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These rare tumors form a spectrum within a rare and difficult to diagnose category of diseases known as histiocytic and dendritic cell neoplasms. It must be distinguished from the interdigitating cell tumor/sarcoma.

The International Lymphoma Study Group has identified the following classification scheme:

Macrophage/Histiocytic neoplasms Histiocytic sarcoma
Dendritic Cell Neoplasms Langerhans Cell Tumor
Langerhans Cell Sarcoma
Interdigitating Cell Tumor/Sarcoma
Follicular Dendritic Cell Tumor/Sarcoma
Histiocytic sarcoma
Langerhans cell tumor/sarcoma
Interdigitating cell tumor/sarcoma
Follicular dendritic cell tumor/sarcoma

Adapted from Pileri SA, Grogan TM, Harris NL, etal. Histopathology 2002;31:1-29.


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Development of follicular dendritic cell sarcoma in hyaline-vascular Castleman's disease of the nasopharynx: tracing its evolution by sequential biopsies.

Chan AC, Chan KW, Chan JK, Au WY, Ho WK, Ng WM.

Department of Pathology, Queen Elizabeth Hospital, Kowloon, Hong Kong.

Histopathology 2001 Jun;38(6):510-8

Hyaline-vascular Castleman's disease (HVCD) and follicular dendritic cell (FDC) sarcoma occurring in the nasopharynx are both extremely rare. We report the first case of transformation of the former into the latter as documented by sequential biopsies. The steps involved in the transformation were described in detail and the possible role of p53 studied.

METHODS AND RESULTS: The patient presented at the age of 23 years with nasopharyngeal HVCD. Hyaline- vascular Castleman's disease with FDC overgrowth was diagnosed in a recurrence 8 years later, and a frank FDC sarcoma developed at the same site 11 years after initial presentation. The patient remained disease-free 3 years after excision and adjuvant chemotherapy. The FDC sarcoma comprised swirling fascicles of spindly cells with indistinct cell borders. The tumour cells expressed the FDC markers CD21, CD35 and CNA.42 and in-situ hybridization for Epstein-Barr virus-encoded RNAs was negative. Over-expression of p53 protein was observed in the FDC sarcoma and an increased number of weakly p53-positive spindly cells could also be demonstrated in the HVCD specimen. This finding suggested a possible role of p53 in the evolution from HVCD to FDC sarcoma. Critical analysis of the literature shows that, among the 13 reported cases of FDC sarcoma associated with Castleman's disease, possible progression from the latter to the former is documented in only two cases.

CONCLUSIONS: The sequential changes observed in the current case provide further evidence to strengthen the role of HVCD as a possible precursor of FDC sarcoma. There is a possible role of p53 in the transformation process but confirmation by future studies is needed.


Classic follicular dendritic reticulum cell tumor of the lymph node developing in a patient with a previous inflammatory pseudotumor-like proliferation.

Cossu A, Lissia A, Dedola MF, Deiana A, Faedda R, Palmieri G, Tanda F.
Hum Pathol. 2005 Feb;36(2):207-11. Abstract quote  

Summary Inflammatory pseudotumor (IPT) and follicular dendritic reticulum cell tumor (FDRCT) are rare entities of the lymph node characterized by spindle-cell proliferation.

We report a case of a 31-year-old woman, who was admitted for biopsy of a lymph node in the left submandibular area. The microscopic examination revealed a proliferation of spindle cells, partially replacing the normal lymph node architecture, suggestive of an IPT. The preserved peripheral portion showed follicular hyperplasia with Castleman-like appearance. Six years later she presented with a new enlargement in the same submandibular area. The nodule was removed, and a diagnosis of a classic FDRCT of the lymph node was made.

The present case is remarkable, and clinicopathological data show that IPT-like proliferations could be in some case an early presentation of FDRCT.








Follicular dendritic cell sarcoma of the breast.

Pruneri G, Masullo M, Renne G, Taccagni G, Manzotti M, Luini A, Viale G.

Department of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan, School of Medicine, Via Ripamonti 435, 20141, Milan, Italy.


