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Advocate Illinois Masonic Medical Center

Advocate Lutheran General Hospital

Jesse Brown Veterans Affairs Medical Center

University of Illinois Medical Center

Illinois Registry of Anatomic Pathology

Case Histories and Diagnoses

April 2, 2012

Case 1: Ovarian Small Cell Carcinoma, Hypercalcemic Type

Manmeet (Manu) Singh, DO; Michael Pins, MD

Clinical History: A 36 year-old Caucasian female (G2P2002) with no significant past medical history presented with pelvic pain. A computed tomography (CT) scan revealed a heterogeneously enhancing, lobulated pelvic mass (~ 12.8 cm) with solid and cystic components.

Diagnosis: Ovarian Small Cell Carcinoma, Hypercalcemic Type

Differential Diagnosis:

• Granulosa cell tumor (adult or juvenile)

• Small cell carcinoma, pulmonary type

• Primitive neuroectodermal tumors

• Desmoplastic small round cell tumor

• Lymphoma

• Melanoma

Key Morphologic Features:

• Gross: Most cases are unilateral, large, predominantly solid pale white to gray masses with necrosis, hemorrhage and cystic degeneration often present

• Microscopic: Diffuse arrangement of small, closely packed cells with scant cytoplasm, round-ovoid nuclei and small nucleoli with frequent mitotic figures; follicle-like spaces filled with eosinophilic content and inconspicuous, fibrous tumor stroma

• Immunohistochemical stains: Positive for EMA (focal) and cytokeratins (focal), WT-1 (diffuse), calretinin and CD10. Negative for desmin, S-100 and inhibin.

• Electron Microscopy: Abundant, dilated rough endoplasmic reticulum forming large intracytoplasmic vesicles filled with granular material; neuroendocrine-type secretory granules not seen

Discussion:

• Categorized as a miscellaneous tumor of the ovary (WHO histological classification)

• Defined as an undifferentiated carcinoma usually associated with paraneoplastic hypercalcemia (2/3 of cases), composed primarily of small cells

• Relatively rare ( < 0.01% of ovarian neoplasms, ~ 400 cases reported)

• Affects young women; considered a highly aggressive tumor with ~ 50% of cases having spread beyond the ovary at time of initial laparotomy

• Large tumor cell variant ( ~ 50% of cases), tumor cells with abundant eosinophilic cytoplasm, which may make a distinction from juvenile granulosa cell tumor challenging

• Histogenesis has not been definitively established and optimal treatment is not known

References:

1. Clement, BP. Selected miscellaneous ovarian lesions: small cell carcinomas, mesothelial lesions, mesenchymal and mixed neoplasms, and non-neoplastic lesions. Mod Pathol. 2005; 18:S113–29.

2. Dickersin GR, Kline IW, Scully RE. Small cell carcinoma of the ovary with hypercalcemia: a report of eleven cases. Cancer. 1982; 49:188–197.

3. McCluggage, W. Glenn. Ovarian Neoplasms Composed of Small Round Cells, A Review. Adv Anat Pathol. 2004; 11:288–296.

4. Scully RE. Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament: Atlas of Tumor Pathology second series, fascicle 23. AFIP: Washington, DC, 1999.

5. Sternberg, Mills, Carter, Darryl. Sternberg's Diagnostic Surgical Pathology. Philadelphia: Wolters Kluwer-Lippincott Williams & Wilkins; 2010.

6. Tavassoli FA, Devilee P. World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of the Breast and Female Genital Organs. Lyon: IARC Press; 2003.

7. Young RH, Oliva E, Scully RE. Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathologic analysis of 150 cases. Am J Surg Pathol. 1994; 18:1102–1116.

Case 2: Diffuse Large B-Cell Lymphoma

La’Tonzia L. Adams, MD, MS; Elliot Weisenberg, MD

Clinical History: A 77 year-old female with a history of DM II, hypertension, hypothyroidism, hypercholesterolemia, obstructive sleep apnea, and atrial fibrillation presented to the emergency room with intermittent right chest pain, dizziness, shortness of breath and anemia. Patient denied loss of consciousness, abdominal pain, nausea, vomiting, and diarrhea. Cardiac studies were unremarkable. Abdominal CT revealed a 12 cm nodule in the right hepatic lobe, diverticulosis, and cholelithiasis.

Diagnosis: Diffuse Large B-Cell Lymphoma

Differential Diagnosis:

• Melanoma

• Metastatic carcinoma

• Hepatocellular carcinoma

• Lymphoma

Morphology:

The cells of this patient’s lymphoma are described as large, markedly atypical cells with pale to clear cytoplasm and apparent cell membranes. The nuclei are large with open to variably condensed chromatin and prominent nucleoli with irregular membranes.

