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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, like adenocarcinomas.

Gross Appearance
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.

Microscopic Features
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.

Gross Appearance
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.

Microscopic Features
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 choriocarcinomas.




Pathologic Types
Adenocarcinoma

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.
SagittalMRI.jpg (49776 bytes)

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 diagnosis.004lungfna.jpg (25086 bytes)

Adenoid Cystic Carcinoma



Bronchioloalveolar

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 surgical resection.

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.
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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 prominant nucleoli.

Bronchogenic Cyst

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.
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The patient's PA chest x-ray showing the tumor in the posterior mediasinum.

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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.


Carcinoid

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.

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PA chest X-ray reveals a large suprahilar density. There is bilateral pleural thickening, with calcification.

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This is a low power photomicrograph of the tumor showing the relatively small, cytologically bland tumor cells forming a nest under the bronchial epithelium.



Chondrosarcoma

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.

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Chest CT shows a nodule behind a rib on the left.

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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.

Histoplasmosis Granuloma
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.

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Chest CT confirms the presence of a less than 1 cm nodule, as well as multiple nodules over the right upper lobe.

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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.


Lymphoma

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
trauma.

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Chest CT confirms the presence of the anterior mediastinal mass.

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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.


Mesothelioma

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.

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A CT demonstrating the tumor compressing the pulmonary artery and collapsing the lung against the chest wall.



Mucoepidermoid Carcinoma

Pericardial Cyst

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.

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The patient's PA chest x-ray demonstrating the mass.

CystBeforeandAfter.jpg (27744 bytes)

Pictures taken during surgery. Above, the forceps are pulling the pericardial cyst.
Below, the patient after the removal of the cyst.

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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 exposures015MediastinalCT.jpg (30329 bytes).

A chest CT reveals that there is no contrast filling of the left pulmonary artery. The mass can be seen within the pulmonary artery.

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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.



Small Cell

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images (x-ray and CT) from a patient with small cell lung carcinoma

Squamous Cell
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.
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A head CT revealed a single lesion of the right parietal lobe.

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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 differentiation.


Teratoma

Thymic Cyst
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.
AntMedMassCT.jpg (27916 bytes)

A mediastinal windows CT scan shows the anterior mediastinal mass. It appears to have a soft tissue quality with sharp boarders and without calcification.

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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.


Thymoma

Thyroid

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.

006PACXR.jpg (45862 bytes)

A PA chest x-ray showing a cavitary lesion in the right lower lobe. Note the air-fluid level within the lesion.
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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.
006HeadCT2.jpg (33904 bytes)

A head CT showing edema surrounding brain metastases in the left parietal lobe.

 
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