Primary adenocarcinoma of the thymus: an immunohistochemical and molecular study with review of the literature

  • Maryam Maghbool1,

    Affiliated with

    • Mani Ramzi2,

      Affiliated with

      • Inga Nagel3,

        Affiliated with

        • Pablo Bejarano4,

          Affiliated with

          • Reiner Siebert3,

            Affiliated with

            • Abolfazl Saeedzadeh1 and

              Affiliated with

              • Yahya Daneshbod1Email author

                Affiliated with

                BMC Clinical Pathology201313:17

                DOI: 10.1186/1472-6890-13-17

                Received: 2 January 2013

                Accepted: 22 May 2013

                Published: 31 May 2013

                Abstract

                Background

                Primary adenocarcinoma of thymus is extremely rare.

                Case presentation

                This is a case of primary adenocarcinoma with intestinal differentiation and focal mucin production in the thymus. Thymic cyst was associated with this tumor. Intestinal differentiation was confirmed by immunohistochemical stain with positivity for CDX-2, CK20, villin, MOC31 and focal positivity of CK7. Array comperative genomic hybridization (CGH) analysis showed a complex pattern of chromosomal imbalances including homozygous deletion at the HLA locus in chromosomal region 6p21.32.

                Conclusion

                This rare tumor shows a similar genetic aberration with other studied thymic epithelial tumors.

                Keywords

                Thymus gland Primary adenocarcinoma Intestinal differentiation Thymic carcinoma Thymoma Molecular study CGH array Immunohistochemical study Literature review

                Background

                Primary thymic carcinomas are very rare tumors. The most common histologic subtypes are squamous cell, adenosquamous/mucoepidermoid, basal cell, large cell undifferentiated, adenocarcinoma, carcinoma with adenoid cystic carcinoma-like features, lymphoepithelioma-like, clear cell, and sarcomatoid carcinomas [1]. Primary thymic adenocarcinoma was first reported in 1989 [2] but has not been accepted as a valid histologic subtype until 1997 [3]. These are uncommon neoplasms. Papillary adenocarcinoma and mucinous adenocarcinoma are the most common variants [1, 46]. Therefore, before a diagnosis of a de novo thymic adenocarcinoma, other possible diagnoses such as: metastatic carcinoma, thymoma and adenocarcinoma arising in a mediastinalteratoma should be excluded [1, 7]. There is little genetic data for thymic carcinomas other than squamous cell carcinomas [8], so we applied a genetic study by array comperative genomic hybridization (CGH) analysis on this case.

                Case presentation

                A 28 year old woman presented with neck and right upper extremity pain accompanied by dyspnea of two years duration. Chest X- ray revealed mediastinal widening (Figure 1A). Chest computed tomography (CT) scan (Figure 1B) showed an anterior mediastinal mass invading in pericardium without extramediastinal extension. An initial clinical impression of a mediastinal germ cell tumor was considered but serum tumor markers such as alpha-feto protein (AFP), Beta-human chorionic gonadotropin (β-hCG), carcinoembryonic antigen (CEA) and CA-125 were normal. CA19-9 level was 2420 U/ml (normal: 0.37U/ml). A mediastinal biopsy was done and showed histologic features of adenocarcinoma. Endoscopy, colonoscopy, abdominopelvicsonography and imaging studies were negative for primary origin. The patient underwent mid-sternotomy. The mass was resected. The patient received chemotherapy (GEMOX) and radiotherapy with two recurrences in 2 years follow up. She is doing well and free of tumor after 6 months.
                http://static-content.springer.com/image/art%3A10.1186%2F1472-6890-13-17/MediaObjects/12907_2013_135_Fig1_HTML.jpg
                Figure 1

                Representative images of radiology, histology, immunostaining as well as results of array-comparative genomic hybridization (array-CGH). A: Chest X ray showed mediastinal widening. B: chest CT scan revealed anterior mediastinal mass that invade pericardium. C: tumoral sheets and glandular structures in desmoplasticstroma (H&E stain, × 400). D: Malignant glands showed diffuse membranous positivity for CD5. (Immunoperoxidase). E: nuclear positivity for CDX-2 in malignant glands (Immunoperoxidase). F: Malignant glands showed diffuse positivity for CK20 (Immunoperoxidase). G: benign columnar linningthymic cyst adjacent to neoplastic glands (H&E stain, × 200). H: neoplastic glands arising in the vicinity of thymic cyst (H&E stain, × 200). I: Array-CGH-results displayed in a whole genome view showed deletion of chromosome 6. J: Homozygously deleted region around the HLA-DRB5-locus in chromosomal region 6p21.32.

