Large Cell Carcinoma & Giant Cell Carcinoma
UNDIFFERENTIATED LARGE CELL CARCINOMA
As its name implies, undifferentiated large cell carcinoma shows no evidence of squamous
or glandular maturation. Thus these tumors are often diagnosed by default, when all other
possibilities have been excluded.
Large cell carcinoma represents 10-20% of bronchogenic tumors. These tumors lack any
diagnosic features to suggest their diagnosis prior to biopsy. They tend to grow rapidly,
metastasize early, and are strongly associated with smoking.
Because of the small samples obtained in biopsies, larger resection specimens often yield
more information and change the diagnosis to adenocarcinoma or squamous cell carcinoma.
Glandular differentiation is found more common than squamous in tumors that have
previously been diagnosed as large cell undifferentiated on small biopsies. This
correlates with the gross observation that these tumors tend to be present peripherally,
Large cell tumors are usually large, bulky, well-circumscribed, pink-grey masses with
extensive hemorrhage and necrosis. Although they commonly have central necrosis, they
rarely cavitate. They tend to present in the mid to peripheral lung zones. They may extend
locally to involve the segmental or subsegmental bronchi.
Undifferentiated large cell carcinoma are defined by the WHO as "a malignant
epithelial tumor with large nuclei, prominant nucleoli, abundant cytoplasm and usually
well defined cell borders, without the characteristic features of squamous cell, small
cell or adenocarcinomas." Their diagnosis is made when elements of squamous ar
glandular differentiation cannot be proven.
The cells are generally round to polygonal and present in groups without any higher
architectural features. As a rule, the nuclei are large and round with prominant nucleoli.
Due to the necrosis that frequently accompanies these tumors, there are zones of dropout
within the middle of the specimens,
which may suggest a glandular lumen. Sometimes there may be a variable population of the
cells that have a clear cytoplasm, however, they stain negatively for mucin with either a
mucicarmine or periodic acid-Schiff with diastase stain. For this reason, obtaining a
mucin stain is imperative to make the diagnosis. It has been reported that in
approximately half of the cases where undifferentiated large
cell carcinoma is suspected, a mucin stain will be positive, thus designating the tumor as
an adenocarcinoma. For a mucin stain to be considered truely positive, intracytoplasmic
mucin must be identified. Extracellular mucin positivity is not significant.
Immunohistochemical stains have shown undifferentiated large cell carcinomas to be a
diverse group of tumors including poorly differentiated adenocarcinomas and squamous cell
carcinomas. Based on cytokeratin expression, there are type major populations within this
category. One group expresses simple epithelial cytokeratins, and is considered to be a
poorly differentiated adenocarcinoma. While the other population, sugggested to be a
poorly differentiated squamous cell carcinoma, expresses cytokeratins more commonly
associated with squamous epithelia.
GIANT CELL CARCINOMA
Giant cell carcinoma is categorized by the WHO as a variant of large cell carcinoma. This
subtype is particularly aggressive and carries a very poor prognosis.
These tumors generally present as a large peripheral mass with a focal necrotic component.
They do not involve the large airways, unless by direct extension.
Giant cell carcinoma is recognized as a large cell carcinoma with a component of highly
pleomorphic multinucleated cells. The nuclei are varied in size and shape. Generally, they
are large and irregularly shaped with clumped chromatin and one or more nucleoli. However,
the range of nuclear features extends to include multiple small nuclei within a cell. It
is considered that at least 30-50% of these
cells be present before making the diagnosis. These cells generally contain a large amount
of finely vacuolated eosinophilic cytoplasm. Cell cohesion is frequently lost. There is
often a necrotic component to these tumors, resulting in a neutrophilic or monocytic
inflammatory cell infiltrate.
