Metastatic neoplasms to the mediastinum account for most of epithelial cell neoplasms. The second most common tumors are thymoma and thymic carcinoma. Primary adenocarcinoma is very rare in mediastinum, so before considering this diagnostic entity, most prevalent tumors such as metastatic adenocarcinomas, germ cell tumors and malignant teratomas must be ruled out [1
]. Through clinical history, imaging studies, absence of extramediastinal tumor and histology, we report a case of primary adenocarcinoma with intestinal differentiation of the thymus with mucin production.
Immunostains are an important tool in the study of mediastinal tumors. For instance CD5 is a leukocyte marker expressed on differentiating thymocytes. It is said to be useful in differentiating thymic from non-thymic carcinomas [4
]. Caution must be given because CD5 is positive in malignant pleural mesothelioma and adenocarcinomas of other (non thymic origin) organs [4
]. It is also important to exclude tumors derived from the lung and pleura by evaluating TTF-1 and calretinin.
The exact origin of thymic adenocarcinoma is not clear. Glandular differentiation is rarely seen in ultrastructural studies of normal thymic epithelial cells [5
]. Also, in the involuted thymus, glandular or tubular structures can be found [7
]. Therefore, adenocarcinomas can result from extreme glandular differentiation during tumor progression.
Review of the literature on thymic adenocarcinoma is shown in Tables
and . Twenty-six cases have been reported. Patients range in age from 15 to 82
years (mean 50 y ±17 y). Male/female ratio is 1.9/1. The most common morphologic subtypes are papillary carcinoma (38%), mucinous adenocarcinoma (34%), conventional adenocarcinoma (0.11%), NOS (0.07%) and papilotubular carcinoma (0.07%). Median age is 52.56
years. Associated findings are thymic cyst in 26% (mostly seen in mucinous subtype), thymoma in 11% (only in papillary subtype) and psammoma bodies in 15% (mostly seen in papillary subtype). Serum tumor markers were increased. CEA in 23% (mostly seen in mucinous subtype), B-HCG in 0.38% (only in conventional subtype) and CA19-9 in 11% (one papillary, one NOS and two mucinous subtypes, including ours). Immunohistochemistry on different subtypes were performed in a limited number of papers and showed positivity in CK7 (7/11), CK20 (6/9), CEA (6/9), Leu M1 (4/5), B-HCG (1/2), CDX-2 (3/4), Muc2 (1/2), Muc5 (2/2), CD5 (8/12), P63 (1/2), CA-19-9 (3/3), CAM5.2 (2/2), CK5,6 (1/2), P53 (2/2), Her2 (1/2) [4
Literature review of clinicopathological data of primary thymic adenocarcinomas
Clinicopathologic data of the thymic adenocarcinoma reported in literature according to the four major subtypes
In our case the adenocarcinoma was associated with a large benign thymic cyst with columnar epithelium. It showed no dysplastic change.
Most of the patients with thymic adenocarcinoma do not have any chief complaint (41%). In symptomatic group, the most common presenting sign is chest pain (0.17%). Other rare signs are cough (0.05%), dyspnea (0.05%), and shoulder pain (0.05%). Weight loss is a rare sign in this tumor (0.05%). Anterior mediastinum is the most common location (79%) followed by right, left, substernal and pretracheal mediastinum (each below%1). Prognosis cannot be accurately evaluated due to low incidence rate of thymic adenocarcinoma. Some patients underwent surgical resection (15 cases), chemotherapy (12 cases) or radiotherapy (19 cases). Clinical outcome showed local recurrences (2 cases), metastatic disease (3 cases) and death due to surgical complication or disease (9 cases). According to Table
, mucinous has much worse prognosis than papillary carcinoma (p value
0.05). There are diverse genetic heterogenecity in thymic tumors. Genetic characterization has concentrated on WHO types A, B3, and C that harbors few lymphocytes [22
]. No chromosomal gain is seen in type A and AB thymomas [8
]. Simultaneous gain of 1q and loss of chromosome 6, and 13q aberrations frequently detected in type B3 thymomas. Loss of heterozygosity (LOH) on chromosome 6 is the most frequent genetic abnormality in thymoma. Recent studies on genetic alterations of thymoma based on (LOH) analyses inferred two different genetic pathways of tumorigenesis of thymoma, and heterogeneous genetic alterations in subtypes of thymoma, were identified by CGH and LOH analyses [22
]. One of the important findings in the thymic epithelial tumor is frequent and multiple genetic aberrations of chromosome 6 that are found in 77.5 percent of them. There are five hotspots of frequent deletions indicating that several putative tumor suppressor genes on chromosome 6 are involved in the development of thymic epithelial tumor [8
]. Deletion sites such as 6q21, 6q23, and 6q25-27 are well established in thymoma. As Zhou et al. reported; the most frequent LOH was found in the 6q23.3-25.3 chromosomal region and the second hot spot of deletions was located in the 6p21 region containing the major histocompatibility (MHC) classes I and II gene loci [22
In our case, the HLA-DRB5-locus in chromosomal region 6p21.32 was homozygously deleted, showing similar genetic aberrations with other thymic epithelial tumors.