Immunohistochemical and special stains:

Positive: LCA, PAX-5, and CD 20

Negative: AE 1/3, CK7/20, HepPar, CD68, Pan Melanoma, AFB, GMS, PAS, CD3

Discussion:

• DLBCL is one of the most common type of lymphoid tumor representing 25 – 30% of adult Non-Hodgkin lymphomas in western countries and is observed higher in developing countries

• Primary hepatic diffuse large B-cell lymphoma is an extraordinarily rare lesion (fewer than 100 cases reported)

• Possibility of systemic lymphoma needs to be excluded

• Described in the setting of immunosuppression, and this possibility should be excluded

• Hepatitis B and C virus infection have been associated with hepatic lymphomas

References:

1. Genvresse I, Spath-Schwalbe E, Meisel H, Kaufmann O, Kruger DH, Possinger K. Primary hepatic or splenic diffuse large B-cell lymphoma and hepatitis C virus infection: a non-fortuitous association? Ann Hematol. 2000; 79(9):530-2.

2. Ma YJ, Chen EQ, Chen XB, et al. Primary hepatic diffuse large B cell lymphoma: A case report. Hepat Mon. 2011; 11(3):203-205.

3. McPherson RA and Pincus MR. Henry's Clinical Diagnosis and Management by Laboratory Methods. 21st ed. Philadelphia, PA: Saunders/Elsevier, 2007.

4. Page RD, Romaguera JE, Osborne B, Medeiros LJ, Rodriguez J, North L, et al. Primary hepatic lymphoma: favorable outcome after combination chemotherapy. Cancer. 2001; 92(8):2023-9.

5. Swerdlow SH, Campo E, Harris NL , et al., eds . WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research on Cancer. 2008.

Case 3: Renal Cell Carcinoma, Clear Cell Type, Metastatic to the Thyroid

Vidya Nagrale, MD; Zbigniew Malecki, MD

Clinical History: An asymptomatic 65 year-old woman was referred to the ENT clinic for an enlarging thyroid nodule. She had a past medical history of benign essential hypertension, diabetes mellitus, and multinodular goiter. She had a thyroid ultrasound which showed a hypoechoic, 2.0 cm mass in the left lobe and two Kim criteria suspicious lesions (1.3 cm and 1.2 cm) on the right side. Her fine needle aspiration cytology was suspicious for papillary carcinoma. She had no history of kidney disease.

Diagnoses: Multifocal thyroid papillary carcinoma, follicular variant;

Multiple nodules suggestive of metastatic renal cell carcinoma, clear cell type

Differential Diagnosis (refers to the clear cell areas in the thyroid other than the obvious papillary carcinoma of the thyroid):

• Parathyroid tumors

• Medullary cancer

• Paraganglioma

• Primary thyroid follicular-derived lesions with clear cells

• Metastatic tumors

Key Microscopic Features:

• Small nests and cords of clear to eosinophilic cells with prominent thin-walled vascular stroma which are positive for CD10 and RCC antigen.

• Papillary carcinoma positive for thyroglobulin and TTF-1

Discussion:

• Renal cell carcinoma is the most common metastatic tumor to the thyroid gland

• Metastases from non-thyroidal malignancy have more of a predilection for abnormal thyroid glands

• Because of the findings further follow up was done. CT showed a right renal mass concerning for renal cell carcinoma. Right radical nephrectomy was performed which revealed a renal cell carcinoma, clear cell type

• Suspect metastatic disease to the thyroid gland in a patient with preexisting thyroid gland abnormalities

References:

1. Chung AY, Tran TB, Brumund KT, et al. Metastases to the thyroid: a review of the literature from the last decade. Thyroid. 2012; 22(3):258-268.

2. Livolsi VA. Surgical pathology of the thyroid. Ed. Bennington JL. Major problems in pathology. 1990; 22:323-350.

3. Bohn OL, De las Casas LE. Tumor-to-tumor metastasis: renal cell carcinoma metastatic to papillary carcinoma of thyroid-report of a case and review of the literature: Head and Neck Pathology. 2009; 3:327-330.

Case 4: Pulmonary Epithelioid Hemangioendothelioma with Pleural Involvement

Qiuying Shi, MD; Ronald Sirota, MD

Clinical History: A 55 year-old male with no significant past medical history presented for evaluation of thoracic pain, cough and shortness of breath while training for a marathon.  A CT scan showed bilateral lower lobe opacities, thickening of the pleura and a nodular opacity in the lingula. A liver mass with a small calcification was also noted.