Immunohistochemical stains can be useful in differentiating this tumor from a wide variety
of other tumors that may be suggested by its histologic appearance. Negative staining for
mucin differentiates it from an adenocarcinoma. Positive staining for cytokeratins is
useful in eliminating sarcomas as a possibility. The loss of cell cohesion may suggest a
lymphoma. However, unlike lymphomas, giant cell
tumors are negative for leukocyte common antigen (CD45). These tumors are sometimes
postive for humoan chorionic gonadotrophin (hCG) and may superficially resemble
R.B. is a 57 year old white female who
presents with a 4 year history of sharp burning pain in the right scapular area that
radiates to the right breast area.
The onset was gradual with the pain worsening over the last 1 to 1.5 years. The pain is
exacerbated with use of her right hand or by long periods of sitting. It is also worse at
night. Hot or cold packs provide some relief.
She reports a poor appetite and has lost 15-20 lb in the last 2 months. Her family members
report that she has some decrease in memory, and has stopped going to bingo and yard
sales, two of her favorite activities. She fatigues easily and has dyspnea on exertion
after walking one to two blocks. She also complains of a chronic cough that is
productive of white phlegm, without hemoptysis. She
denies fevers, chills or night sweats.
The alcohol-fixed, Papanicolaou-stained smears of the lung aspirate contain cohesive
groups of cytologically malignant cells with increased nuclear:cytoplasmic rations,
nuclear pleomorphism, and prominent nucleoli. The vague acinar arrangement of the cell
groups and absence of any squamous
features is suggesstive of an adenocarcinoma. A mucin stain or immunohistochemistry could
be performed on additional unstained smears or cell block material to confirm the
Adenoid Cystic Carcinoma
Histologically, the tumors are well-differentiated, with a peglike cellular growth
along alveolar walls.
The cells secrete mucin and surfactant apoprotein. This can lead to bronchorrhea which is
an excessive discharge of mucus from the air passages of the lungs. Although
bronchioloalveolar carcinoma usually spreads through the airways, it may also metastasize
by lymphatic and hematogenous routes. Due to this growth pattern, the metastatic and local
invasive potential of this tumor is unpredictable. Consequently, histological findings are
not useful in predicting survival. Unlike
other adenocarcinomas, bronchioloalveolar carcinoma often develops multifocally. Patients
with extensive consolidation or multifocal disease have a poor prognosis. The lepidic
growth pattern may result in lesions of heterogeneous radiologic opacity. In a few cases
the tumor resembles lobar pneumonia, and this pattern also has a poor prognosis.
Bronchioloalveolar carcinoma can manifest as a single peripheral nodule or mass usually in
the upper lung. Most commonly, this nodule is well-circumscribed. This form of tumor has a
better prognosis for surgical resection. However, because of the multifocal nature of this
disease, patients should be carefully evaluated for other disease before considering
L.M. is a 66 year old man currently being evaluated for clinical stage C prostate
cancer. A pre-operative chest x-ray revealed a suspicious lesion in the right lung, and
was referred for evaluation. He denies fevers, headaches, dysphagia, or chest discomfort,
however he does have dyspnea on exertion and occasional hemoptysis. He has a 25 pack year
smoking history, but he quit smoking 25 years ago.
Images from the pleural fluid obtained by pleurocentesis. In the upper image, note the
large tumor cells within and adjacent to the cluster of cells. The lower image is a
close-up of the cells. Again, note their size, as well as the large nuclei which contain
E.C. is a 65 year old woman referred to the clinic for the evaluation of a lung mass
found on a CT scan. The scan was obtained to look for metastatic spread of her breast
cancer before beginning chemotherapy. Three weeks prior to clinic she underwent a left
breast biopsy and modified radical mastectomy to remove a 5 x 6 cm breast mass identified
as infiltrating ductal breast carcinoma extending into the lymphatics. Surgically her
breast cancer was classified as a stage IIIA. Her only
complaints are low back pain persisting for several years and shortness of breath on
exertion. She denies bony pain, abdominal pain, or neurologic symptoms.
