Clinical History
A 62-year-old man had a mild cough but was otherwise completely
asymptomatic and healthy. A routine chest X-ray demonstrated a small (3 to 4 cm) mass that was centrally
located in the lower lobe of the left lung. Bronchoscopy was performed and described the presence of a
"fleshy" tumor. The mass was brushed and washed. Past medical history was significant for a high grade
(Gleason 8) adenocarcinoma of the prostate that was resected nine years earlier. Although focal capsule
penetration was evident, all lymph nodes were negative (Figures A,B,C).
Case 1 - Figure A - Interlacing capillaries dominate this field which demonstrates a clean smear background. The capillary array is surrounded by individually dispersed small cells and small aggregates of similar cells; these cells are characterized by solitary small dark nuclei and high nuclear-to-cytoplasmic ratios. Similar appearing small cells are attached at various points along the length of the capillaries (Papanicolaou stain, low power).
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Case 1 - Figure B - Scattered small cells possess slightly ovoid nuclei with distinct but delicate membranes, chromatin which is moderately intensely stained, and chromocenters or minute nucleoli. Where visible, cytoplasm is scanty, cyanophilic, and somewhat granular. Distinctly absent are mitotic figures, necrotic debris, and lymphoglandular bodies (Papanicolaou stain, high power).
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Case 1 - Figure C - This cohesive aggregate of small cells demonstrates a high density of nuclei due to high nuclear-to-cytoplasmic ratios. There is a vague suggestion of acinar or rosette formation within the aggregate. Distinctly granular chromatin is present within the small round or ovoid nuclei. Although crowded, true nuclear molding is not apparent (Papanicolaou stain, high power).
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Cytologic Findings
The smears of the brushing were highly cellular and
included abundant flat and folded sheets of benign respiratory mucosa. At times, this mucosa was in
direct contact with aggregates of the small neoplastic cells. Most of the neoplastic cells were
unassociated with any other tissue or matrix components. They were individual scattered, present in
small cohesive clusters, and in moderately sized aggregates. At times, the latter had a 3-dimensional
quality, but generally represented flat sheets with rather well defined edges. The neoplastic cells were
rather homogeneous in appearance in that they had solitary round and slightly ovoid nuclei with thin but
distinct membranes and generally inconspicuous nucleoli. The chromatin was not extremely
hyperchromatic. The chromatin granularity varied from fine to coarse; the latter gave a more
characteristic "salt and pepper" quality. Within some of the solid aggregates of neoplastic cells, there
were rudimentary or definite acini present. These were characterized by central granular, green
cytoplasm surrounded by homogeneous neoplastic nuclei. Some of the larger tissue fragments included
anastomosing capillary blood vessels. Characteristically, the neoplastic cells were directly attached to
the external surfaces of some of the capillaries. Only a minority of the individually dispersed
neoplastic cells demonstrated a plasmacytoid appearance. The cytologic diagnosis on the brushings was
"carcinoid tumor." The washings were negative for neoplastic cells.
Histologic and Clinic Follow-up
A left lower lobectomy was performed.
The histologic diagnosis was carcinoid tumor (Grade I neuroendocrine carcinoma). In addition, two lymph
nodes were examined microscopically and both were negative for metastatic neoplasm. Although the
follow-up is short term (approximately 9 months), the patient is alive, well, and shows no evidence of
residual neoplasm.
Discussion
Carcinoid tumors account for approximately 2% of all primary neoplasms of the lung. These
tumors occur in all age groups, but primarily in adults. Although rare in children, they are the most
common true neoplasms of the lung in the pediatric population. The vast majority of pulmonary carcinoid
tumors arise centrally in association with large bronchi. A small proportion occurs peripherally within
the lung (many of these have a predominant spindle-cell constituency and therefore are not considered any
further). Most bronchial carcinoid tumors behave in completely benign fashion. However, between 5% and
20% may metastasize at least regional lymph nodes. Still, only rarely do patients die of primary
carcinoid tumors of the lung. The clinical course of an individual patient cannot be predicted
accurately on the basis of the morphology of a conventional carcinoid tumor. As an introduction to the
neuroendocrine neoplasms of the pulmonary system, it is prudent to review briefly the histologic
classification proposed by Travis et al in 1998. These authors divided these tumors into four major
groups. The carcinoid tumors were defined as neoplasms, which histologically demonstrated neuroendocrine
morphology with an absence of necrosis and a low mitotic rate. More specifically, in histologic
sections, there were less than two mitotic figures per 10 high power microscopic fields (HPMF).
