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Background

C.A.S.T.L.E is an acronym for carcinoma with thymus-like differentiation. This rare tumor occurs in the head and neck region and has been identified in organs such as thyroid gland. It derives its name from the histologic resemblance to the thymus gland.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/
Other Diagnostic Testing
 
Gross Appearance
and Clinical Variants
 
Histopathological Features
and Variants
 
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

 

HISTOLOGICAL TYPES CHARACTERIZATION
GENERAL  
Tumors of the neck showing thymic or related branchial pouch differentiation: a unifying concept.

Chan JK, Rosai J.

Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
Hum Pathol. 1991 Apr;22(4):349-67 Abstract quote.  

A number of rare tumors occurring in the soft tissues of the neck and the thyroid gland, reported in the literature under a variety of designations, show complete to partial histologic resemblance to the fetal, mature, or involuted thymus and mediastinal thymomas. This family of tumors spans a range of histologic appearances and behaviors from completely benign lesions to metastasizing malignant tumors.

After reviewing the previously reported and new cases, we have been able to delineate four reasonably well-defined clinicopathologic entities within this spectrum. On the benign end is "ectopic hamartomatous thymoma," which occurs in the soft tissues of the lower neck. It is characterized by spindle epithelial cells, solid or cystic epithelial islands, and adipose cells which intermingle haphazardly to impart a hamartomatous quality. In the middle of the spectrum are the ectopic cervical thymomas which are usually benign, but can sometimes be locally invasive and can exceptionally metastasize. They are histologically identical to mediastinal thymomas, and residual ectopic thymus is not uncommonly identifiable in the periphery of the tumor.

On the malignant end are tumors we have designated as "spindle epithelial tumor with thymus-like differentiation" (SETTLE) and "carcinoma showing thymus-like differentiation" (CASTLE). Tumors of the SETTLE type occur in the thyroid gland of young patients, and are highly cellular tumors comprised of compact bundles of long spindle epithelial cells which merge with tubulopapillary structures and/or mucinous glands.

Tumors of the CASTLE type are histologically similar to thymic carcinoma of the lymphoepithelioma or squamous cell variety. We postulate that this family of tumors arises either from ectopic thymus or remnants of branchial pouches which retain the potential to differentiate along the thymic line.
SKIN  
Carcinoma with thymus-like differentiation arising in the dermis of the head and neck.

Bayer-Garner IB, Kozovska ME, Schwartz MR, Reed JA.

Marshfield Clinic, Marshfield, WI, USA.

J Cutan Pathol. 2004 Oct;31(9):625-9. Abstract quote  

Carcinoma exhibiting thymus-like differentiation (CASTLE) is a rare, distinct tumor of the thyroid gland or soft tissue of the head and neck that may simulate primary squamous cell carcinoma or lymphoepithelioma, and which contains features reminiscent of thymic differentiation including Hassall's corpuscles, occasional perivascular spaces, and the presence of lymphocytes. Ectopic thymic tissue may result from incomplete descent or persistence of the cervical portion of the thymus and may occur anywhere along the course of the embryonic descent from the angle of the mandible to the sternal notch.

Herein, we report two cases of dermal extrathyroidal CASTLE. The differential diagnosis of squamoid carcinoma with features of thymic differentiation includes extrathyroidal CASTLE, a primary squamous cell carcinoma with thymic differentiation, lymphoepithelioma-like carcinoma of the skin, and metastatic squamous cell carcinoma of unknown primary.

It is essential that the latter two be ruled out before accepting the diagnosis of an extrathyroidal carcinoma with thymus-like differentiation.
THYROID  
Thyroid spindle epithelial tumor with thymus-like differentiation (SETTLE): is cytopathological diagnosis possible?

Kloboves-Prevodnik V, Jazbec J, Us-Krasovec M, Lamovec J.

Department of Cytopathology, Institute of Oncology, Zaloska 2, 1000 Ljubljana, Slovenia.
Diagn Cytopathol. 2002 May;26(5):314-9. Abstract quote  

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare tumor of the thyroid gland which occurs predominantly in children, adolescents, and young adults. It usually presents as a painless neck or thyroid mass and only exceptionally as a diffusely enlarged thyroid gland, without metastatic disease at diagnosis.

We report on the case of 12-yr-old girl who had diffusely enlarged thyroid gland for about 1 yr and was initially treated for thyroiditis. Fine-needle aspiration biopsy (FNAB) was performed 8 mo after the first admission. Cytological examination of smears showed unusual morphological features. FNAB smears were cellular, with dissociated cells, naked oval nuclei, aggregates, and groups. Three main cell types were observed: spindle, epithelioid, and epithelial. These cells were uniform, cytologically bland, with few mitotic figures. The distinction between these cells was not always unequivocal. In the background of the smears abundant red extracellular material in the form of fine, dust-like granules and irregular patches were present. It was also observed in some aggregates and groups of tumor cells. Spindle and epithelioid cells were immunocytochemically diffusely pan-cytokeratin-positive. In the differential diagnosis, medullary thyroid carcinoma and SETTLE were suggested. The final histological diagnosis was SETTLE. In cases of SETTLE presented as a diffuse thyromegaly the correct diagnosis may be delayed because clinically and ultrasonographically thyroiditis is suspected.

To avoid such a delay, FNAB should be used preoperatively. It can provide specific cytological diagnosis based on morphological features and certain immunocytochemical characteristics of the tumor.

