IRAP CASE #1

Presenter: Dragos Luca, M.D.

DIAGNOSIS: Anaplastic Large Cell Lymphoma of the Urinary Bladder

IMPORTANT DIFFERENTIAL DIAGNOSIS:

*Hodgkin lymphoma

*Metastatic carcinoma

*Malignant melanoma

*Sarcoma

*Diffuse large B-cell lymphoma

*Other T-cell lymphomas

COMMON CLINICAL FEATURES:

*70% - advanced disease (Stage III-IV)

*Peripheral and/or abdominal lymphadenopathy

*Extranodal infiltrates

*Bone marrow involvement

*B symptoms, especially high fever

KEY MORPHOLOGIC FEATURES:

*Hallmark cells, doughnut cells, wreath-like cells

*Prominent eosinophilic nucleoli

*Characteristic intrasinusoidal growth pattern in lymph nodes

ANCILLARY STUDIES:

*ALK positivity

*CD30 positivity (membrane and Golgi)

*Cytogenetics: t(2;5)(p23;35) – ALK/NPM

EPIDEMIOLOGY:

*3% of adult non-Hodgkin lymphomas

*10-30% of childhood lymphomas

OTHER IMPORTANT FEATURES:

*ALK positivity – the most important prognostic indicator (good prognosis)

REFERENCES:

1. Jaffe ES, Harris NL, Stein H, Vardiman JW. World Health Organization Classification of Tumours: Tumours of Haematopoietic and Lymphoid Tissue. 2001, Chapter 7.

2. Ohsawa M, Aozasa K, Horiuchi K, Kanamaru A. Malignant Lymphoma of Bladder. Cancer, September 15, 1993, Vol. 72, No. 6, 1969-1974.

3. Kempton CL, Kurtin PJ, Inwards DJ, Wollan P, Bostwick DG. Malignant Lymphoma of the Bladder. Am J Surg Pathol 21(11): 1324-1333, 1997.

4. Bates AW, Norton AJ, Baithun SI. Malignant Lymphoma of the Urinary Bladder. J Clin Pathol 2000; 53: 458-461.

5. Forrest JB, Saypol DC, Mills SE, Gillenwater JY. Immunoblastic Sarcoma of the Bladder. J Urol, 1983, August, Vol 130: 350-351.

6. Chaitin BA, Manning JT, Ordonez NG. Hematologic Neoplasms with Initial Manifestation in Lower Urinary Tract. Urology, January 1984, Vol. XXIII, 1: 35-42.

7. Sufrin G, Keogh B, Morre RH, Murphy P. Secondary Involvement of the Bladder in Malignant Lymphoma. J Urol, August 1977, Vol. 118: 251-253.

8. Freeman C, Berg JW, Cutler SJ. Occurrence and Prognosis of Extranodal Lymphomas. Cancer, January 1972, Vol. 29, 1: 252-260.

9. Givler RL. Involvement of the Bladder in Leukemia and Lymphoma. J Urol 1971 May; 105(5): 667-70.

10. Sheehan EE, Greenberg SD, Scott R. Metastatic Neoplasms of the Bladder. J Urol September 1963, 90(3): 281-284.

11. Miyake O, Namiki M, Sonoda T, Kitamura H. Secondary Involvement of Genitourinary Organs in Malignant Lymphoma. Urol Int, 1987; 42(5): 360-2.

12. Makinen J, Alfthan O, Vuori J. Malignant Lymphoma of the Urinary Bladder. Eur Urol, 1979; 5(1): 45-7.

13. Ganem EJ, Batal JT. Secondary Malignant Tumors of the Urinary Bladder. J Urol, June 1956, 75(6): 965-972.

IRAP CASE #2

Presenter: Nawwar Swedan, M.D.

DIAGNOSIS: OSTEOPETROSIS (ADULT TYPE II)

COMMON CLINICAL AND LABORATORY FEATURES:

Multiple fracture with minor trauma, Short stature, dense bone and anemia
Acid phosphatase and BB CK elevated.

KEY MORPHOLOGIC FEATURES:

Diffuse bone sclerosis and unabsorbed primary spongiosa fills the metaphysis and diaphysis with board stream of calcified cartilage encased by bone.

EPIDEMIOLOGY:

Infantile AR: 2/million

Intermediate AR Very rare

Adult AD: 10/million

DIFFERENTIAL DIAGNOSES (Selected partial list):

Osteopoikilosis

Fluorosis

Hypervitaminosis A, D

Myelofibrosis (sclerotic type II)

Osteoblastic metastases

Paget’s disease

Hepatitis C

Drug induced osteopetrosis

TREATMENT:

Splenectomy and restriction of dietary calcium may bring temporary improvement.

