Case Studies

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Case Studies Part 3
Neoplasia
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CASE 1

• History
• A 44 year old woman comes to you because of
  spotting between menstrual periods. She tells you
  that she had an abnormal Pap smear "about 10
  years ago" but did not return to the clinic.
  Further history reveals that she has had multiple
  sexual partners over the last 30 years. On
  physical examination, you find a large fungating
  area with erosion on the cervix. A biopsy is
  taken.

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Basal cells
Normal cervix is seen at high power, with non-keratinizing squamous epithelium. The basal cells are seen at the right, and there is progressive maturation to the surface, where the flattened squamous cells have a low nuclear/cytoplasmic ratio with abundant pale-staining cytoplasm containing glycogen. The epithelium lies above the basement membrane. The submucosa is at the far right.
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Stratified Non-keratinizing squamous epithelium
Endocervix
Endocervical glands
Normal cervix with stratified non-keratinizing squamous epithelium merges at the transformation zone (squamocolumnar junction) to endocervix lined by tall mucinous columnar cells as seen here at low power. The endocervix has underlying endocervical glands that are also lined by tall mucinous columnar cells.
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Superficial cell
Basal cells
Intermediate cell
Slide 1.1This is the original Pap smear. How would you describe the cells? The cells are "atypical" and show variation in size and shape as well as increased nuclear chromatin (hyperchromasia)
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Transition zone
Carcinoma in situ
Basal layer
Slide 1.2This microscopic appearance is representative of the lesion from which the cells on the original Pap smear came from 10 years ago. What is the process? Normal squamous epithelium merges into a more disordered epithelium that is dysplastic
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Slide 1.3The gross appearance of the cervical lesion is seen. Describe the lesion. A mass is present that has an exophytic (growing outward from the epithelial surface) appearance. The surface is rough, irregular, and different in color from the surrounding epithelium
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Mitotic figure
Slide 1.4The high power microscopic appearance of the lesion is seen. Describe the appareance. Cells are arranged in irregular sheets and nests. The cells show pink cytoplasm and have occasional intercellular bridges. The nuclei are quite atypical
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Questions for discussion

• 1. Why do you think the Pap smear showed 10 years
  ago? What natural history of neoplasia could be
  represented here?
• 2. What factor or factors may have played a role
  in the development of the neoplasm?
• 3. What are the pathologic features that provide
  clues to the diagnosis?
• 4. How would you grade and stage this neoplasm?

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CASE 1 Squamous cell carcinoma of the cervix

• Answers
• Why do you think the Pap smear showed 10 years
  ago? What natural history of neoplasia could be
  represented here?
• The Pap smear showed a dysplasia. There are
  increasing severities to dysplasia and, if left
  untreated, there is a good possibility of
  progression to carcinoma. This illustrates the
  concept of metaplasia- dysplasia-carcinoma.
• What factor or factors may have played a role in
  the development of the neoplasm?
• In this case, the sexual history suggests the
  possibility of association with human
  papillomavirus (HPV) infection. This is an
  example of viral oncogenesis. Other examples
  include Epstein-Barr virus and lymphomas or
  nasopharyngeal carcinomas, as well as hepatitis
  virus and hepatocellular carcinoma.
• What are the pathologic features that provide
  clues to the diagnosis?
• The gross appearance is a mass lesion. It is
  arising on an epithelial surface, which suggests
  a carcinoma. Cytologic features of neoplasia
  include hyperchromatism, pleomorphism, increased
  nuclear/cytoplasmic ratio. Cells with such
  features are said to be less "differentiated"
  from the normal counterpart. Tumor cells that do
  not resemble the cell of origin are said to
  exhibit anaplasia.
• How would you grade and stage this neoplasm?
• Grading is based upon the degree of
  differentiation. Most tumors are graded on a
  scale of I to III or I to IV, with the III or IV
  representing the least amount of differentiation.
  Staging is based upon the extent of spread of the
  tumor. Stages are usually given as I to IV, or as
  a TNM classification for local, nodal, and
  distant spread.

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CASE 2

• History
• A 56 year old male has had a chronic cough for
  many years, but in the past few days has noticed
  that the sputum contains streaks of blood. You
  discover that he has an 85 pack/year smoking
  history. He has also gained about 10 kg in the
  past two months, mostly evident as truncal
  obesity. On physical examination, you palpate
  firm, enlarged lymph nodes in the cervical
  region. His liver also seems to be enlarged.
  Abdominal striae are present and the abdomen is
  enlarged, but without a fluid wave.