 

SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHER
CHARACTERIZATION
SPECIAL STAINS  
IMMUNOPEROXIDASE  
Immunohistochemical staining for bcl-2 and mcl-1 in intrathyroidal epithelial thymoma (ITET)/carcinoma showing thymus-like differentiation (CASTLE) and cervical thymic carcinoma.

Dorfman DM, Shahsafaei A, Miyauchi A.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Mod Pathol. 1998 Oct;11(10):989-94. Abstract quote  

Intrathyroidal epithelial thymoma (ITET)/carcinoma showing thymus-like differentiation (CASTLE), a rare thyroid neoplasm, was recently shown to be immunoreactive for CD5, providing immunophenotypic evidence of previously postulated thymic differentiation.

To assess whether ectopic malignant neoplasms with thymic differentiation display other markers associated with thymic carcinoma, we studied five cases of ITET/CASTLE, two cases of cervical thymic carcinoma, and one case of cervical thymoma for bcl-2 and mcl-1 immunoreactivity. Both of these antiapoptosis proto-oncogenes have been reported to be expressed by the majority of true thymic carcinomas but only a minority of thymomas. All of the five cases of ITET/CASTLE, both CD5-positive cervical thymic carcinomas, and one CD5-negative cervical thymoma were immunoreactive for bcl-2, as were 10 (91%) of 11 thymic carcinomas arising in the thymus, in contrast to 6 (25%) of 24 benign and invasive thymomas arising in the thymus. Similarly, all of the five cases of ITET/CASTLE, both cervical thymic carcinomas, but not the cervical thymoma, were immunoreactive for mcl-1, as were 9 (90%) of 10 thymic carcinomas, in contrast to 6 (33%) of 18 benign and invasive thymomas.

We conclude that dual immunoreactivity for bcl-2 and mcl-1 is a feature of malignant neoplasms with thymic differentiation in general, both within the thymus and at ectopic sites.
Intrathyroidal epithelial thymoma (ITET)/carcinoma showing thymus-like differentiation (CASTLE) exhibits CD5 immunoreactivity: new evidence for thymic differentiation.

Dorfman DM, Shahsafaei A, Miyauchi A.

Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.

Histopathology. 1998 Feb;32(2):104-9. Abstract quote  

AIMS: Cases of intrathyroidal epithelial thymoma (ITET)/carcinoma showing thymus-like differentiation (CASTLE) were examined for CD5 immunoreactivity, a feature of true thymic carcinoma, but not other thymic epithelial neoplasms or carcinomas of other sites. ITET/CASTLE, a rare, low-grade malignant neoplasm arising within the thyroid gland which resembles lymphoepithelioma-like and squamous cell carcinoma of the thymus, is postulated to arise from remnants of branchial pouch capable of thymic differentiation, but thymic differentiation in this neoplasm remains unproven.

METHODS AND RESULTS: The largest published series of cases of ITET/CASTLE was examined for CD5 immunoreactivity using an anti-CD5 antibody reactive in fixed, paraffin-embedded tissue with microwave antigen retrieval. Neoplastic cells in all five cases of ITET/CASTLE studied were immunoreactive for CD5, including foci of tumour metastatic to lymph node and lung. In contrast, none of five cases of thyroid carcinoma with squamous differentiation was immunoreactive for CD5. A minority of cases of typical thyroid carcinomas showed some weak immunoreactivity for CD5. Other carcinomas of the head and neck were nonimmunoreactive for CD5.

CONCLUSIONS: CD5 immunoreactivity in ITET/CASTLE is new evidence in support of thymic differentiation in this neoplasm.
ELECTRON MICROSCOPY  
Spindle epithelial tumor with thymus-like differentiation: a case report with cytologic, histologic, immunohistologic, and ultrastructural findings.

Su L, Beals T, Bernacki EG, Giordano TJ.

Department of Pathology, University of Michigan Medical Center, Ann Arbor, USA.

Mod Pathol. 1997 May;10(5):510-4 Abstract quote

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare and distinctive low-grade neoplasm of thymic or related branchial pouch differentiation. The tumor usually presents in the thyroid or lateral neck of children and adolescents and could mimic spindle-cell carcinoma, synovial sarcoma, or malignant teratoma.

We report the clinical, cytologic, histologic, immunohistochemical, and ultrastructural features of a SETTLE present for 10 years in a 15-year-old boy. The fine-needle aspirate, initially interpreted as synovial sarcoma, contained numerous clusters of bland spindle cells, with a few detached sheets of columnar mucous cells in a homogeneous background of dissociated spindle cells. Mitoses, necrosis, and atypia were not present. The excised tumor was a well-circumscribed, white-tan mass, with occasional microcysts. Microscopically, the mass consisted of a lobulated, highly cellular, spindle-cell neoplasm arranged in intersecting, whorled, and storiform fascicles separated by fibrous bands. Entrapped within the fibrous bands were squamous-lined cysts and benign-appearing glands lined by columnar epithelium with goblet cells or ciliated pseudostratified epithelium. Immunohistochemically, the spindle cells showed diffuse reactivity for cytokeratins, smooth muscle actin, muscle-specific actin, and MIC-2, and they were negative for epithelial membrane antigen, calcitonin, and thyroglobulin.

Ultrastructurally, numerous perinuclear tonofilaments, some aligned with mature desmosomes, were identified in the spindle cells. Occasional cells showed thin filaments with fusiform dense bodies occupying the peripheral cytoplasm.

These findings distinguish SETTLE from ectopic thymoma, synovial sarcoma, medullary carcinoma, and teratoma, and they support a thymic epithelial origin for SETTLE, possibly with myoepithelial differentiation.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
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 October 2, 2004

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