Neuroendocrine morphology was defined as tumor cells present in organoid nests and cords with distinct
peripheral palisading of the nuclei. A major thrust of this publication was to expand the diagnosis of
the atypical carcinoid tumor. This neoplasm also had a neuroendocrine morphology but demonstrated
increased mitotic activity and/or distinct tumor necrosis. To qualify as an atypical carcinoid tumor,
the neoplasm needed to possess between 2 and 9 mitotic figures per 10 HPMF in histologic sections. The
most common neuroendocrine neoplasm, namely, small cell carcinoma, required a mitotic activity exceeding
10 mitoses per 10 HPF. For the most part, the neoplastic cells are small and homogeneous in appearance
with coarsely granular, hyperchromatic chromatin, sharply angulated nuclear contours, and generally
inconspicuous nucleoli. Their nuclear-to-cytoplasmic ratios (N/C) are very high. The fourth category in
the scheme of Travis et al, namely, large cell neuroendocrine carcinoma, does not fall into the
differential diagnosis of carcinoid tumor. This neoplasm, in histologic section, had 11 or more mitotic
figures per 10 HPMF. In addition, necrosis tends to be much more extensive than with the atypical
carcinoid tumor. The individual neoplastic cells are quite large, variably pleomorphic, have greater
volumes of cytoplasm, and hence lower N/C ratios than in either type of carcinoid neoplasm. In addition,
nucleoli are much better developed than in either carcinoid tumor. This classification system poses
several potential diagnostic challenges for cytology.
However, in general, I believe that carcinoid tumors can be reliably diagnosed in the vast majority of
patients in cytologic preparations including sputums, bronchial brushings, and both transthoracic and
transbronchial aspiration biopsies. Typical carcinoid tumors often yield moderately to highly cellular
smears in aspiration biopsies but manifest lower cellularity in exfoliative material, especially sputum
specimens. In some samples, the neoplastic cells are present primarily in cohesive aggregates, whereas
in others, individually dispersed tumor cells comprise the majority of the neoplastic elements. In most
samples, both individual tumor cells and clusters are evident. One arrangement of the tumor cells which
is quite characteristic of carcinoids is the association one or a few layers of uniform neoplastic cells
along the surface of straight and branched capillaries. Although this is typical of fine needle
aspiration biopsies, as witnessed in our case, this can also be seen in bronchial brushings. Also
characteristic is the finding of rosettes or small acini.
A striking attribute of carcinoid tumors in cytologic smears is the marked uniformity of the tumor
cells. They have round, oval, or cuboidal contours, and scant but obvious basophilic and at times
granular cytoplasm. Each cell has a solitary round to ovoid nucleus, which is also quite homogeneous in
diameter. Stippled chromatin yields the characteristic "salt and pepper" pattern. If present, nucleoli
are small and inconspicuous. When individually distributed, the neoplastic cells may demonstrate a
plasmacytoid appearance.
The cytologic differential diagnosis of carcinoid tumors includes both benign and malignant entities.
Due to the relatively bland appearance of the nuclei, one must consider reserve cell hyperplasia in
exfoliative samples. The latter is a benign reactive process which occurs in response to a number of
noxious stimuli to the bronchial mucosa. Histologically, multiple layers of small uniform cells with
solitary ovoid nuclei, darkly stained chromatin, and scanty cytoplasm are present beneath a layer of
ciliated columnar epithelial cells. In exfoliative smears, one typically finds several tightly cohesive
clusters consisting of 10 or more cells. Due to their very N/C ratios, these aggregates may appear very
darkly stained and suggest a carcinoid tumor or small cell carcinoma. However, individually dispersed
hyperplastic reserve cells are unexpected. Furthermore, on closer inspection, these cells are small,
strikingly monotonous in appearance, and possess an orderly pattern of arrangement. A very helpful clue
in many examples is the presence of small numbers of columnar cells with cilia at one edge of the
aggregates. One must also consider benign and malignant lymphocytes in the differential diagnosis. This
is because of the small nature of the cells, their high N/C ratios, and the tendency in some specimens
for marked dispersion of the neoplastic carcinoid cells. However, true intercellular cohesion will be
seen in at least a proportion of the carcinoid tumors, but not with benign or malignant lymphocytes.
Lymphoglandular bodies are associated with lymphocytes, not carcinoid tumors.
A major point in the differential diagnosis with carcinoid tumor is other primary neuroendocrine
neoplasms, namely, atypical carcinoid tumors and small cell carcinoma. I believe that one can reliably
distinguish carcinoid tumors and small cell carcinomas in cytologic preparations in the overwhelming
majority of instances. With small cell carcinoma, each malignant tumor cell possesses a single nucleus
that varies from ovoid to sharply angulated and irregular. In contrast to carcinoid tumors, the
chromatin is coarsely granular or densely homogeneous. Marked hyperchromasia is the rule in contrast to
carcinoids. In many tumor cells, nucleoli are not evident but may be more so in aspiration biopsies.