The patient's PA chest x-ray showing the tumor in the posterior mediasinum.
Low power photomicrograph of the cyst wall demonstrates all of the benign tissue types
normally found in bronchial structures. Note the single epithelial layer, the underlying
smooth muscle cells, and the mature cartilage (in the image on the right). Mature
cartilage is often present in the wall of a bronchial cyst.
K.V. is a 55 year-old female patient with increased fatigue, dyspnea on exertion, and a
persistent dry cough. She denies fever, chills, or hemoptysis, and has no recent weight
change. She smokes half of a pack of cigarettes per day and has a 60 pack year history.
PA chest X-ray reveals a large suprahilar density. There is bilateral pleural
thickening, with calcification.
This is a low power photomicrograph of the tumor showing the relatively small,
cytologically bland tumor cells forming a nest under the bronchial epithelium.
Y.Z. is a 55 year old, male college professor who was referred from his local physician
for evaluation of persistently elevated serum thyroglobulin.
His past medical history is significant for papillary carcinoma of the thyroid. Fourteen
years previously he had a total thyroidectomy and right modified radial neck dissection.
Chest CT shows a nodule behind a rib on the left.
Low and high power photomicrographs of the chondrosarcoma. The lesion shows the
abundant blue-grey chondroid matrix typical of cartilaginous growths. The features which
distinguish this lesion as a malignant cartilaginous neoplasm are its marked cellularity
and the pleomorphism of the individual chondrocytes.
A.E. is a 57 year old man who presents with a right upper lobe pulmonary nodule that was
detected on a routine chest X-ray. His only complaints are fatigue and diffuse muscle
aches. He is a seventy pack year smoker who quit within the past few weeks.
Chest CT confirms the presence of a less than 1 cm nodule, as well as multiple nodules
over the right upper lobe.
A photomicrograph of a granuloma, the upper image is low power view. In the center is
the necrotic core, which is surrounded by epitheloid histiocytes and a chronic
inflammatory reaction. The lower field is a close-up of the three classical layers of a
granuloma: the central zone of necrosis, the middle zone of epithelioid histiocyes, and
the outer cuff of small lymphocytes. Note that some of the
epithelioid histiocytes have coalesced into multinucleated giant cells.
R.C. is a 53 year old man recently seen in the emergency room for the evaluation of
hemoptysis. A chest x-ray showed an anterior mediastinal mass, which was confirmed on CT.
He now presents a week later in clinic for follow-up. The hemoptysis has continued,
however the sputum no longer contains large clots but does not contain streaks of blood.
He denies any fever, chills, or recent
Chest CT confirms the presence of the anterior mediastinal mass.
The tumor is removed from the chest cavity. Upon examination, a portion of the resected
right upper lobe (RUL), pericardium (P), and tumor (T) are seen.
Mixed Small Cell and Large Cell
H.Y. is a 48 year old woman complaining of progressive shortness of breath, hemoptysis,
and weight loss. She has a long history of dyspnea on exertion. Her cough has been
productive of yellow sputum for several months, however, over the past few days she has
developed hemoptysis. She has lost 30
pounds over the last six months, and she complains of anorexia. She also complains of left
sided pleuritic chest pain over the last two months, but she denies fevers, chills or
sweats. She has a 70 pack year smoking history.
A CT demonstrating the tumor compressing the pulmonary artery and collapsing the lung
against the chest wall.
A.O. is a 64 year old woman who was referred to the clinic after an abnormal density in
the left suprahilar area was found on a preoperative chest x-ray prior to the resection of
her bladder tumor. She denies any dyspnea, orthopnea, edema, cough, hemoptysis,
fevers, chills, night sweats, or weight loss.
The patient's PA chest x-ray demonstrating the mass.
Pictures taken during surgery. Above, the forceps are pulling the pericardial cyst.
Below, the patient after the removal of the cyst.
