Proliferation.

Shilo K, Foss RD, Franks TJ, Deperalta-Venturina M, Travis WD.

From the Departments of *Pulmonary and Mediastinal Pathology and daggerOral and Maxillofacial Pathology, Armed Forces Institute of Pathology, Washington, DC; and double daggerDepartment of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI.

Am J Surg Pathol. 2005 Mar;29(3):407-411. Abstract quote  

We report 6 cases of low-grade pulmonary mucoepidermoid carcinoma displaying a striking lymphoplasmacytic infiltrate. All six tumors had a typical pulmonary mucoepidermoid carcinoma presentation as a polypoid endobronchial mass involving the proximal bronchi.

The patients were 3 females and 3 males with a mean age of 33 years (range, 5-61 years). Half of the patients were asymptomatic, while half experienced mild symptoms of pneumonia, asthma-like symptoms, or hemoptysis. No tumor-related deaths were observed, with a mean follow-up of 51 months. The tumor size ranged from 2.1 to 3.4 cm (mean, 2.9 cm).

The tumors characteristically displayed an elaborate tubulocystic epithelial component composed of intermediate, epidermoid, and mucus-producing cells, and variable numbers of clear cells, multinucleated giant cells, columnar cells, and oncocytic cells. The tumors' lymphoplasmacytic infiltrate with occasional Russell bodies was sufficiently intense to raise concern of a low-grade lymphoma. All tested tumors were immunoreactive with CK7 while nonreactive with TTF-1 and CK20.

Recognition of this histologic variant is important for a correct diagnosis of low-grade pulmonary mucoepidermoid carcinoma. The dense lymphoplasmacytic infiltrate is similar to that previously described in salivary glands as tumor-associated lymphoid proliferation.
PLEURA  
Primary Mucoepidermoid Carcinoma of the Pleura A Clinicopathologic Study of Two Cases

Cesar A. Moran, MD, and Saul Suster, MD
Am J Clin Pathol 2003;120:381-385 Abstract quote

Two cases of primary mucoepidermoid carcinoma of the pleura are described. The patients are 2 men, 48 and 61 years old. Clinically, both men sought care because of chest pain in the right side and breathing difficulty.

Neither of the patients had a history of head and neck tumor, and physical examination revealed that no tumor was present in the head and neck area. Radiographic studies in both men disclosed the presence of a pleural-based mass. Both men underwent surgical excision of the mass. Histologically, in both cases the pleura showed areas of fibrinous pleuritis with an underlying neoplastic cellular proliferation composed of cells with epidermoid features without keratinization and presence of mucocytes.

Both tumors were classified as low-grade tumors. Both patients were alive and well 8 and 12 months after surgical resection. The cases herein presented highlight the importance of including other epithelial tumors in the differential diagnosis of pleural tumors.
SKIN  
Mucoepidermoid carcinoma of the skin: a distinct entity from adenosquamous carcinoma: a case study with a review of the literature.

Riedlinger WF, Hurley MY, Dehner LP, Lind AC.

From the Lauren V. Ackerman Laboratory of Surgical Pathology, Barnes-Jewish Hospital, Washington University Medical Center, St. Louis, MO.

Am J Surg Pathol. 2005 Jan;29(1):131-5. Abstract quote

Mucoepidermoid carcinoma (MEC) of the skin is an exceedingly rare but distinctive neoplasm with respect to its histopathologic features. It is similar if not identical in most respects to MEC of the salivary gland, a neoplasm whose prognosis is correlated with the pathologic grade.

We report a case of MEC of the skin in a 79-year-old white woman who presented with an axillary mass. Beneath an unremarkable epidermis, a circumscribed, cystic neoplasm, unattached to the surface, was characterized by the presence of vague lobules of low-grade-appearing squamous cells accompanied by mucigenic and clear cells. A mucin stain highlighted the mucigenic cells and immunohistochemistry revealed pan-cytokeratin, cytokeratin 7, polyclonal carcinoembryonic antigen, and epithelial membrane antigen positivity. The cytokeratin 20 and gross cystic disease fluid protein were nonreactive. Inconsistency was encountered in the literature where some confusion existed as to whether MEC is synonymous with adenosquamous carcinoma of the skin. Elsewhere in the body, the latter tumor type is a squamous and gland-forming neoplasm with intermediate- to high-grade features rather than a tumor with mucigenic cells intermingled among intermediate and squamous cells.