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Metaplasic cells
Slide 2.1The cytologic appearance of cells in the sputum is shown. Describe the appearance. The atypical cells present have marked hyperchromatism with very high N/C ratio. These cells are not very large
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Slide 2.2This is the gross appearance of the lesion in the lung? How would you describe it? The off-white mass extends irregularly along the bronchovascular tree. There is no single large well-circumscribed mass.
Cancer (white)
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Small cell carcinoma
Slide 2.3This is the microscopic appearance of the lesion. Describe it. There are sheets of small blue cells with no features of normal pulmonary cells. The degree of anaplasia is marked
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Questions for discussion

• 1. What procedures can you do to further discover
  the cause of his problems?
• 2. What environmental cause(s) could have
  contributed to his disease? What neoplasms are
  associated with what environmental etiologies?
• 3. How do you explain his weight gain along with
  the physical findings? What usually happens to
  persons with a malignant neoplasm?
• 4. How do you explain the lymph node findings?
  Name the ways that tumors can spread.

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CASE 2 Small cell anaplastic ("oat cell")
carcinoma of the lung with metastases

• What procedures can you do to further discover
  the cause of his problems?
• Diagnostic procedures could include a chest
  x-ray, sputum cytology, and bronchoscopy.
• What environmental cause(s) could have
  contributed to his disease? What neoplasms are
  associated with what environmental etiologies?
• The probable environmental cause in his case was
  smoking. Other associations with chemical
  carcinogens include asbestos and mesothelioma,
  estrogens and endometrial carcinoma, vinyl
  chloride and hepatic angiosarcoma. Associations
  with radiation esposure include bone cancer,
  leukemias, and thyroid cancer.
• How do you explain his weight gain along with the
  physical findings? What usually happens to
  persons with a malignant neoplasm?
• Most patients with malignant neoplasms that are
  extensive have weight loss. In his case, the
  physical findings suggest a possible
  paraneoplastic syndrome. The oat cell cancer may
  be secreting an ACTH- like substance that is
  leading to increased glucocorticoid production
  and Cushing's syndrome. (Weight gain)
• How do you explain the lymph node findings? Name
  the ways that tumors can spread.
• The enlarged lymph nodes (and liver) suggest
  metastatic disease. Carcinomas like to spread via
  lymphatics, first to local nodes and then to
  distant sites. They may also spread
  hematogenously. Any tumor can spread by local
  extension. Tumors arising adjacent to mesothelial
  surfaces (particularly in ovary) can spread by
  "seeding" over the surface. Sarcomas like to
  spread via the bloodstream and less commonly via
  lymphatics.

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CASE 3

• History
• A 21 year old male is found to have a positive
  stool guaiac from rectal examination during a
  routine physical. He tells you that several
  relatives died from "cancer of the bowel" at an
  early age.

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Polyp
Slide 3.1Describe the gross appearance of the colon (this patient had a similar disease). Multiple mass lesions are present. They are polypoid. The polyps are on long stalks. They are well-circumscribed.
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Slide 3.2Describe the microscopic appearance of this small polypoid lesion from the colon of this patient. The glands in this polyp are more crowded and have cells that are more hyperchromatic than the adjacent normal colonic mucosa of the stalk, but overall they are well-differentiated. This is a benign adenomatous polyp.
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Cancer
Slide 3.3How does the microscopic appearance of a 4 cm mass lesion in the colon seen here at low power differ from the polyp in the last Slide 3.2? The glands are much more irregular and have less differentiation. This is adenocarcinoma of the colon.
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Slide 3.4How does the microscopic appearance of a 4 cm mass lesion in the colon seen here at high power differ from the polyp in the last Slide 3.2? The glands are much more irregular and have less differentiation. This is adenocarcinoma of the colon.
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Questions for discussion

• 1. What further procedure(s) can be done to
  determine what his problem is?
• 2. What are the genetics of neoplasia? Discuss
  oncogenes and tumor suppressor genes. What is
  happening in this case? What produces cell
  transformation?
• 3. What are tumor markers? Is such a marker
  useful in this case?

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CASE 3 Familial polyposis of colon

• What further procedure(s) can be done to
  determine what his problem is?
• A colonoscopy could define the lesions present.
  Radiographic procedures may also help (barium
  enema).
• What are the genetics of neoplasia? Discuss
  oncogenes and tumor suppressor genes. What is
  happening in this case? What produces cell
  transformation?
• Some neoplasms are associated with oncogenes
  (e.g., the result of a genetic a point mutation
  to activate a ras oncogene, or a chromosomal
  translocation to activate a c-myc oncogene) and
  others with faulty tumor suppressor genes
  (anti-oncogenes) such as p53 in some colon,
  breast, lung, and liver neoplasms. A few tumors
  are even associated with faulty genes that allow
  excessive growth.
• What are tumor markers? Is such a marker useful
  in this case?
• Tumor markers are substances within or secreted
  by neoplasms that can be immunohistochemically or
  in serum. Colon cancers, for example, are
  associated with production of carcinoembryonic
  antigen (CEA colon cancer marker). No marker is
  completely specific for a given tumor, nor are
  the markers always sensitive enough to detect all
  cases. Therefore, tumor markers are not useful as
  general screening tests in the general
  population. However, tumor markers can be applied
  in specific situations to help confirm a
  diagnosis or to follow up a patient after
  treatment.