The upper image is a low power photomicrograph of the simple cyst. At this power note
the vascularized fibrous connective tissue of the wall. The lower picture is a view of a
similiar area at high power. The cyst is lined by a simple epithelium ranging from
cuboidal to flat. This type of epithelial lining is characteristic of mesothelium. Note
the absence of any evidence of malignancy, such as an infiltrating population of cells or
significant cytologic atypia.
Pulmonary Artery Angiosarcoma
J.B. is a 35 year old male who came to the clinic for a second opinion of a left upper
lobe infiltrate. He reported that he had been healthy all of his life until 6 months
ago, when he began to experience symptoms of cough and pleuritic chest pain with dyspnea
at minimal exertion. Initially he was treated for pneumonia, however, he remained
symptomatic following treatment with various antibiotics.
Bronchoscopy was used to examine his left upper lobe, but there were no endobronchial
lesions and transbronchial biopsies were nondiagnostic. He was then treated for a fungal
infection, since his fungal titers were borderline. This new treatment failed to resolve
his symptoms. He also reported a 25 pound weight loss with loss of appetite over the last
3 months, but he denied fevers, chills, nausea,
vomiting, or environmental exposures.
A chest CT reveals that there is no contrast filling of the left pulmonary artery. The
mass can be seen within the pulmonary artery.
A normal day 5 post-operative chest X-ray reveals that he still has an air fluid level
in the upper fifth of his left chest cavity. His right chest is clear.
images (x-ray and CT) from a patient with small cell lung carcinoma
E.C. is a 57 year old white male who presents with a 3 month history of right-sided
anterior chest pain radiating to his arm. He also complains of hoarseness for the last
month and a 10 lb weight loss.
A head CT revealed a single lesion of the right parietal lobe.
Selected images from the transthoracic fine needle aspirate biopsy. These cells were
stained using the standard Papanicolaou technique. Atypical cells such as these, with
their classical "tadpole" morphology, are diagnostic of squamous cell carcinoma.
All of these cells exhibit increased nuclear size, nuclear irregularity, and nuclear
hyperchromasia. The cytoplasm is very uniform and lacks vacuolization. The glassy orange
appearance of the cytoplasm is indicative of keratin formation, a feature of squamous
A.G. is a 58 year old man evaluated for an anterior mediastinal mass. He was in good
health until he noted a single episode of diaphoresis, light headedness and near syncope
while walking to his car. He saught emergency care. A chest x-ray demonstrated a right
hilar and anterior mediastinal fullness. A chest CT confirmed an anterior mediastinal
mass. He denies fever, chills, dyspnea, cough, hemoptysis
or weight loss.
A mediastinal windows CT scan shows the anterior mediastinal mass. It appears to have a
soft tissue quality with sharp boarders and without calcification.
A high power photomicrograph of the proliferative epithelium lining the wall of the
thymic cyst. Multiloculated cysts have a multilayered proliferative epithelial
lining while unilocular cysts have a simple squamous epithelial lining.
Undifferentiated Large Cell
J.D. is a 56 year old man who noted the onset of a productive cough, malaise, fatigue,
right lower extremity weakness and low grade temperatures 3 weeks before presentation. He
has a 40 pack year smoking history and denies alcohol use.
A PA chest x-ray showing a cavitary lesion in the right lower lobe. Note the air-fluid
level within the lesion.
Several fields from the fine needle aspiration biopsy. Each field contains malignant
cells which are characterized by their clumping, large size, increased
nuclear-to-cytoplasmic ratio, and irregularly shaped nuclei with multiple nucleoli.
Because of their large size, nuclear features and the lack of evidense of squamous or
glandular differentiation, these cells are classified as nonsmall cell lung cancer. In
contrast, small cell lung cancer cells are smaller, contain little cytoplasm, and the
nuclei contain very dense chromatin.
A head CT showing edema surrounding brain metastases in the left parietal lobe.