                Pathologic findings

                The mediastinal biopsy showed a moderately differentiated adenocarcinoma with a desmoplastic and necrotic stroma (Figure 1C). Scattered small mucinous lakes were noted in the stroma. The stroma also showed foci of calcification and occasional psammoma bodies. Intracytoplasmic and stromal positive reactions were seen on mucicarmin stain. The excised tumor showed similar morphological and immunohistochemical characteristics. In one of the sections, a unilocunar large cyst with columnar epithelium, in vicinity of the tumor was also identified (Figure 1G, H). Small foci of remnant of thymic tissue were identified. Immunohistochemical (IHC) study showed positivity for CK, EMA, CK20 (Figure 1D), CDX-2 (Figure 1E), CK7, CD5 (Figure 1F), villin, HMWK(focal) and MOC31 but ER, PR, TTF-1, GCDFP-15, P63, CD30, PLAP, chromogranin, calretinin and CD117 were all negative. Commercial sources, clones, and working dilutions of antibodies used in the study are listed in Table 1. Extensive histologic and immunohistochemical study of the whole specimen showed no evidence of teratomatous or germ cell elements.
                Table 1

                Comercial sources, clones, and working dilutions of antibodies used in this case

                Antibody

                Dilution

                Clone

                Vendor

                HMWK

                Ready to use

                34 βE12

                Novocastra, New Castle, UK

                EMA

                Ready to use

                GP1.4

                Novocastra, New Castle, UK

                CK

                Ready to use

                AE1/AE3

                Novocastra, New Castle, UK

                CK20

                Ready to use

                PW31

                Novocastra, New Castle, UK

                CDX-2

                1: 100

                AMT28

                Novocastra, New Castle, UK

                CK7

                Ready to use

                RN7

                Novocastra, New Castle, UK

                CD5

                Ready to use

                4C7

                Novocastra, New Castle, UK

                Villin

                1: 200

                CWWB1

                Novocastra, New Castle, UK

                MOC31

                1: 50

                MOC31

                Novocastra, New Castle, UK

                ER

                Ready to use

                6 F11

                Novocastra, New Castle, UK

                PR

                Ready to use

                16

                Novocastra, New Castle, UK

                TTF-1

                1: 200

                SPT24

                Novocastra, New Castle, UK

                GCDFP-15

                Ready to use

                23A3

                Novocastra, New Castle, UK

                P63

                1: 25

                7JUL

                Novocastra, New Castle, UK

                CD30

                Ready to use

                JCM182

                Novocastra, New Castle, UK

                PLAP

                Ready to use

                8A9

                Novocastra, New Castle, UK

                Chromogranin

                Ready to use

                5H7

                Novocastra, New Castle, UK

                CD117

                Ready to use

                T595

                Novocastra, New Castle, UK

                Calretinin

                1: 200

                CAL6

                Novocastra, New Castle, UK

                Genetic abberations in formalin-fixed paraffin-embedded tissue

                Array CGH on this case was performed using the Human Genome Microarray 180A platform (Agilent, Santa Clara, USA). The experimental procedures were performed according to the protocols provided by the manufacturers. Slides were scanned with the G2565CA Microarray Scanner (Agilent) at a scan resolution of 5 μm. Signal intensities from the generated images were measured and evaluated with Feature Extraction 10.10.11 and Agilent Genomic Standard Workbench Edition 6.5.0.58 (AGW6.5) software (Agilent) applying the Aberration Detection Method-2 (ADM-2) algorithm with a threshold of 6.0. It showed a complex karyotype with multiple gains and losses. Part of the HLA-DR5 locus in chromosomal region 6p21.32 seemed to be homozygously deleted (Figure 1I, J).

                Consent

                “Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.”