As in the case of MEC and adenosquamous carcinoma elsewhere in extracutaneous sites, we would propose that a pathologic distinction should be made in the skin for the sake of consistency and for prognostic purposes. Additionally, the immunophenotype of our case is similar to at least two other cases of cutaneous MEC, as well as MEC of the salivary gland, to support the hypothesis that this neoplasm is adnexal rather than epidermal in origin.

 

HISTOLOGICAL TYPES CHARACTERIZATION
General Under the microscope, the tumor has been divided into low, intermediate, and high grade histologies. It is composed of epidermoid cells, mucous secreting cells, and intermediate cells sharing features between the other two. Clear cells are also common.

Mucoepidermoid Carcinoma A Clinicopathologic Study of 80 Patients With Special Reference to Histological Grading

Margaret S. Brandwein, M.D.; Katya Ivanov, M.D.; Derrick I. Wallace, M.D.; Jos J. Hille, D.D.S.; Beverly Wang, M.D.; Adham Fahmy, D.D.S.; Carol Bodian, Ph.D.; Mark L. Urken, M.D.; Douglas R. Gnepp, M.D.; Andrew Huvos, M.D.; Harry Lumerman, D.D.S.; Stacey E. Mills, M.D.

From the Departments of Otolaryngology (M.S.B., D.I.W., J.J.H., A.F., M.L.U.), Pathology (M.S.B., J.J.H., B.W., A.F., H.L.), and Biostatistics (C.B.), Mount Sinai School of Medicine (K.I.), New York, NY; the Departments of Pathology of Memorial Sloan Kettering Cancer Center (A.H.), New York, NY; and University of Virginia (S.E.M.), Charlottesville, Virginia; and Rhode Island Hospital/Brown University, (D.R.G.), Providence, Rhode Island, U.S.A.

Am J Surg Pathol 2001;25:835-845 Abstract quote

We sought to review our experience with salivary mucoepidermoid carcinoma (MEC) over two decades to confirm the validity and reproducibility of histologic grading and to investigate MIB-1 index as a prognosticator. Diagnosis was confirmed on 80 cases, and chart review or patient contact was achieved for 48 patients, with follow-up from 5 to 240 months (median 36 months). Immunohistochemistry with citrate antigen retrieval for MIB-1 was performed on a subset of cases. Kaplan-Meier survival curves were generated for each stage, site, and grade according to our proposed grading system.

To address the issue of grading reproducibility, 20 slides were circulated among five observers, without prior discussion; slides were categorized as low-, intermediate-, or high-grade according to one's ``own'' criteria, and then according to the AFIP criteria proposed by Goode et al. Weighted kappa () estimates were obtained to describe the extent of agreement between pairs of rating. The Wilcoxon signed rank test or the Friedman test as appropriate tested variation across ratings. There was no gender predominance and a wide age range (1586 years, median 49 years). The two most common sites were parotid and palate. All grade 1 MECs presented as Stage I tumors, and no failures were seen for this category. The local disease failure rates at 75 months for grades 2 and 3 MEC were 30% and 70%, respectively. Tumor grade, stage, and negative margin status all correlated with disease-free survival (DFS) (p = 0.0091, 0.0002, and 0.048, respectively). The MIB index was not found to be predictive of grade. Regarding the reproducibility of grading, the interobserver variation for pathologists using their ``own'' grading, as expressed by the value, ranged from good agreement ( = 0.79) to poor ( = 0.27) (average = 0.49). A somewhat better interobserver reproducibility was achieved when the pathologists utilized the standardized AFIP criteria (average = 0.61, range 0.380.77). This greater agreement was also reflected in the Friedman test (statistical testing of intraobserver equality), which indicated significant differences in using one's own grading systems (p = 0.0001) but not in applying the AFIP ``standardized'' grading (p = 0.33). When one's own grading was compared with the AFIP grading, there were 100 pairs of grading ``events,'' with 46 disagreements/100 pairs. For 98% of disagreements, the AFIP grading ``downgraded'' tumors. This led us to reanalyze a subset of 31 patients for DFS versus grade, for our grading schema compared with the AFIP grading. Although statistical significance was not achieved for this subset, the log rank value revealed a trend for our grading (p = 0.0993) compared with the Goode schema (p = 0.2493).

