History: a 55 Year-Old Woman with a 41 Centimeter Retroperitoneal Mass

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Case #1

History: A 55 year-old woman with a 41 centimeter retroperitoneal mass.

Diagnoses: A. Lipoma B. Myxoid Liposarcoma C. Sclerosing Well-Differentiated Liposarcoma

Answer: C, Sclerosing Well-Differentiated Liposarcoma

Description: The specimen is from a fatty tumor which has areas composed of relatively normal appearing fatty tissue admixed with sclerosing dense areas of fibrosis. There are atypical cells with hyperchromatic nuclei and occasional lipoblasts can be identified within the more lipomatous portions of the tumor. In addition, scattered large atypical cells often with multiple nuclei are found in the more fibrotic bands running through the tumor. Discussion: Liposarcomas may occur in various regions but the extremities, particularly the thigh, and the retroperitoneum are the most common sites for malignant adipose tumors. The retroperitoneum is the second most common location for liposarcomas. In this site, the tumors are usually quite large in size, as in the case presented here. Liposarcomas in the retroperitoneum often take a while to be recognized and by the time the patient comes to operation they are usually of a large size. In general, liposarcomas are divided into multiple subtypes including well-differentiated liposarcoma, myxoid liposarcoma, round-cell liposarcoma, and pleomorphic liposarcoma. This particular tumor falls into the category of a well differentiated liposarcoma of the sclerosing type. In order to establish the diagnosis one must identify lipoblasts. These cells characteristically have lipid-like droplets that are defined and the nucleus is usually distorted by the pressure of the expanding lipid within the cell. These cells may vary in size and some may actually reach giant cell proportions. This tumor can be distinguished from the myxoid variant of the well differentiated liposarcoma because it lacks myxoid areas as well as the classical vascular proliferation associated with the myxoid liposarcoma. It is impostant to distinguish this well differentiated liposarcoma from a lipoma. The scattered lipoblasts as well as the hyperchromatic atypical nuclei help in making this distinction. These cells are most commonly found in the fibrosing area of the tumor. This sclerosing type of well differentiated liposarcoma most often does occur in the retroperitoneum or inguinal regions. It may also be found in other sites including extremities. Liposarcomas of the retroperitoneum have a relatively high rate of recurrence, probably due to the difficulty in obtaining a complete excision of the tumor mass. Although multiple recurrences with this type of tumor are reported, patients with the low-grade well differentiated types of liposarcoma survive for multiple years despite local recurrences. Metastases of liposarcomas correlate with the histologic type and in the well differentiated liposarcomas metastases are uncommon.

1 Case #2

History: 81 year-old female with lower back mass.

Diagnoses: A. Acute Leukemia B. Merkel Cell Carcinoma C. Lymphoblastic Lymphoma

Answer: B, Merkel Cell Carcinoma

Description: The tumor in this case is located primarily in the subcutaneous tissue because this particular tumor is actually a recurrence. The tumor is composed of small blue cells with scant cytoplasm and a high nuclear-to-cytoplasmic ratio. The nuclei are round and vesicular and often have a somewhat glassy or fine nuclear chromatin. Small nucleoli may be observed. The tumor is associated with a large amount of necrosis and mitotic figures are easily identified. In some areas the cells seem to nest together in a somewhat cohesive pattern. In this case the differential diagnosis of small round-cell tumors. The differential diagnosis would include acute leukemia, lymphoblastic lymphoma, and metastatic small cell carcinoma from other sites. Immunohistochemistry can be extremely helpful in making this diagnosis. Cells of Merkel cell tumors are positive for low-molecular weight keratin, neurofilaments and also stain for neuron enolase. The positivity for keratin is predominantly of the CK-20 type and has a characteristic perinuclear dot-like staining pattern. The consistent immunoreactivity for neurofilaments can be helpful in making the distinction between small cell carcinoma of the lung and other organs. Another feature that would be helpful in distinguishing this from a metastasis of the lung is that small cell carcinoma of the lung is usually positive for TTF-1 whereas Merkel cell tumors would be negative. The small cells of Merkel cell tumors are negative for the usual hematologic markers which would be positive in leukemia and lymphoma. In addition, sometimes in cases of Merkel cell carcinoma the cells show focal activity for other markers such as chromogranin and synaptophysin. Chromosomal abnormalities have been identified in some cases of Merkel Cell carcinoma. These abnormalities have been of chromosomes 11 and 12 and are seen in 20-30% of cases studied. These tumors are aggressive tumors, and as in this case it is a recurrence of the original presentation. In addition to recurrence, this tumor has the ability to metastasize to distant sites as well as lymph nodes. The recommended initial treatment for Merkel cell carcinoma is wide resection and lymph node dissection. Other modes of additional therapy such as radiation and chemotherapy have also been applied, particularly for recurrence and metastatic tumors.