Diagnosis: Pulmonary epithelioid hemangioendothelioma with pleural involvement

Differential Diagnosis:

• Metastatic tumor (carcinoma or sarcoma)

• Pulmonary adenocarcinoma

• Mesothelioma

• Epithelioid angiosarcoma

• Epithelioid hemangioendothelioma

Key Morphologic Features:

• Gross: Multiple pulmonary nodules with slow to very little growth

• Microscopic: Fusiform vascular nodules demonstrating cords and nests of pleomorphic epithelioid cells, intracytoplasmic vacuoles, occasional intraluminal RBCs in a background myxoid stroma with low mitotic activity.

• Electron Microscopy: Focal, dense, intra-cytoplasmic structures most consistent with Weibel-Palade bodies

Discussion:

• Pulmonary epithelioid hemangioendothelioma is classified into 5 categories and the epithelioid type is most common

• It is typically positive for vascular biomarkers.

• The epithelioid type usually has intermediate malignant potential.

• However, the pulmonary form, especially when pleural involvement occurs, is more aggressive.

References:

1. Sofie Verbeke, et al. Distinct histological features characterize primary angiosarcoma of bone. Histopathology. 2011; 58:254–264.

2. Eun Young Kim, et al. Thoracic epithelioid hemangioendothelioma: imaging and pathologic features, Acta Radiologica. 2011; 52:161–166.

3. Arianeb Mehrabi, et al. Primary Malignant Hepatic Epithelioid Hemangioendothelioma, A Comprehensive Review of the Literature With Emphasis on the Surgical Therapy. Cancer. 2006; 107:2108–21.

4. M. Kitaichi, et al. Pulmonary epithelioid haemangioendothelioma in 21 patients, including three with partial spontaneous regression, Eur Respir J. 1998; 12:89–96.

5. Eun Young Kim, et al. Thoracic epithelioid hemangioendothelioma: imaging and pathologic features; Acta Radiologica. 2011; 52:161–166.

6. Hala R. Makhlouf. Epithelioid Hemangioendothelioma of the Liver. A Clinicopathologic Study of 137 Cases, Ann Thorac Surg. 2006; 82:2010-2013.

7. Costantino Errani, et al. A Novel WWTR1-CAMTA1 Gene Fusion Is a Consistent Abnormality in Epithelioid Hemangioendothelioma of Different Anatomic Sites. Genes, Chromosomes and Cancer. 2011; 50(8), online.

Case 5: Gastric Synovial Sarcoma

Rohini Chennuri, MD; Michael Pins, MD

Clinical history: A 58 year-old female presented to the Emergency Department with an episode of syncope, black stools, hematemesis and 10 pound weight loss over 2 months. A gastric mass was discovered during an endoscopic examination.

Diagnosis: Gastric Synovial Sarcoma

Differential Diagnosis:

• GIST- Gastrointestinal stromal tumor

• Smooth muscle tumor (Leiomyoma/Leiomyosarcoma)

• MPNST

• Carcinosarcoma

• Synovial sarcoma

• Angiosarcoma/Kaposi sarcoma

• Melanoma

Key Morphologic Features:

• Gross: Pink/tan soft tissue 4.6 cm in greatest dimension, with a serosal surface and an ulcerated mucosal surface with raised edges

• Microscopic: Spindle cell proliferation with elongated, pleomorphic spindle cells and frequent mitoses growing in a sheet-like haphazard arrangement in a variable collagenous background located in the lamina propria with extension into the muscularis propria and the subserosal adipose tissue

• Immunohistochemical stains: Focally positive for CKAE1:3, MAK6, EMA, CAM5.2, S100 and CD56; Negative for CD117, CD34, SMA, Desmin, Pan melanoma, CD99, Fli-1, HHV8

• FISH (using SYT break apart probe): Rearrangement involving the SS18 (SYT) gene

Discussion:

• Primary gastrointestinal tract involvement is rare

• First large study of 10 gastric synovial sarcomas in 2008

• Prognosis of gastric synovial sarcomas is much better compared to gastric sarcomatoid carcinoma

• IHC has overlapping features with MPNST and sarcomatoid carcinoma

• SYT (SS18) FISH is highly specific and also a highly sensitive test

• Gastric synovial sarcoma should be always considered in the differential diagnosis of KIT-negative gastric spindle cell neoplasms

References:

1. Makhlouf HR, Ahrens W, Agarwal B. Synovial sarcoma of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 10 cases. Am J Surg Pathol. 2008 Feb; 32(2):275-281.

