Cytologic patterns

 
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The following are the general categories of cytologic interpretation:

  • Non-diagnostic
  • Inflammation
  • No cytologic abnormalities
  • Hyperplasia/dysplasia
  • Neoplasia

Note:  Often more than one category is present, as inflammation can result in dysplastic changes in the surrounding tissue and inflammation often accompanies a neoplastic process.

Non-diagnostic samples

Many reasons for obtaining a non-diagnostic sample exist including:

  • Poor cellularity of the sample:  due to poorly exfoliating lesion or poor sample collection.
  • Excessive blood contamination:  leukocytes present due to blood contamination are not included in the sample cellularity and do not aid in interpretation of the lesion.
  • Many smudged or ruptured cells: this may result from exuberant collection methods or smear preparation, though some tumor cells are excessively fragile and prone to rupture.
  • Sampling error: aspiration of surrounding fat or other structure, ex. aspiration of the mandibular salivary gland when attempting lymph node aspiration.

If the sample has adequate cellularity and the cells are well-stained and well-preserved, the next step in cytologic diagnosis is the identification of cell-types present.  Does the smear contain inflammatory cells or tissue cells (or both)?  If the slide contains mostly inflammatory cells, then the inflammation should be further characterized and an attempt made to identify the cause of the inflammation (such as infectious agents, foreign bodies).

Inflammation

Based on your identification of inflammatory cells and their relative proportions, inflammatory responses should be classified as:

Suppurative

  • >85% neutrophils
  • Non-degenerate:  suspect immune-mediated, sterile irritants (bile, urine), neoplastic lesions
  • Degenerate:  suspect bacterial sepsis, look carefully for phagocytized organisms

Histiocytic/macrophagic

  • Macrophages predominate, may see multinucleate forms.
  • Suspect foreign body, fungal or specific bacterial infections (such as Mycobacterium, Nocardia, or Actinomyces spp.).

Mixed

  • Neutrophils and macrophages +/- lymphocytes and plasma cells
  • Suspect chronic tissue injury such as lick granulomas, but can also be seen in reaction to foreign bodies, fungi and bacteria.

Eosinophilic

  • >10-20% eosinophils
  • Suspect hypersensitivity/allergic conditions, some infectious diseases such as parasitic disease and some fungal infections, as well as neoplastic processes (such as mast cell tumors).

Lymphocytic or lymphoplasmacytic

  • Heterogeneous mix of mostly small lymphocytes along with plasma cells and other inflammatory cells.
  • Suspect antigenic/immune stimulation, early viral infections or chronic inflammation.
  • A homogenous population in the absence of other inflammatory cells is suggestive of lymphoma.

No cytologic abnormalities

Cells are present in normal numbers for the tissue aspirated and do not possess significant criteria of malignancy.  This finding is most common when aspirating internal organs or lymph nodes, as most skin and subcutaneous masses represent a true pathologic process.

Hyperplasia/dysplasia

The strict definition of hyperplasia is an increase in the number of cells in a tissue; however, the term is often used in a more generic fashion in cytology as a non-neoplastic enlargement of a tissue.  Hyperplasia is often the result of hormonal influences (ex. benign prostatic hyperplasia), tissue injury (ex. hepatic nodular hyperplasia) or antigenic stimulation (lymphoid hyperplasia).  Aspiration of hyperplastic lesions may result in a higher than expected cellularity and cells may display some weak criteria of malignancy, such as a mildly increased N:C ratio, darker blue cytoplasm, slightly more prominent nucleoli or finer chromatin.

Dysplasia, or disordered growth, is most often seen in epithelial tissue secondary to inflammation or irritation.  Dysplasia results in loss of uniformity of the individual cells and disordered architectural arrangement of the cells.  Dysplasia can be cytologically difficult to distinguish from neoplasia as dysplastic lesions often contain more criteria of malignancy than strictly hyperplastic lesions.

Although hyperplasia and dysplasia are non-neoplastic processes, they likely represent a continuum with benign neoplasia.  Cytologically, a hyperplastic process can be difficult to distinguish from a benign neoplastic process and if there is significant dysplasia within the tissue, one must exercise caution as to not interpret dysplasia as malignant neoplasia.  Histopathologic assessment of the tissue should always be done if there is any doubt.

Neoplasia

Neoplasia is suspected when an atypical cell population is present, particularly if an inflammatory response is lacking.  This may include identification of a monomorphic population of cells in an atypical location, such as a large number of mast cells aspirated from a subcutaneous mass or a neoplastic process may be suspected on finding cells with highly atypical morphology (displaying numerous criteria of malignancy) for the site aspirated.  Neoplastic processes can then be further divided into four general tumor categories:  epithelial, mesenchymal, discrete (round) cell and naked nuclei neoplasms.

Epithelial neoplasms (adenomas/carcinomas)

The cells in epithelial neoplasms are arranged in cohesive clusters.  If the cells have a glandular origin (adenocarcinoma) acinar formation may be apparent.  Cells generally have the following features:

  • Large, round to polygonal cells
  • Distinct cell borders
  • Tightly adherent to each other, often with tight junctions (desmosomes) visible
  • Round to oval nuclei
  • ex. perianal adenoma, transitional cell carcinoma, bronchoalveolar adenocarcinoma

Note: As carcinomas become less differentiated they lose some of these features and often become less cohesive, special staining techniques can be necessary in these situations to confirm an epithelial origin.