2 Case #3

History: This is a 77 year-old male with a liver mass.

Diagnosis: A. Metastatic Undifferentiated Carcinoma B. Hepatocellular Carcinoma C. Metastatic Malignant Melanoma Answer: C, Metastatic Malignant Melanoma

Description: The case is that of a large liver mass associated with extensive necrosis. The mass is composed of confluent nodules of large cells with abundant pink cytoplasm and large nuclei with prominent nucleoli. The cells tend to grow in large sheets and cords and do not show evidence of any glandular or squamous differentiation. In addition, no obvious bile pigment is identified within the cells. Discussion: This case raises basic differential diagnosis between a primary hepatocellular carcinoma versus a metastasis of a large pink-cell tumor to the liver. The history is helpful in such cases, particularly if the patient is known to have a previously known primary. Immunohistochemistry can be particularly helpful in distinguishing between undifferentiated carcinoma and malignant melanoma and it is also helpful in further defining the carcinoma if the tumor is indeed epithelial in origin. In this case, stains for keratin were negative. The tumor stained positively for HMB- 45and Melan-A, helping to establish the diagnosis of metastatic malignant melanoma. Other large pink cell tumors which would enter into the diagnosis in addition to hepatocellular carcinoma would include tumors from the kidney and adrenal gland which can be tumors with abundant pink or clear cytoplasm. In this case, the patient had a known history of malignant melanoma, making the diagnosis somewhat easier.

3 Case #4

History: 77 year-old male with a pancreatic mass.

Diagnoses: A. Serous Cystadenoma B. Mucinous Cystadenoma C. Intraductal Papillary Mucinous Neoplasm Answer: A, Serous Cystadenoma

Description: The mass in this pancreas consists of multiple cystic spaces which are lined by small cuboidal or flattened cells with little in the way of cytologic atypia. In addition, the cells lack mucin production and contain glycogen. In general, papillary proliferation is not striking in these tumors. Occasional pseudopapillae which can be seen in this case may be observed. The space between the cysts is lined by loose fibrous tissue which occasionally may show evidence of calcification.

Discussion: Cystic tumors of the pancreas must be distinguished from non-neoplastic cysts which can occur in the pancreas, such as pseudocysts, etc, however, the most important distinction is between the microcystic cystadenoma and the group of mucinous cystic neoplasms. Most cases of microcystic cystadenoma are usually solitary but there are scattered examples of multricentric tumors in the literature. This tumor is composed of multiple small cysts; more importantly, the epithelial lining of these cysts lacks significant mucin production. Papillary proliferations are usually absent or not striking but small areas of papillary growth may be seen. Most patients with this tumor are usually elderly and there is no sex predilection. These tumors are in general benign. There are examples of diabetes being associated with this tumor in which compression by the cystic tumor leads to significant destruction of islet cells. Also, when the tumor is located in the head of the pancreas, these tumors may be associated with gastrointestinal or biliary obstruction. The mucinous cystic tumors of the pancreas tend to be seen in this slightly younger age group and predominate in women. In contrast to the cystadenoma, the spaces of this tumor are lined by cells containing significant mucin production. Mucinous tumors of the pancreas need to be sampled carefully to determine if they are benign mucinous cystadenoma versus a malignant cystadenocaricnoma. The microcystic serous cystadenoma is a benign tumor and excision is usually curative.

4 Case #5

History: 21 year-old female with thyroid mass.