This clinicopathologic analysis confirms the predictive value of tumor staging and three-tiered histologic grading. Our grading exercise confirms that there is significant grading disparity for MEC, even among experienced ENT/oral pathologists. The improved reproducibility obtained when the weighted AFIP criteria were used speaks to the need for an accepted and easily reproducible system. However, these proposed criteria have a tendency to downgrade MEC. Therefore, the addition of other criteria (such as vascular invasion, pattern of tumor infiltration [i.e., small islands and individual cells vs cohesive islands]) is necessary. We propose a modified grading schema, which enhances predictability and provides much needed reproducibility.

Histologic Grade Criteria
Low Well formed glandular structures or microcysts lined by a single layer of mucus-secreting columnar cells
May have papillary infoldings
Intermediate Solid areas of epidermoid cells or squamous cells with intermediate basaloid cells
Papillary cystic infoldings of epidermoid or basaloid cells
High Majority of cells present as solid nests and cords of intermediate basaloid cells and epidermoid cells
Prominent nuclear pleomorphism
Cystic component usually <20%
Rare glands although occasionally the glandular component may predominate
More mitotic figures (usually >4/10hpf), necrosis, and perineural invasion
VARIANTS  
SCLEROSING MUCOEPIDERMOID CARCINOMA  
Sclerosing mucoepidermoid carcinoma of the parotid gland.

Fadare O, Hileeto D, Gruddin YL, Mariappan MR.

Departments of Pathology, Yale University School of Medicine, Yale-New Haven Hospital, New Haven, Conn 06504, USA.
Arch Pathol Lab Med. 2004 Sep;128(9):1046-9. Abstract quote  

Although mucoepidermoid carcinoma is the most common primary malignancy of the salivary glands, the sclerosing morphologic variant of this tumor is extremely rare, with only 6 reported cases. As its name suggests, sclerosing mucoepidermoid carcinoma is characterized by an intense central sclerosis that occupies the entirety of an otherwise typical tumor, frequently with an inflammatory infiltrate of plasma cells, eosinophils, and/or lymphocytes at its peripheral regions.

The sclerosis associated with these tumors may obscure their typical morphologic features and result in diagnostic difficulties. Tumor infarction and extravasation of mucin eventuating in reactive fibrosis are 2 mechanisms of formation that have been suggested as underlying this morphologic variant.

We describe herein another case of sclerosing mucoepidermoid carcinoma that was diagnosed in a 44-year-old woman and review the relevant literature. Morphologic evidence in support of the mucin extravasation hypothesis was identified, as small pools of mucin were present throughout the tumor. However, there was no concentration of the mucin pools near the areas with the most viable tumor cells, which would have provided evidence for a temporal sequence that eventuates in lack of mucin in the most sclerotic regions.
Sclerosing mucoepidermoid carcinoma with eosinophilia of the salivary glands.

Urano M, Abe M, Horibe Y, Kuroda M, Mizoguchi Y, Sakurai K, Naito K.

Department of Surgical Pathology, Fujita Health University, School of Medicine, Aichi, Japan.
Pathol Res Pract. 2002;198(4):305-10. Abstract quote  

We encountered two cases of low malignant mucoepidermoid carcinoma with scanty cellular atypism which originated in the parotid or submandibular gland and was characterized by marked fibrosis and eosinophilic infiltration within tumor tissue despite the predominance of the squamous component.

Here we report these two cases and provide a review of the literature. We believe that clinically these two tumors with stromal fibrosis and eosinophilic infiltration have a low malignant potential, although histological examination revealed a scanty mucus-producing epithelial component. Therefore, we consider this type of tumor as a new subtype of mucoepidermoid carcinoma. A low-malignant mucoepidermoid carcinoma with stromal fibrosis and eosinophilic infiltration, as described in these two cases, may be misdiagnosed as a highly malignant mucoepidermoid carcinoma or squamous cell carcinoma because of its histologically scanty mucus-producing epithelial component.

The objective of this study was to clarify their differences and to discuss the rendering of an accurate histological diagnosis, the degree of malignancy in relation to prognosis prediction, and the choice of therapy. In addition, we propose regarding this type of tumor as a new subtype of mucoepidermoid carcinoma.


SPECIAL STAINS AND IMMUNOPEROXIDASE  
MUC  
MUC1, MUC2, MUC4, and MUC5AC expression in salivary gland mucoepidermoid carcinoma: diagnostic and prognostic implications.

Handra-Luca A, Lamas G, Bertrand JC, Fouret P.

Service d'anatomie et de Cytologie Pathologiques, Hopital Jean Verdier, Universite Paris, XIII, Paris, France.
Am J Surg Pathol. 2005 Jul;29(7):881-9. Abstract quote  

We determined whether immunostaining for mucins could provide a better characterization of salivary gland mucoepidermoid carcinoma (MEC).