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CASE 4

• History
• A 49 year old female has been bothered by
  headaches for several months. She also has
  difficulty hearing on the left. She blames it on
  the teenagers at the house next door playing rock
  music.

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Mass 8th Nerve Tumor - Schwannoma
Slide 4.1This is the gross appearance of a similar lesion in another patient. Describe the location and appearance. The tumor is well-circumscribed and is located in the region of the cerebellopontine angle, which is where the eighth nerve is. The tumor is tan and homogenous.
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Slide 4.2This is the low power microscopic appearance of the lesion. Describe the findings. The cells are fairly monotonous, without areas of hemorrhage or necrosis. There is no evidence for invasion.
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Slide 4.3What do you see in this high power microscopic appearance? What is the cell of origin? The cells have long, thin nuclei and abundant pale pink cytoplasm resembling the Schwann cells of nerve trunks. The cells show minimal hyperchromatism and pleomorphism.
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Question for discussion

• What further procedure(s) can be done to
  determine what her problem is?
• How do you tell a benign from a malignant
  neoplasm?
• How can a histologically benign neoplasm still
  cause problems for the patient?

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CASE 4 Schwannoma of eighth nerve

• What further procedure(s) can be done to
  determine what her problem is?
• Simple physical examination will determine a not
  so subtle hearing loss, though audiometry could
  be helpful in determing the nature of the loss.
  In her case, there was evidence for
  nerve-deafness on the left. If an intracranial
  mass lesion is suspected, a MRI scan of the head
  will aid diagnosis.
• How do you tell a benign from a malignant
  neoplasm?
• Benign tumors are characterized by their greater
  degree of differentiation, slower growth,
  circumscription, lack of metastases, etc.
• How can a histologically benign neoplasm still
  cause problems for the patient?
• Even benign neoplasms can cause problems based
  upon their location--they can produce a mass
  effect to occlude, obstruct, or cause pressure
  injury to surrounding structures.

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CASE 5

• History
• A 61 year old male has noted lower back pain for
  about a year accompanied by a 40 lb weight loss.
  You can find nothing notable on physical
  examination.

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Slide 5.1This is the gross appearance of the neoplasm. The mass is quite large, with a yellow-tan cut surface and irregular borders. It is surrounded by soft tissue and muscle.
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Slide 5.2This is the low power microscopic appearance. Describe it. The cells have a spindly appearance, and the neoplasm is quite cellular.
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Mitosis in 4 directions
Slide 5.3This is the high power microscopic appearance. Describe it. The cells are markedly hyperchromatic and pleomorphic, with mitoses present. There is no discernible pattern.
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Questions for discussion

• 1. What further procedure(s) can be done to
  determine what his problem is?
• 2. What are some reasons for such a profound
  weight loss?
• 3. What use can be made of immunohistochemistry
  to determine the nature of the neoplasm?
• 4. What features distinguish a carcinoma from a
  sarcoma? How are tumors classified on the basis
  of their embryologic origin?
• 5. What determines the prognosis with neoplasia?

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CASE 5 Malignant fibrous histiocytoma (MFH) of
retroperitoneum (a sarcoma)

• What further procedure(s) can be done to
  determine what his problem is?
• A CT or MRI scan may help. In this case, a CT
  scan revealed a mass in the left thigh region. He
  was taken to surgery and the mass was removed.
• What are some reasons for such a profound weight
  loss?
• Most of the time, such profound weight loss is
  involuntary (i.e., not from going on a diet) and
  usually points to a neoplasm (though sometimes
  chronic infectious diseases such as tuberculosis
  may be associated with weight loss).
• What use can be made of immunohistochemistry to
  determine the nature of the neoplasm?
• Immunohistochemical stains on tissue biopsies
  can help to determine the type of neoplasm when
  the HE histopathologic appearance is that of an
  "anaplastic" or "undifferentiated" neoplasm.
  Staining with intermediate filaments such as
  vimentin are typical of sarcomas. Staining with
  cytokeratins point to an epithelial origin (a
  carcinoma). Staining with leukocyte comman
  antigen suggests a lymphoma.
• What features distinguish a carcinoma from a
  sarcoma? How are tumors classified on the basis
  of their embryologic origin?
• A carcinoma arises from epithelium (embryologic
  ectoderm) and tends to be composed of cells that
  are polygonal and form cohesive nests or
  clusters. Keratin formation in cell clusters
  suggests squamous cell carcinoma, while mucin
  production in glandular configurations suggests
  adenocarcinoma. Carcinomas tend to spread to
  lymph nodes. A sarcoma arises from mesenchymal
  cells of mesodermal embryologic origin ("soft
  tissues"). Sarcomas tend to be composed of
  spindle cells. They often form big masses.
• What determines the prognosis with neoplasia?
• Prognosis is determined by the cell type,
  location, grade, and stage. Obviously, a benign
  tumor such as a lipoma on the trunk can grow
  slowly for years and produce no problems.
  However, an oat cell carcinoma that grows quickly
  and spreads early and has no early signs or
  symptoms will have a very poor prognosis.