High-dose calcitrol has been used to stimulate osteoclast formation and function.

Interferon-Y, steroids and parathyroid hormones have been tried with different degrees of responses.

Bone marrow transplantation is being used for cure of patients mainly with the infantile form.

REFERENCES:

1. Kocher MS, Kasser JR: Osteopetrosis. American Journal of Orthopedics, 2003;32:222-228

2. Whyte M: Osteopetrosis. Royce PM, EDS. Connective Tissue and Its Heritable Disorders. Wiley-Liss Inc, 2002: 789-807.

3. Gregory R Mundy: Osteopetrosis. Bone Remodeling and its Disorders. Martin Dunitz,1999:208-239.

IRAP CASE 3

Presenter: Saad Blaney, M.D.

DIAGNOSIS: LEFT SURAL NERVE BIOPSY: LEPROUS NEUROPATHY, TUBERCULOID TYPE.

CLINICAL HISTORY:

46-year-old Mexican male with a known history of asymptomatic hepatitis C that he contracted 16 years ago as a complication of blood transfusion. He presented for routine physical examination for insurance purposes. He started a course of interferon therapy due to elevated ALT and AST. During the course of the therapy, he started complaining of pain, paresthesias and sensory loss of the hands, fingers and lower extremities. Sural nerve biopsy was done two weeks later.

KEY MICROSCOPIC FEATURES:

The lesion shows exuberant non-caseating granulomatous inflammation in the endoneurium with numerous epithelioid macrophages and scattered multinucleated giant cells. Scattered intracellular clusters of bacilli are seen. The bacilli stain positive with Fite stain. There is severe loss of myelinated axons with increased nerve diameter.

DIFFERENTIAL DIAGNOSIS:

1- Infectious processes (e.g. fungal, mycobacterial)

2- Sarcoidosis

3- Lymphoma

SPECIAL STUDIES:

v CD68: strongly positive

v S-100: positive in Schwann cells and weakly positive staining of the macrophages

v CD3: focally positive

v CD5: focally positive

v Fite stain: clusters of positive bacilli

v Acid-fast bacilli: negative

v GMS: negative

REFERENCES:

1. Connor D., Chandler F., Schwartz D., Manz H., Lack E. Pathology of Infectious Diseases. 1997; 605-13

2. Bakers B., Evans M., DeCastro F., Schosser R. Leprosy In A Mexican Immigrant. 2003; 101(7): 289-94

3. Connor D., Palmer P., Reeder M., Dunn I. Tropical Medicine Central Resourse. 2000

4. Gormus BJ, Baskin GB, Xu K, Ratterree MS, Mack PA, Bohm RP Jr, Meyers WM, Walsh GP. Anti-Leprosy Protective Vaccination Of Rhesus Monkeys With BCG Or BCG Plus Heat-Killed Mycobacterium Leprae: Lepromin Skin Test Results. Lepr Rev. 2002 Sep; 73(3): 254-61

5. Stearns AT. Leprosy: A Problem Solved By 2000? Lepr Rev. 2002 Sep; 73(3): 215-24.

6. Rai U. India's Vaccine Inventor: Gursaran Talwar. IDRC Rep. 1995 Jan; 22(4): 10.

7. Kaur I, Dogra S, Kumar B, Radotra BD. Combined 12-Month WHO/MDT MB Regimen And Mycobacterium W. Vaccine In Multibacillary Leprosy: A Follow-Up Of 136 Patients. Int J Lepr Other Mycobact Dis. 2002 Sep; 70(3): 174-81.

IRAP CASE 4

Presented by: Ronald M. Angeles, M.D.

DIAGNOSIS: MESONEPHRIC ADENOCARCINOMA OF THE UTERINE CERVIX

MESONEPHRIC CARCINOMA:

v rare tumor of the cervix

v 23 cases reported (1990 – 2001)

v median age of diagnosis: 52 years

v abnormal bleeding with a visible cervical lesion

v arise in mesonephric remnants in lateral wall of cervix

MORPHOLOGY:

v Architecture

- ductal – most common

- sex cord-like, retiform, small tubular, solid, and biphasic

IMMUNOHISTOCHEMISTRY:

v CD10 is the most helpful marker for this tumor

DIFFERENTIAL DIAGNOSES:

v endocervical adenocarcinoma

v endometrioid adenocarcinoma

v clear cell carcinoma

v mesonephric hyperplasia

PROGNOSIS:

v Based on published studies, its behavior is characterized by local recurrences but long periods of survival

REFERENCES:

1. Clement PB, Young RH, Keh P, et al. Malignant mesonephric neoplasms of the uterine cervix: a report of eight cases, including four with a malignant spindle cell component. Am J Surg Pathol 1995;19:1158-71.