Although the neoplastic cells are relatively homogeneous, some degree of variability in nuclear size and
shape will be evident in most instances. Many tumor cells possess little or no visible cytoplasm
resulting in extremely high N/C ratios; they are higher than typically seen with carcinoids. Within
cohesive aggregates, nuclear molding is often well developed, not so in carcinoid tumors. Due to the
fragility of the malignant nuclei, streaks of chromatin are commonly experienced in smears, especially
aspiration biopsies and brushings. Such is usually not the case with carcinoid tumors. I have not
witnessed the close association of small cell carcinoma with capillaries in any form of cytologic
preparation. The smear background may contain necrotic debris, in addition to the streaks of smeared
DNA.
I believe that it may be difficult or even impossible to diagnosis with certainty an atypical
carcinoid tumor in cytologic preparations. All published studies with cytomorphologic criteria are based
on older histologic definitions of atypical carcinoids and not that of Travis et al. In addition, some
of the published morphologic investigations have included both exfoliative and aspiration samples, and it
is my opinion that different specimen types may result in somewhat subtle differences in cytomorphology.
Perhaps most importantly, the counting of mitotic figures in cytologic smears, both exfoliative and
aspiration in types, is not an established procedure that has been validated in comparison with tissue
sections. The accurate counting of mitotic figures in histologic samples is crucial in distinguishing
atypical carcinoids from typical carcinoids in many instances. Using published but variable criteria for
the cytologic diagnosis of an atypical carcinoid, these neoplasms manifest as tumor cells with more ovoid
and irregularly shaped nuclei, more coarsely granulated chromatin, and more darkly stained chromatin with
prominent nucleoli than is seen in the typical carcinoid. Furthermore, some investigations have included
a greater degree of pleomorphism with the presence of large neoplastic cells as an attribute of atypical
carcinoids. The necrotic debris is frequently described as a cytologic feature in these specimens.
However, in my experience, it is focal.
Finally, other neoplasms need to be considered in the differential diagnosis. This includes the rare
primary adenoid cystic carcinoma of the upper respiratory tract. The neoplastic cells are small,
homogeneous, and have high N/C ratios. True nuclear molding is not evident, similar to carcinoid
tumors. However, one can usually identify tumor cells encasing spheres of collagenous matrix material.
This will be especially useful in the differential diagnosis with carcinoid. Metastases also need to be
included, e.g., lobular carcinoma of the breast and granulosa cell tumors of the ovary.
Comparison of Cytologic Features of Typical and Atypical Carcinoid
Tumors
| Feature | Carcinoid | Atypical Carcinoid |
| Cellular arrangements | Flat to 3-D cohesive aggregates | Smaller groups Acini common |
| Cell size | Small | Small (to moderate) |
| Cell contour | Round-oval | Round, oval, spindled |
| N/C | High | High |
| Chromatin | Finely-moderately granular | Coarsely granular |
| Nucleoli | Small | Small to moderate |
| Mitotic figures | Absent | Present |
| Necrotic debris | Absent | Present focally |
Comparison of Cytologic Features of Typical Carcinoid and Small Cell
Carcinoma
| Feature | Carcinoid | Small Cell Carcinoma |
| Cell arrangements | Flat to 3-D cohesive aggregates, Individual cells, Association with capillaries | Loose cluster, Molding, Streaming single cells |
| Cell size | Small | Smaller |
| Cell Contour | Round-oval | Round to angular |
| N/C | High | Higher |
| Chromatin | Finely to moderately granular | Coarsely granular or homogeneous |
| Nucleoli | Small | Small |
| Mitotic Figures | Absent | May be numerous |
| Necrosis | Absent | May be abundant Basophilic streaking |
References
- Travis WD, et al. Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 1998;22:934-944.
- Jordan AG, et al. The cytodiagnosis of well-differentiated neuroendocrine carcinoma. A distinct clinicopathologic entity. Acta Cytol 1987;31:464-470.
- Szyfelbein WM, et al. Carcinoids, atypical carcinoids, and small-cell carcinomas of the lung: differential diagnosis of fine-needle specimens. Diagn Cytopathol 1988;4:1-8.
- Mitchell ML, et al. Capillaries. A cytologic feature of pulmonary carcinoid tumors. Acta Cytol 1991;35:183-185.
- Frierson AF Jr, et al. Fine needle aspiration cytology of atypical carcinoid of the lung. Acta Cytol 1987;31:471-475.
- Wiatrowska BA, et al. Large cell neuroendocrine carcinoma of the lung: proposed criteria for cytologic diagnosis. Diagn Cytopathol 2001;24:58-64.
- Geisinger KR, et al. Modern Cytopathology. Churchill Livingstone, 2004, Philadelphia. pp. 415-423.