                Discussion

                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, 35, 7, 8]. 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, 7, 8]. Caution must be given because CD5 is positive in malignant pleural mesothelioma and adenocarcinomas of other (non thymic origin) organs [4, 8]. 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 2 and 3. 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) [47, 918].
                Table 2

                Literature review of clinicopathological data of primary thymic adenocarcinomas

                Author

                Year

                Sex

                Age

                Symptoms

                Tumor type

                Site

                RX

                Outcome

                Associated findings

                Moriyama S [2]

                1989

                F

                51

                Hyperthyroidism

                Papillo-tubular

                Right lobe of the thymus

                S

                No recurrence for 14 years

                Multiple thymic cysts

                Babu MK [19]

                1994

                M

                50

                NA

                Conventional

                NA

                 

                Alive after 4 months

                Congenital thymic cyst

                Makino Y [6]

                1998

                M

                39

                Chest pain

                Papillary carcinoma

                NA

                S,R

                Alive after 5 months

                NA

                Matsuno [5]

                1998

                M

                70

                Not mentioned

                Papillary carcinoma

                Anterior mediastinum

                S,R

                Recurrence after 8 months

                Numerous psammoma bodies

                F

                69

                Not mentioned

                Papillary carcinoma

                Left lower pole of the thymus

                S

                Not mentioned

                Thymoma of medullary type

                F

                61

                Not mentioned

                Papillary carcinoma

                Substernalmediastinal mass

                S,R,C

                Died after 7 months

                Chronic elephantiasis nostrasverrucosum in skin

                M

                57

                Not mentioned

                Papillary carcinoma

                Anterior mediastinum

                S,R,C

                Alive after 5 years

                No

                Shimono [20]

                2001

                M

                61

                facial edema, general fatigue

                Not specified

                Anterior mediastinum

                S,R,C

                Alive after 53 months

                No

                Zaitlin [21]

                2003

                F

                51

                Asymptomatic

                Papillary carcinoma

                Anterior left mediastinum

                S,R

                Died after 26 months

                Thymic cyst

                Choi WW [7]

                2003

                M

                39

                Cough&lethargy

                Papillary carcinoma

                Anterior mediastinum

                S,R,C

                Alive after 3 years

                NA

                M

                15

                Dry cough

                Mucinous carcinoma

                Right anterior mediastinum

                S,R

                Died after 26 months

                Thymiccyst&cribriform, carcinomatous gland in thymic medulla

                Misao [10]

                2004

                M

                59

                Accidental finding in chest x ray

                Not specified

                Anterior Mediastinum

                S,C

                Died after 24 months

                No

                Takahashi F [1]

                2004

                M

                49

                Accidental finding in chest x ray

                Mucinous carcinoma

                Anterior mediastinum

                R

                Died 11 months after DX

                Increased CA19-9, CEA

                Seki, ErinaMD [11]

                2004

                M

                 

                Left shoulder pain

                Mucinous adenocarcinoma with pleural dissemination

                Anterior mediastinum

                R.C

                Alive in 11 months after surgery.

                No

                Yoshino M [12]

                2005

                F

                29

                Accidental finding in chest x ray

                Papillary carcinoma

                Anterior mediastinum

                S

                Not mentioned

                Type A thymoma, Psammoma bodies and follicles

                PayalKapur [4]

                2006

                M

                41

                Not mentioned

                Mucinous carcinoma

                Anterior mediastinum

                R,c

                2 recurrence in 3 years

                Multiple thymic cysts

                ToyomitsuSawai [9]

                2006

                M

                34

                Accidental finding in chest x ray

                Moderately differentiated adenocarcinoma

                Right anterior mediastinum

                R,C

                Lung metastasis after eight months of surgery

                Increased CA19-9, CEA

                Seong H. Ra [13]

                2007

                F

                61

                Hoarseness, dysphagia, left shoulder pain, and fatigue

                Mucinous carcinoma

                Superoanterior mediastinum

                S,R

                Metastatic disease to retroperitoneal lymph nodes at 5 months

                Psammoma bodies

                F

                82

                Shortness of breath, chest tightness, back stiffness, and weight loss of 15 lb

                Mucinous carcinoma

                Anterior mediastinum

                S

                Passed away due to surgical complications

                Thymiccyst, signetringlike features

                Furtado [14]