Virchows Arch 2002 Aug;441(2):194-9 Abstract quote

Extranodal follicular dendritic cell sarcoma (FDCS) is an extremely uncommon tumor with only a single case arising in the breast having been reported. We describe the clinico-pathological features of an additional FDCS of the lower outer quadrant of the right breast in a 40-year-old woman. The tumor showed three patterns of growth, i.e., diffuse, myxoid and fascicular. The neoplastic cells were large, polygonal, with a slightly eosinophilic cytoplasm and oval or convoluted nuclei. They were intermingled with small lymphocytes, plasma cells and a few bizarre multinucleated giant cells. In the fascicular areas, the cells were spindled, while in the myxoid areas they showed a dendritic-like appearance, with long cytoplasmic processes. Mitoses were numerous and often atypical. The neoplastic cells were intensely immunoreactive for CD21, S-100 protein and epithelial membrane antigen, and focally for CD35, CD68 and cytokeratins. Polymerase chain reaction analysis did not reveal any Epstein Barr virus genome in the neoplastic tissue. Electron microscopy highlighted numerous interdigitating cytoplasmic processes with intercellular junctions of the serrated, immature desmosomal or undifferentiated types. The post-surgical course of the patient was uneventful and she is currently free of disease 19 months after surgery.

Follicular dendritic cell sarcoma of the pharyngeal region: histologic, cytologic, immunohistochemical, and ultrastructural study of three cases.

Dominguez-Malagon H, Cano-Valdez AM, Mosqueda-Taylor A, Hes O.

Departamento de Patologia, Instituto Nacional de Cancerologiia, Mexico, DF.
Ann Diagn Pathol. 2004 Dec;8(6):325-32. Abstract quote

Follicular dendritic cell sarcoma is a tumor of recent description and characterization; it is often underdiagnosed because it is easily confused with other entities.

Three cases of follicular dendritic cell sarcoma are described in the present article. The first occurred in the parapharyngeal space in a 29-year-old woman who developed multiple recurrences over the span of 10 years. The second was located in the left tonsil in a 48-year-old man, and the third case developed in the parapharyngeal space in a 26-year-old man. All cases were positive for CD21 and CD35 and ultrastructurally they displayed a morphologic spectrum. The first case featured spindle cells with interdigitated long cell processes joined by well-developed desmosomes. In the other two cases there were round to ovoid cells with interwoven processes connected by occasional desmosomes. Including these three cases, a total of 20 follicular dendritic cell sarcoma of the pharyngeal region have been reported to date.

The clinical behavior of these tumors is similar to other low-grade sarcomas.

Extranodal Follicular Dendritic Cell Sarcoma of the Head and Neck Region: Three New Cases, with a Review of the Literature

David A. Biddle, M.D., Jae Y. Ro, M.D., Ph.D., Gil S. Yoon, M.D., Yap-Whang H. Yong, M.D., Alberto G. Ayala, M.D. and Nelson G. Ordonez, M.D.

Department of Pathology (DAB, JYR, AGA, NGO), The University of Texas M. D. Anderson Cancer Center, Houston, Texas; The Oncology Centre (YHY), Mount Elizabeth Medical Center, Singapore; and Department of Pathology (GSY), Asan Medical Center, Seoul, Korea

Mod Pathol 2002;15:50-58 Abstract quote

Extranodal follicular dendritic cell (FDC) sarcoma of the head and neck region is uncommon, with 16 well-documented cases previously reported (four in the tonsil, four in the pharynx, two in the palate, five in the soft tissue, and one in the thyroid).

We here report an additional three cases of extranodal FDC sarcoma in the tonsil (two cases) and pharynx (one case). In these new cases, the neoplastic cells were arranged in diffuse, fascicular, and vaguely whorled growth patterns. A background lymphocytic infiltrate was sprinkled throughout the neoplasms, with focal prominent perivascular cuffing. Scattered multinucleated giant cells were present.

Immunohistochemically, tumor cells were strongly and diffusely positive for follicular dendritic cell markers CD21 and CD35. Tumor cells were diffusely positive for fascin and negative for leukocyte common antigen, S-100 protein, cytokeratin, and Epstein-Barr virus (EBV) latent membrane protein-1 (EBV-LMP). EBV was also not detected in the tumor cells by in situ hybridization for EBV-encoded RNAs. FDC sarcomas are probably an underrecognized neoplasm, especially when they occur in extranodal sites in the head and neck region. Two of the three new cases we report were initially misdiagnosed, and five cases of extranodal FDC sarcoma in the head and neck region reported in the recent literature were initially misdiagnosed.

Our aim is to complement the current understanding of this neoplasm and alert pathologists to this rare entity in this region to avoid misdiagnosis. Recognition of extranodal FDC sarcoma requires a high index of suspicion, but this tumor has numerous distinctive histological features that should bring the neoplasm into the differential diagnosis. Confirmatory immunohistochemical staining with follicular dendritic cell markers such as CD21 and/or CD35 is essential for the diagnosis. Correct characterization of this neoplasm is imperative given its potential for recurrence and metastasis.