We investigated 63 MECs by immunohistochemistry for MUC1, MUC2, MUC4, and MUC5AC. Mucin expressing cell types and labeling patterns were recorded. The results were compared with microscopic grade, tumor-associated lymphoid infiltrate, mucin expression in surrounding salivary glands, clinical features, and outcome. MUC1 and MUC4 labeled the apical membrane of glandular tumor cells and the entire membrane of intermediate, clear, and epidermoid tumor cells. MUC2 and MUC5AC were expressed in the cytoplasm of glandular, mucous, and intermediate tumor cells.

In contrast to MUC1, MUC4 expression decreased with tumor grade (P < 0.01). Unlike MUC2, MUC5AC was expressed in more than 50% of high-grade tumors, including 2 cases that were not stained with Alcian blue. MUC1 and MUC5AC were associated with tumor-associated lymphoid infiltrates (P < 0.05), but not with tumor-associated lymphoid follicles. The proportions of tumors expressing mucins were 71% for MUC1, 21% for MUC2, 79% for MUC4, and 68% for MUC5AC. MUC1 and MUC5AC were more frequently expressed in tumors than in surrounding glands (P < 0.0001). MUC1 expression correlated with shorter progression-free survival (P < 0.05).

In conclusion, mucin expression in MEC differs from that in salivary glands. Intermediate cells express MUC1 and MUC4 all along their cell surface and MUC2 and MUC5AC in their cytoplasm. Staining for MUC5AC in high-grade tumors can be helpful for distinguishing high-grade MEC from squamous cell carcinoma. While MUC4 is related to tumor differentiation, MUC1 expression indicates a worse prognosis.
Expression of Membrane-Bound Mucins (MUC1 and MUC4) and Secreted Mucins (MUC2, MUC5AC, MUC5B, MUC6 and MUC7) in Mucoepidermoid Carcinomas of Salivary Glands.

Alos L, Lujan B, Castillo M, Nadal A, Carreras M, Caballero M, de Bolos C, Cardesa A.

From the Departments of *Pathology and double daggerOtolaryngology, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain; daggerDepartment of Pathology of Hospital Princeps d'Espanya, Bellvitge, Barcelona, Spain; and section signUnitat de Biologia Celular i Molecular, Institut Municipal d'Investigacio Medica, Barcelona, Spain.

Am J Surg Pathol. 2005 Jun;29(6):806-813. Abstract quote  

Mucins are glycoproteins normally synthesized by a variety of secretory epithelial cells. The aim of this study was to investigate the expression of mucins (MUC1, MUC2, MUC4, MUC5AC, MUCB, MUC6, MUC7) in mucoepidermoid carcinomas, the most frequent malignant tumor of salivary glands.

Forty mucoepidermoid carcinomas and twenty-two normal salivary glands were studied for these mucins by immunohistochemistry from formalin-fixed and paraffin-embedded material. Normal salivary glands frequently expressed MUC1 and MUC4, mainly in ductal cells; MUC5B and MUC7 stained mucous and serous acini respectively of submandibular and minor salivary glands; and MUC5AC and MUC2 were poorly detected in excretory ducts. All mucoepidermoid carcinomas expressed MUC1, and 38/40 tumors expressed MUC4. Both membrane-bound mucins stained membranes and cytoplasm of all cell types (epidermoid, intermediate, mucous, clear and columnar). MUC5AC and MUC5B stained glandular differentiated cells in most tumors (29/40 and 33/40 cases, respectively). MUC6 was positive in 13/40 tumors, and both MUC2 and MUC7 in only 2/40 tumors. The high expression of MUC1 was related to high histologic grades, high recurrence and metastasis rates and a shorter disease-free interval (P < 0.05).

Conversely, MUC4 high expression was mainly related to low-grade tumors, lower recurrence rates and a longer disease-free interval (P < 0.05). In conclusion, mucoepidermoid carcinomas of salivary glands usually express MUC1, MUC4, MUC5AC and MUC5B; less frequently MUC6; and rarely MUC2 and MUC7. This mucin expression pattern can be useful for diagnostic purposes. Therefore, MUC1 expression is related to tumor progression and worse prognosis, whereas MUC4 expression is related to a better prognosis.