Diagnoses: A. Follicular Adenoma B. Follicular Carcinoma C. Hyperplastic Nodule Answer: B, Follicular Carcinoma

Description: Within the thyroid there appears to be a solitary mass which is surrounded by a dense fibrous capsule. The proliferation within the mass is extremely cellular compared to the surrounding thyroid tissue. The proliferation within the mass grows in a solid sheet-like pattern; the cells have pale pink cytoplasm and relatively round appearing nuclei. The nuclei lack significant grooves and do not appear to be overlapping, which are characteristics seen in follicular variant of papillary thyroid cancer. An occasional mitotic figure is observed, but they are relatively rare. The growth within the nodule does show evidence of thyroglobulin production. The most striking abnormality within the capsule is the evidence of vascular invasion by the tumor. These areas do indeed appear to be definite vascular invasion as the foci are lined by endothelial cells surrounding the vessel. In addition to the easily identified areas of vascular invasion, the tumor also shows focal capsular penetration as well. Discussion: The major differential diagnosis in this case is between a follicular adenoma versus a minimally invasive follicular carcinoma. This lesion does appear to have a dense fibrous capsule which would not be seen in the usual hyperplastic nodule. The fact that the tumor is much more cellular than the surrounding thyroid tissue and also surrounded by a dense fibrous capsule brings one to the major differential between follicular adenoma versus follicular carcinoma. Another entity which might come into consideration might be the follicular variant of papillary carcinoma, however, this lesion lacks the nuclear features typical of papillary carcinoma. In making the distinction between follicular carcinoma and follicular adenoma it is extremely important to carefully examine the capsule surrounding the tumor mass. The most important observation in making the diagnosis of malignancy is the demonstration of blood vessel and/or capsular invasion. When one observes vascular invasion it is important to see clusters of tumor cells attached to the wall of the vessel which may or may not be associated with thrombus material. Sometimes immunohistochemical stains to identify endothelial cells may be helpful in identifying vascular invasion within the vessels of the capsule. When using capsular invasion as a criteria for malignancy, interruption of the capsule should be obvious and must be distinguished from peculiar cuts through the capsule which may actually mimic capsular invasion. Sometimes one sees the tumor extending through the capsule in a mushroom-like fashion. It is also important to remember that some of these lesions have had needle biopsies prior to excision and fine needle aspiration may result in areas of capsular rupture. The latter type of capsular rupture may be suspected when there are areas of recent hamorrhage, stromal fibrosis, and hemosiderin associated with the area suspicious for capsular invasion. As one of the primary criteria for establishing the diagnosis of follicular carcinoma is vascular invasion. It

5 is not surprising that the mode of metastasis for this tumor is usually blood-borne, particularly to the lung and bones in contrast to the nodal metastases which are characteristically seen in papillary thyroid carcinoma. The prognosis of follicular carcinoma is usually related to the degree of encapsulation and extent of invasiveness of the tumor.

6 Case # 6

History: 50 year-old male with external auditory canal mass.

Diagnoses: A. Benign Mixed Tumor B. Adenoma C. Adenoid Cystic Carcinoma Answer: C, Adenoid Cystic Carcinoma

Description: The lesion shows skin with underlying glandular tumor infiltration. The tumor appears to be infiltrative and ill-defined in size. This tumor shows features typical of adenoid cystic carcinoma; it show the glands growing in a cribriform pattern, the cells are relatively bland in appearance, and often grow in gland-like spaces filled with homogeneous eosinophilic material. This tumor has a well-known tendency for invasion into perineural spaces which also correlates with its pattern of spread. Most of the glandular spaces which are observed are not true glandular spaces but instead represent cavities containing reduplicated basal lumina material produced by the tumor cells. Description: In the external ear canal almost any type of adnexal tumor can involve the skin of this region. The four major categories of tumors of adnexal tumors of the ear include: adenoma, benign mixed tumor, syringocystadenoma papilliferum and adenocarcinoma. The clinical presentation may be similar for all these tumors, however, the malignant tumors are usually ulcerated and sometimes painful. The adenoma of the external ear canal is an encapsulated tumor composed of glandular proliferations lined by apocrine cells. The cells are bland and mitotic figures are rare. Pleomorphism, necrosis, and other evidence of aggressive behavior is lacking. Typical benign mixed tumors of the external ear canal have an appearance similar to those occurring in other salivary glands. They are well-circumscribed lesions and bland in appearance. The adenocarcinoma of the xternal ear canal is usually a well-differnetiated adenocarcinoma that may at times be difficult to distinguish from adenoma. Pleomorphism, some cytologic atypia, the lack of myoepithelial layer, and lack of necrosis and invasive growth pattern are helpful in making this distinction. The tumor in this case has the classical appearance of an adenoid cystic carcinoma. This tumor does have a tendency to infiltrate in the perineural regions which can lead to local recurrence. This tumor can be associated with distant metastasis.