2. Ordi J, Nogales FF, Palacin A, et al. Mesonephric adenocarcnoma of the uterine corpus: CD10 expression as evidence of mesonephric differentiation. Am J Surg Pathol 2001; 25:1540-5.

3. Silver SA, Devoaussoux-Shisheboran M, Mezetti T, et al. Mesonephric adenocarcinomas of the uterine cervix: a study of 11 cases with immunohistochemical findings. Am J Surg Pathol 2001;25:379-87.

4. Ordi J, Romagosa C, Tavassoli FA, et al. CD 10 expression in epithelial tissues and tumors of the gynecologic tract: a useful marker in the diagnosis of mesonephric, trophoblastic and clear cell tumors. Am J Surg Pathol 2003; 27:178-86.

5. Ferry JA, Scully RE. Mesonephric remnants, hyperplasia and neoplasia in the uterine cervix: a study of 49 cases. Am J Surg Pathol 1990;14:1100-11.

IRAP CASE 5

PRESENTER: Ewa Borys, M.D.

DIAGNOSIS: MANTLE CELL LYMPHOMA, WITH MORPHOLOGIC FEATURES OF MARGINAL ZONE LYMPHOMA

DIFFERENTIAL DIAGNOSES:

Marginal zone lymphoma
Follicular center lymphoma
Small lymphocytic lymphoma/Chronic lymphocytic leukemia
Lymphoblastic lymphoma

MORPHOLOGIC FEATURES:

v Primarily diffuse growth pattern.

v Scattered fine fibrillary fibrosis and prominent fibrosis around blood vessels.

v Prominent foci of cells with a moderately abundant pale cytoplasm, resembling marginal zone B cells.

ANCILLARY STUDIES:

Immunohistochemistry

positive: LCA, CD5, CD20, BCL2, Cyclin D1

negative: CD3, CD43

Flow cytometry - CD19+, CD20+, CD5+, CD10-, CD23-.

CONCLUSIONS:

Cyclin D1 immunohistochemistry is useful in recognizing variant MCL cases, which can mimic other more indolent low-grade B-cell lymphomas and is now essential for the routine diagnosis of patients with MCL.

REFERENCES:

1. Yatabe, Y. et al. Morphological spectrum of cyclin D1-positive mantle cell lymphoma: Study of 168 cases. Pathology International. 2001; 51:747-761.

2. Campo, E. et al. Mantle-cell lymphoma. Seminars in Hematology.1999; 36(2):115-127.

3. Swerdlow, S. et al. The morphologic spectrum of non-Hodgkin’s lymphomas with bcl1/cyclin D1 gene rearrangements. The American Journal of Surgical Pathology. 1996; 20(5):627-640.

4. Belaud-Rotureau, M. et al. A comparative analysis of FISH, RT-PCR, PCR, and immunohistochemistry for the diagnosis of mantle cell lymphomas. Modern Pathology. 2002;15(5):517-525.

5. Jaffe, E.S. World Health Organization Classification of Tumours. Tumours of Hematopoietic and lymphoid Tissues. IARCPress. Lyon, 2001.

IRAP CASE 6

PRESENTER: Carolina Camacho–Prihar, M.D.

DIAGNOSIS: CHONDROID CHORDOMA

DIFFERENTIAL DIAGNOSIS

v Myxoid chondrosarcoma

v Giant vertebral notochordal rest

CLINICAL HISTORY

46 year old female, who presented lower back pain for the last six months. No weakness or paresthesias in her legs.

MICROSCOPIC FEATURES

The lesion has lobulated architecture, with lobules separated by fibrous septa. The lobules contain cells arranged in cords, columns, sheets or trabeculae. Some of the cells have eosinophilic, non-vacuolated cytoplasm; others contain single, large vacuoles giving a signet ring appearance, and others have the prototypical multivacuolated or bubble like cells. All the cells are set within an abundant myxoid matrix. Mild nuclear pleomorphism with infrequent mitotic figures. Focal areas of cartilaginous tissue with apparent chondrocyte cells situated in wide lacunae of hyaline cartilage

SPECIAL STUDIES

Immunohistochemistry:

Positive: Keratin (AE1/AE3, Mak-6), EMA, S-100, NSE

Electron Microscopy:

v Intracytoplasmic vacuoles of different sizes, containing glycogen or strands of amorphous mucin

v Clusters of mitochondria partially surrounded by single RER cisternae

v Desmosomes with associated intermediate filaments,

REFERENCES

1. Rich TA, Schiller A, Suit HD, et al. Clinical and pathological review of 48 cases of chordoma. Cancer 1885;56:182-87

2. Salisbury JR. The pathology of the human notochord. J Path 1993;171:253-5

3. Salisbury JR, Deverell MH, Cookson MJ, et al. Three –dimensional reconstruction of the human embryonic notochords: clue to the pathogenesis of chordoma. J path 1993;171:58-62

4. Yamaguchi T, Yamato M, Saotome K. First histologically confirmed case of classic chordoma arising in a precursor benign notochordal lesion: differential diagnosis of benign and malignant notochordal lesions. Skeletal Radiol 2002;31:414-18

5. Kyriakos M, Totty WG, Lenke LG. Giant vertebral Notocordal Rest. Am J surg path 2003;27 (3):396-406

6. Kay PA. M.D., PhD., Nascimento AG, M.D. et al. Cytomorphologic findings in 14 cases diagnosed by fine needle aspiration. Acta cytol 2003;47:2002-208

7. Cibas Edmund,Ducatman Barbara. Cytology Diagnostic principles and clinical correlates. Second edition 2003; 435

8. Gray Winfred, Mcknee Gracet. Diagnostic cytophatology. Second edition 2003;924-25

9. Robert A. Erlandson, PhD. Diagnostic transmission Electron Microscopy of tumors.1994: 324-26

10. Fletcher C. D.M. Diagnostic Histopathology of tumors. Second edition Vol 2: 1584-5

11. Hornick JL. M.D., Fletcher C.D. MD, Myoepithelial tumors of soft tissue. A clinicopathologic and immunohistochemical study of 101 cases with evaluation of prognostic parameters. Am J Surg Path 2003;27 (9): 1183-96

IRAP CASE 7

PRESENTER: Fadi Salem, M.D.

DIAGNOSIS: METASTATIC MALIGNANT MELANOMA TO THE CERVIX.

Histology: Diffuse infiltration of non-cohesive large to medium sized pleomorphic cells with abundant eosinophilic cytoplasm and oval irregular nuclei with pink prominent nucleoli.

DIFFERENTIAL DIAGNOSIS:

v Undifferentiated carcinoma.

v Large cell non-Hodgkin’s lymphoma.

v Malignant melanoma.

SPECIAL STUDIES:

v S-100

v HMB-45

v Keratin.

v CEA

CLINICAL HISTORY:

40 y/o female underwent colposcopy and cervical biopsy several months after the finding of LGSIL in a pap smear. On exam, she was noted to have an enlarged mass in the cervix.

The patient had a history of skin lesion diagnosed as malignant melanoma 3 years ago, with metastases to two lymph nodes.

Recently, she had a total hysterectomy, bilateral salpingo-oophorectomy and a segment of sigmoid colon resection, which showed extensive infiltration of the cervix, one of the ovaries and the serosa of sigmoid colon by the tumor.

METASTATIC MALIGNANT MELANOMA:

v Universal mimicker.

v Has to be considered in all undifferentiated carcinoma.

v Immunohistochemistry is important for diagnosis.

v Cervix, ovaries and GI tract are uncommon locations for metastasis.

TREATMENT

v Surgery, radiation, chemotherapy and immunotherapy.

REFERENCES:

1. Skin Pathology. David Weedon.2^nd edition. Churchill 2002.

2. Diagnostic Immunohistochemistry. David J. Dabbs. 2001.

3. Lever's Histopathology of the Skin 8^TH, Christin Jaworsky, Walter F. Lever, Rosalie Elenitsas.8^th ed.

4. Pathology of the female productive tract. Pobboy, Anderson, Russel. 2001.

5. Differential Diagnosis in Surgical Pathology. Haber, Gattuso, Spitz and David. 2002.

6. Modern Surgical Pathology. Weidner, Cote, Suster and Weiss. 2003.

7. Prognostic Factors in Metastatic Melanoma: A Pooled Analysis of Eastern Cooperative Oncology Group Trials.J Clin Oncol 18:3782-3793.2000.

8. Malignant melanoma metastatic to the gastrointestinal tract. I. Panagiotou, E. N. Brountzos, D. Bafaloukos, C. Stoupis, P. Brestas and D. A. Kelekis. Melanoma Research 2002, 12, pp. 169-173.

9. Malignant Melanoma Metastatic to the Ovary: Presentation and Radiological Characteristics. M. Moselhi, J. Spencer, and G. Lane, MRCOG. GYNE ONCOL 69, 165–168, 1998.

10. AJCC, Cancer Staging Manual, 6^th edition, 2002.