Mesenchymal neoplasms (sarcomas)

Mesenchymal neoplasms carry features of their embryonic tissue of origin, the mesenchyme.  Cells are individualized and often associated with an extracellular matrix.  Mesenchymal cells often do not exfoliate well and aspirates may be of low cellularity making a definitive cytologic diagnosis difficult.  Cells generally have the following features:

  • Spindle, oval or stellate shaped cells
  • Indistinct cell borders
  • Cells generally exfoliate in low numbers, and are scattered individually (though thick groupings can be seen in some tumors)
  • Cells are often associated with an extracellular matrix
  • Round to oval nuclei
  • ex. fibrosarcomas, soft tissue sarcomas, osteosarcomas, chondrosarcomas

Discrete (round) cell neoplasms

Discrete or round cell tumors often have a hematopoietic origin and as the term suggests, consists of individualized round cells.  Cells tend to exfoliate readily and as such aspirates are often of high cellularity. Morphologic features of the cells are used to classify discrete cell neoplasms further:

Mast cell tumor

  • Degree of granularity and cellular atypia varies with stage of differentiation.
  • Low grade tumors (grade I) tend to consist of well-granulated, uniform mast cells, while cells from high grade (grade III) tumors often have few to no granules and marked cellular atypia with a high mitotic rate.
  • Tumor grading done by histopathology
  • Note: Mast cell granules, especially those of high grade tumors, may not stain with Diff-Quik® type stains. Giemsa or toluidine blue may be needed to visualize the granules.

Histiocytoma

  • Cell of origin is the epidermal Langerhans cell, not truly a neoplastic process but more of a reactive process and as such they usually regress without treatment
  • Variably distinct cell borders with round to oval nuclei, can be indented
  • Moderate to abundant amounts of clear to light blue cytoplasm
  • Minimal cellular atypia, uniform cell size and morphology – bland appearance
  • Often accompanied by variable numbers of small lymphocytes (tumor infiltrating cytotoxic T-cells)
  • DDx: plasmacytoma, granulomatous inflammation, systemic histiocytosis, lymphoma
  • Note: Histiocytomas generally consist of very bland, minimally atypical cells.  If a high degree of cellular atypia (numerous criteria of malignancy) are found and a histiocytic lineage is still suspected, histiocytic sarcoma should be considered a differential diagnosis.

Plasmacytoma

  • Solid, well-circumscribed masses commonly found on digits, ears and mouth
  • Distinct cell borders
  • Variable amounts of blue cytoplasm (often deep blue), some have perinuclear clear zones
  • More atypia (anisocytosis and anisokaryosis) than histiocytic tumors
  • Nuclei are round, occasionally oval, eccentrically placed
  • Binucleation, and occasional multinucleation is common
  • DDx: histiocytoma, lymphoma

Cutaneous lymphoma

  • Solitary to multiple nodules, plaques or ulcerative/exfoliative lesions
  • Monomorphic population of lymphocytes (can be small, intermediate or large) in the absence of plasma cell or an inflammatory infiltrate
  • Scant light to mid-blue cytoplasm, variably prominent nucleoli
  • Epitheliotropic lymphoma – epidermis and adnexal involvment (T-cell)
  • Non-epitheliotropic – dermis and subcutaneous involvement (B-cell)
  • DDx: chronic inflammatory dermatitis, histiocytoma

Transmissible venereal tumor

  • Seen in warm climates, sexually transmitted
  • Histiocytic cell origin but with abnormal karyotype
  • Monomorphic population of round cells with round nucleus, coarse chromatin, prominent nucleoli
  • Abundant light blue cytoplasm with frequent punctate vacuoles
  • Mitotic figures often present

Naked nuclei neoplasms

Naked nuclei neoplasms represent a distinct group of tumors that are usually of endocrine or neuroendocrine origin.  Cells often exfoliate in large numbers but are fragile and aspirates contain many bare nuclei from ruptured cells.  Intact cells are often found in loosely attached sheets or packets surrounded by numerous bare nuclei.  Cells have the following features:

  • Round to polygonal cells
  • Indistinct cell borders
  • Often very few cytologic criteria of malignancy despite an aggressive biological behavior
  • ex. thyroid tumors, pancreatic islet cell tumors, paragangliomas

 

Epithelial

Mesenchymal

Round cell

Neuroendocrine

Typical cellularity of aspirates

High Low
(May be high in a few specific tumors)
High High, with very large numbers of individualized free nuclei from ruptured cells (“naked nuclei”)

Cell Associations

Clusters (adherent); rarely see acinar formation if glandular origin Individual cells, or in some non-cohesive aggregates Individual cells Clusters (adherent); rarely see acinar formations

Cell Shapes

Variable: Often polygonal, columnar, or cuboidal Spindled to stellate to irregular Round(ish) Generally round or cuboidal

Cell Size

Medium to large Medium Small to medium Small to medium

Cell Borders

Distinct Often indistinct Distinct Indistinct

Nuclear Shape

Round to oval Oval to elongated Round, sometimes indented Round

Other Characteristics

Some tumor types may be associated with extracellular matrix Cytoplasmic purple granules in mast cell tumors may occasionally stain poorly with Diff-Quik Tend to lack cytologic features of malignancy regardless of biologic behavior

Examples of tumors

Benign: Adenomas
Malignant: Carcinomas
Benign:“-omas”, e.g. fibromas
Malignant: Sarcomas
Lymphoma
Plasmacytoma
Mast cell tumor
Histiocytoma
TVT
Insulinoma
Thyroid tumors
Anal sac AdCA
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