Cytologic patterns

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 High Low High High, with very large

of aspirates (May be high in a few numbers of
specific tumors) individualized free
nuclei from ruptured
cells (“naked nuclei”)
Cell Associations Clusters (adherent); Individual cells, or in Individual cells Clusters (adherent);
rarely see acinar some non-cohesive rarely see acinar
formation if glandular aggregates formations
origin

Cell Shapes Variable: Often Spindled to stellate to Round(ish) Generally round or

polygonal, columnar, or irregular cuboidal
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 Round

indented

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

Examples of Benign: Adenomas Benign:“-omas”, e.g. Lymphoma Insulinoma

tumors Malignant: Carcinomas fibromas Plasmacytoma Thyroid tumors
Malignant: Sarcomas Mast cell tumor
Histiocytoma
TVT