A wide array of cytoskeletal abnormalities is encountered at different sites and under different pathological conditions. Benign and malignant conditions of the liver, ovarian tumours, renal cell carcinomas, renal oncocytomas, soft tissue sarcomas, and central nervous system tumours have all been noted to contain hyaline bodies of some type.14
Thus far, only two reports of so called “rhabdoid” pancreatic endocrine tumours have appeared in the literature.5,6
In an analysis of pancreatic endocrine tumours in our records, cells of this morphology have been noted focally in occasional cases. However, the case presented in this report is the only one encountered thus far composed of a large population of “rhabdoid” cells.
The prototypic inclusion body in endocrine lesions is the fibrous body seen in some pituitary adenomas, especially the sparsely granulated somatotroph adenoma.15
The seminal observation of these juxtanuclear intermediate filaments was by Racadot and colleagues in 1964.16
The cells of the pituitary adenoma that they described were characterised by round hyaline masses often indenting or causing a concavity of the nucleus.16
Electron microscopic examination showed that these bodies consist of aggregates of intermediate filaments in which occasional neurosecretory granules and mitochondria were also present.16
Cardell and Knighton were the first to use the term “fibrous bodies”, which has become the most common and frequently used term to describe this phenomenon in the pituitary.17
Conditions in which cytoplasmic juxtanuclear aggregates of intermediate filaments are present are diverse and the pathogenesis of these structures is not known. It has been suggested that they are caused by cell damage and apoptosis.14
However, not all cells with intracytoplasmic inclusions exhibit evidence of damage. Indeed, in pituitary tumours, there is no correlation between the formation of fibrous bodies and evidence of cell damage. Among pituitary growth hormone producing adenomas, the densely granulated tumours lack fibrous bodies; these lesions tend to occur in younger patients, often express prolactin and the α subunit of glycoprotein hormones, harbour Gsα mutations,18
and respond well to somatostatin analogue treatment.19
In contrast, sparsely granulated somatotroph adenomas are diagnosed on the basis of the fibrous body formation20
; these lesions tend to occur in older patients, are rarely plurihormonal, do not harbour Gsα mutations, and do not respond well to somatostatin analogues.19
The appearance of these filamentous structures in H&E stained sections is variable; some tumours may not have detectable inclusions within the cytoplasm. They may be seen on toluidine blue stained, plastic embedded, semi-thin sections as a well defined, pale, globoid cytoplasmic inclusion. In some cases, they represent an ultrastructural observation only. However, keratin immunohistochemistry highlights the presence of juxtanuclear globular structures. At the ultrastructural level, intracytoplasmic fibrillary inclusions or whorls have been noted in endocrine tumours of the bronchus and rectum, paragangliomas of the cauda equina,13
and in an endocrine tumour of the pancreas.21
Paranuclear or juxtanuclear intermediate filaments are also characteristic of Merkel cell neuroendocrine carcinomas.
“We advocate the use of the descriptive term cytokeratin aggresomes for tumours containing juxtanuclear aggregates of keratin filaments, because this is more reflective of the structural abnormality causing the characteristic morphological appearance”
The term “rhabdoid” has been used to describe tumours composed of cells with globular cytoplasmic inclusions that are intensely eosinophilic/acidophilic.22
It is obviously reflective of the striking similarity and resemblance to rhabdomyoblasts. Thus, a recently described case similar to the one we present was identified as a “rhabdoid” pancreatic neuroendocrine carcinoma.5
The nomenclature describes a “rhabdomyoblast-like” appearance but implies that the cells are not true rhabdomyoblasts. The term has been further exploited to describe “rhabdoid-like” inclusions—pale, lightly eosinophilic cytoplasmic inclusions within a deeply eosinophilic cytoplasm that are keratin negative and are composed of both thick and thin filaments, not intermediate filaments.23
In contrast, the “signet ring cell” pancreatic tumour described by Stokes and colleagues11
was composed of cells with inclusion bodies consisting of multilayered, concentric, osmiophilic lamellae or myelin figures,11
ascribed to an abnormal accumulation of degenerating organelles. These features are different from the hyaline or plasmacytoid cells seen in myoepitheliomas and pleomorphic adenomas of salivary glands,24,25
in which the cells have a diffusely hyaline, eosinophilic cytoplasm with an eccentrically located nucleus, but do not have hyaline globular, inclusion-like bodies. The cell morphology that is highlighted in this case is also different from the commonly encountered “plasmacytoid” cells seen with air dried Diff-Quik stained fine needle aspiration specimens of endocrine tumours.26
Once again, cytoplasmic inclusions are not present.
The widespread use of “rhabdoid” as a purely descriptive term is somewhat entrenched in the literature, with an ever expanding list of tumours (“composite extrarenal rhabdoid tumours”) exhibiting this characteristic cell type. The resemblance to rhabdomyoblasts is superficial and based on morphological mimicry, and “rhabdoid” does not reflect histogenesis or cell structure. In fact, it is merely a convenient term. In this context, it loses relevance and may lead to the erroneous interpretation of histogenesis in tumours harbouring cells with a similar morphology. We advocate the use of the descriptive term “cytokeratin aggresomes” for tumours containing juxtanuclear aggregates of keratin filaments, because this is more reflective of the structural abnormality causing the characteristic morphological appearance.27
This term was first used by Johnston and colleagues to describe the redistribution of the intermediate filament protein vimentin to form a cage surrounding a pericentriolar core of aggregated, ubiquitinated protein.27
We feel that this phenomenon is especially true in the case of tumours with a neuroendocrine histogenesis, and because the same process occurs in the pituitary, the use of “cytokeratin aggresomes” is more inclusive and unifying. The exact incidence and relevance of cells bearing this characteristic morphology in pancreatic endocrine tumours is not clear at this juncture.
Take home messages
- We describe a pancreatic endocrine tumour with an unusual morphological appearance
- This case highlights the spectrum of changes that can be seen with cytoplasmic, juxtanuclear intermediate filament aggregation and that the application of the term “rhabdoid” as an all embracing term is inappropriate
- Use of the term “cytokeratin aggresomes” has the advantage of alluding to the pathological feature, rather than implying histogenesis, and unifies the identical process that occurs across several tumours
The use of the term “rhabdoid” in pancreatic endocrine tumours especially is not a particularly apt appellation, and is not necessarily reflective of histogenesis. The light microscopy of routinely stained H&E sections of some PETs may be normal, but there may be immunohistochemical and/or ultrastructural evidence of intracytoplasmic whorls of intermediate filaments. In other cases, cytoplasmic inclusions may be detected in individual cells or they may be highly conspicuous on routine sections examined by light microscopy. It is important to point out that a range of morphological appearances can be encountered as a result of cytoplasmic aggregates of intermediate filaments; some cells resembling signet ring cells and others “rhabdoid” cells. The case described here illustrates that intracytoplasmic juxtanuclear intermediate filaments can cause a range of cytomorphological appearances and that the application of the term “rhabdoid” as an all embracing term is inappropriate. The use of the term “fibrous bodies” (as seen and used in the pituitary) may also be inappropriate. “Cytokeratin aggresomes” does have the advantage of alluding to the pathological feature, rather than implying histogenesis, and does unify the identical process that occurs across several tumours.