2. Billings SD, Meisner LF, Cummings OW, Tejada E. Synovial sarcoma of the upper digestive tract: a report of two cases with demonstration of the X;18 translocation by fluorescence in situ hybridization. Mod Pathol. 2000 Jan; 13(1):68-76.

3. Tanas MR, Goldblum JR. Fluorescence In Situ Hybridization in the Diagnosis of Soft Tissue Neoplasms: A Review. Adv Anat Pathol. 2009; 16:383–391.

4. Olsen SH, Thomas DG, Lucas DR. Cluster analysis of immunohistochemical profiles in synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma.

Modern Pathology. 2006; 19:659–6.

5. Rosai, J. Rosai and Ackerman’s Surgical Pathology, 9th ed. St. Louis: Mosby, 2004.

Case 6: Histiocytic Sarcoma

Sangeeta Mehendale, MD; Steven Garzon, MD; Frederick Behm, MD

Clinical History: A 2 year-old female child presented with an enlarging and inflamed left eye lesion for 2 weeks that began following an eye injury during an accidental fall. The patient’s medical history, her review of systems, and her physical exam were unremarkable except for the ocular lesion. An MRI revealed an aggressive infiltrative process predominantly involving the left orbital soft tissues and the lateral wall of the left maxillary sinus.

Diagnosis: Histiocytic Sarcoma

Differential Diagnoses:

• Anaplastic Large Cell Lymphoma

• Myeloid Sarcoma

• Langerhans Cell Neoplasm

• Hodgkin Lymphoma

• Histiocytic Sarcoma

• Rhabdoid Tumor

• Rhabdomyosarcoma

Key Microscopic Features:

• Diffuse non-cohesive cells, a monomorphic/pleomorphic proliferation of large cells

• Cells: Large round-oval

• Cytoplasm: abundant eosinophilic, fine vacuoles

• Nuclei: large, irregular, folded, eccentric, vesicular, multinucleated, hallmark-cell-like, Reed-Sternberg-cell-like

• Sinusoidal distribution: LN, liver, spleen

• IHC: Positive for histiocytic markers: CD163, CD68, lysozyme; absence of Langerhans cell markers, dendritic cell markers, myeloid markers; CD45+, CD45RO+, HLA-DR+; S100 weak, CD4 positive

Discussion:

• Histiocytic sarcoma is a rare entity and constitutes less than 1% of hematolymphoid tumors.

• Most cases present at extranodal sites. The disease often presents as a widespread disease. The sites involved include skin, gastrointestinal tract, liver, spleen, lymph nodes, and bone.

• Predominantly an adult disease, with rare reports of pediatric cases

• Prognosis in pediatric cases is poor and similar to adults, with favorable outcome seen with localized disease

• Histiocytic sarcomas have often been reported in patients with a concurrent (or with a previous history of) B- and T- cell lymphoma, rarely myelodysplastic syndrome, leukemia, and germ cell tumors.

• There is no standard treatment regimen for patients with histiocytic sarcoma

References:

1. Chen W, Lau SK, Fong D, Wang J, Wang E, Arber DA, Weiss LM, Huang Q. High frequency of clonal immunoglobulin receptor gene rearrangements in sporadic histiocytic/dendritic cell sarcomas. Am J Surg Pathol. 2009;33: 863-73.

2. Feldman AL, Arber DA, Pittaluga S, et al. Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone. Blood. 2008 15;111: 5433-9.

3. Hornick JL, Jaffe ES, Fletcher CD. Extranodal histiocytic sarcoma: clinicopathologic analysis of 14 cases of a rare epithelioid malignancy. Am J Surg Pathol. 2004;28:1133.

4. Lau SK, Chu PG, and Weiss, LM. CD163 A Specific Marker of Macrophages in Paraffin-Embedded Tissue Samples. Am J Clin Pathol. 2004; 122:794-801.

5. Pileri SA, Grogan TM, Harris NL, et al. Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases. Histopathology. 2002;41:1-29.

6. Onciu M. Histiocytic Proliferations in Childhood. Am J Clin Pathol. 2004;122(Suppl 1):S128-S136.

7. Vos JA, Abbondanzo SL, Barekman CL, Andriko JW, Miettinen M, Aguilera NS. Histiocytic sarcoma: a study of five cases including the histiocyte marker CD163. Mod Pathol. 2005;18:693-704.

8. , Histiocytic Sarcoma.

9. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues, 4th ed. Lyon, France: WHO Press; 2008.

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