 

DIFFERENTIAL DIAGNOSIS CHARACTERIZATION
Goblet cells Sialometaplasia
Salivary cyst
Mucinous cystadenoma/cystadenocarcinoma
Oncocytic and squamoid cells Oncocytoma
Oncocytic carcinoma
Metastatic squamous cell carcinoma
High grade salivary duct carcinoma
Acinic cell carcinoma
Clear cells Oncocytoma
Metastatic renal cell carcinoma
Metastatic melanoma
Acinic cell carcinoma
Sebaceous adenoma/carcinoma
Clear cell myoepithelioma/carcinoma
Clear cell carcinoma
Epithelial-myoepthelial carcinoma

Differential Diagnosis of Atypical Squamous Proliferations Within the Oral Cavity

Histology Necrotizing Sialometaplasia Mucoepidermoid Carcinoma, Low Grade Squamous Cell Carcinoma
Architecture/growth Retention of lobular architecture Haphazard, infiltrative growth Haphazard, infiltrative growth
Cellular components Smooth, round to oval nests of metaplastic squamous epithelium with bland cytology
Residual ductal lumina with mucous cells
Admixture of mucous, intermediate,and epidermoid cells
Bland cytology
Irregular cell nests
Nests and cords of squamous cells with irregular outlines and variable amounts of cytologic atypia
No mucin within tumor
Cyst formation Absent Present and prominent Absent
Surface epithelium May show pseudoepitheliomatous hyperplasia, usually not connected to main lesion Uninvolved
Not connected with tumor
Often dysplastic and/or in direct continuity with the carcinoma
May ulcerate
Extravasated mucin necrosis May be present
Lobular infarction of salivary gland acini
Absent May show tumor necrosis
Inflammation May be prominent May be prominent with mucin extravasation

May be present
Association desmoplasia

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
Prognostic Factors  

Prognostic Significance of p27 and Ki-67 Expression in Mucoepidermoid Carcinoma of the Intraoral Minor Salivary Gland

Mitsukuni Okabe, D.M.D., Hiroshi Inagaki, M.D., Takayuki Murase, M.D., Masahisa Inoue, D.M.D., Noriyuki Nagai, D.M.D. and Tadaaki Eimoto, M.D.

Department of Pathology (MOHI, TM, TE), Nagoya City University Medical School, Nagoya, Japan; and Department of Oral Pathology (MI, NN), Okayama University Dental School, Okayama, Japan

Mod Pathol 2001;14:1008-1014 Abstract quote

p27 and Ki-67, a universal cyclin-dependent kinase inhibitor and a proliferative cell marker, respectively, have been useful in predicting clinical aggressiveness in various human tumors.

We studied clinicopathologic significance of these molecules in mucoepidermoid carcinoma of the intraoral minor salivary gland.

Expression of p27 and Ki-67 was assessed immunohistochemically in primary mucoepidermoid carcinomas from 31 patients without distant metastasis at surgery. Correlation each of p27 and Ki-67 expression was analyzed with various clinicopathologic parameters including age, sex, primary tumor site, tumor size, nodal metastasis, clinical stage, and histologic grade. The latter was evaluated using a point-scoring scheme of Auclair et al. that consists of five histologic factors (intracystic component, neural invasion, necrosis, mitosis, and anaplasia). p27 expression was correlated inversely with histologic grade (P = .007), but with none of other factors. When the correlation of p27 expression was further examined with each of the histologic factors, it was correlated significantly with intracystic component, but not with neural invasion, necrosis, mitosis, or anaplasia. Ki-67 expression was correlated significantly with histologic grade only in the clinicopathologic factors (P < .0001), and in the histologic factors, with necrosis, mitosis, and anaplasia. Multivariate prognostic analyses were performed to identify independent risk factors for both disease-free and overall survivals. Large tumor size (P = .031, relative risk = 5.5) and low p27 expression (P = .012, relative risk = 5.2) were risk factors for worse disease-free survival. Low p27 expression (P = .015, relative risk = 15.2) was selected as a risk factor for worse overall survival. Other factors including age, sex, tumor site, nodal status, clinical stage, histologic grade, and Ki-67 did not emerge as independent risk factors in either prognostic analysis.

These data suggest that p27 may be useful in estimating prognosis of the patients who have mucoepidermoid carcinoma of the intraoral minor salivary gland.

Histologic Grade 5 YRS 10 YRS 15 YRS Metastatic Rate
Low 92% 90% 82% 2.5% (minor) 5% (major)
Intermediate 49% 42% 33%  
High 49% 42% 33% 55% (major) 80% (minor)

TREATMENT

Surgical removal

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Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.


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Last Updated July 28, 2005

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