                2008

                M

                44

                Accidental finding in chest x ray

                Papillary carcinoma

                Pretracheal region

                S,R,C

                Alive for 24 months

                Psammoma bodies

                HosakaY [15]

                2009

                M

                36

                Accidental finding in chest x ray

                Moderately differentiated adenocarcinoma with papillary formation

                Right anterior mediastinum

                R

                Alive in 11 years after surgery

                Type AB thymoma

                Toshiji I [16]

                2009

                M

                54

                Cough, fever, dyspnea,chest pain, facial edema

                Poorly differentiated sarcomatoid tumor cells partially composed of papillotubular adenocarcinoma

                Anterior mediastinum

                R

                Passed away 56 days after the initialsymptoms

                Slight elevation of sialyl Lewis-x antigen,soluble interleukin-2 receptor

                Maeda D [17]

                2009

                F

                52

                Bulging of the left parasternal region

                Mucinous carcinoma

                Anterior mediastinum

                S,R,C

                Lung metastasis after 7 months

                Thymic cyst

                M

                38

                Chest pain

                Mucinous carcinoma

                Anterior mediastinum

                S,R,C

                Died 12 months after diagnosis

                No

                M

                55

                Chest tightness

                Mucinous carcinoma

                Anterior mediastinum

                S,R,C

                Died 24 months after diagnosis

                No

                Yong Joon Ra [18]

                2010

                M

                68

                Dyspnea and chest pain on left anteriorchest

                Conventional

                Anterior mediastinam

                Not mentioned

                Not mentioned

                Slightly increased (β-hCG) level

                Current case

                2010

                F

                28

                Neck and right upper extremity pain and dyspnea

                Mucinous

                Anterior mediastinam

                S,R,C

                Two recurrences in two years follow up

                Thymic cyst and psammoma bodies, increased CA19-9

                Abbreviations: NA not available, S Surgery, R Radiotherapy, C Chemotherapy, Thy Thymectomy.

                Table 3

                Clinicopathologic data of the thymic adenocarcinoma reported in literature according to the four major subtypes

                Tumor subtype

                Total case

                Male/Female

                Median age

                Associated thymic cyst

                Associated thymoma

                Associated psammoma body

                Associated serum tumor markers

                CEA

                B-HCG

                AFP

                CA19-9

                Papilotubular

                2

                1

                52.5

                1

                0

                0

                    

                Conventional

                3

                3

                50.6

                1

                0

                0

                1

                1

                  

                Papillary

                10

                1.5

                49.5

                1

                3

                3

                1

                  

                1

                NOS

                2

                2

                60

                0

                0

                0

                1

                  

                1

                Mucinous

                9

                2

                50.2

                4

                0

                1

                3

                  

                1

                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 3, 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, 23]. 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, 22, 23]. 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, 24].

                In our case, the HLA-DRB5-locus in chromosomal region 6p21.32 was homozygously deleted, showing similar genetic aberrations with other thymic epithelial tumors.

                Conclusion

                This primary adenocarcinoma of the thymus with intestinal differentiation shows homozygous deletion of part of the HLA- locus in chromosomal region 6p21.32 confirmed by CGH array. It is associated with a benign thymic cyst. This is the first genetic study on a primary thymic adenocarcinoma (mucinous type), which shows a similar genetic aberration with other thymic epithelial tumors. We suggest adding genetic study to clinicopathologic and imaging workup for confirmation of diagnosis of a primary thymic tumor.

                Declarations

                Acknowledgements

                We like to thank Professor K. Daneshbod for his scientific comments and guidance and Mrs. F. Hadad, for performing immunohistochemicalstainings.

                Authors’ Affiliations

                (1)
                Department of Molecular Pathology, Dr Daneshbod Pathology Laboratory
                (2)
                Department of Hematology- Oncology, Shiraz University of Medical Sciences
                (3)
                Institute of Human Genetics, Christian-Albrechts University Kiel and University Hospital Schleswig-Holstein
                (4)
                Department of Pathology, JMH/University of Miami School of Medicine

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                25. Pre-publication history

                  1. The pre-publication history for this paper can be accessed here:http://​www.​biomedcentral.​com/​1472-6890/​13/​17/​prepub

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                This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.