Follicular dendritic cell tumor of the mediastinum

Ambrogio Fassina, MD
Filippo Marino, MD
Alessandro Poletti, MD
Federico Rea, MD
Natale Pennelli, MD
Vito Ninfo, MD

Ann Diagn Pathol 5:361-367, 2001. Abstract quote

Follicular dendritic cell tumor (FDT) is a rare neoplasm usually occurring in the laterocervical lymph nodes, but presentations elsewhere are also well documented.

We report a case of FDT in a 48-year-old man with myasthenia gravis, in whom a slow-growing mediastinal mass that had been surgically excised manifested after 3 years with a local recurrence in the same site. The lesion was aspirated and cytology showed a tumor composed of groups of oval or elongated cells intermingled with several mature small lymphocytes. On histology, the tumor was highly cellular with abundant perivascular lymphocytic infiltration; large cells with pale, eosinophilic cytoplasm and round nuclei, arranged in fascicles often showed a storiform pattern. Occasional binucleated cells were also present.

A panel of antibodies showed positivity only for CD21 and CD35, and a weak response to S-100. Electron microscopy showed that the layer cells had convoluted nuclei and elongated interdigitating processes with desmosome-like junctions.

The definitive diagnosis of FDT can be concluded only with positive immunostaining for CD21 and CD35. However, in the presence of a mixed population of lymphocytes and larger eosinophilic cells the hypothesis of FDT should always be considered.



Inflammatory Pseudotumor-Like Follicular Dendritic Cell Tumor A Distinctive Low-Grade Malignant Intra-abdominal Neoplasm With Consistent Epstein–Barr Virus Association

Wah Cheuk, etal.

Am J Surg Pathol 2001;25:721-731 Abstract quote

Follicular dendritic cell (FDC) tumors are uncommon neoplasms that can involve lymph nodes or extranodal sites. They can exhibit a broad spectrum of histologic appearances and behavior, but the intra-abdominal ones usually pursue an aggressive course.

The purpose of this study was to characterize a distinctive variant of FDC tumor morphologically mimicking inflammatory pseudotumor through analysis of the clinicopathologic features of 11 cases. The patients included 10 women and one man (age range, 19–61 years; median age, 40 years) who presented with abdominal discomfort or pain. Six patients had systemic symptoms such as marked weight loss, fever, or malaise. All tumors occurred in intra-abdominal sites: liver (n = 7), spleen (n = 3), and peripancreatic region (n = 1). Of the nine patients with follow-up data, six were alive and well, one developed recurrence at 9 years, and two had repeated recurrences over many years.

Grossly, the tumors were usually solitary and fleshy, punctuated by areas of hemorrhage and necrosis. Histologically, in a background of abundant lymphocytes and plasma cells were dispersed spindle or ovoid cells with vesicular nuclei and distinct nucleoli. The degree of nuclear atypia was variable, and some nuclei could be grotesque or resemble Reed–Sternberg cells. Focally, spindle cell fascicles could be formed. The atypical cells were immunoreactive for FDC markers such as CD21/CD35, CD23, and CNA.42. In situ hybridization for Epstein–Barr virus (EBV)-encoded RNA was positive in all cases, remarkably highlighting the spindle cells and their atypia. EBV–latent membrane protein-1 was expressed commonly, albeit often focally and weakly.

Therefore, inflammatory pseudotumor-like FDC tumor represents a distinctive variant of FDC tumor that differs from conventional FDC tumor in the following aspects: marked female predominance; selective localization in intra-abdominal sites, especially the liver and spleen; frequent presence of systemic symptoms; indolent behavior despite an intra-abdominal location; dispersed distribution of tumor cells and prominent lymphoplasmacytic infiltration; and consistent association with EBV.

Reticulum Cell Sarcoma of Lymph Node with Mixed Dendritic and Fibroblastic Features

Dan Jones, M.D., Ph.D., Mitual Amin, M.D., Nelson G. Ordonez, M.D., Armand B. Glassman, M.D., Kimberly J. Hayes, B.S. and L. Jeffrey Medeiros, M.D.

Division of Pathology and Laboratory MedicineUniversity of Texas-M.D. Anderson Cancer Center, Houston, Texas

Mod Pathol 2001;14:1059-1067 Abstract quote

We report a case of clinically aggressive reticulum cell sarcoma with mixed follicular dendritic cell (FDC) and fibroblastic reticular cell (FRC) features.

Histologically, the tumor was confined to lymph nodes occurring as a multifocal epithelioid and spindle cell proliferation with appreciable mitotic rate and numerous admixed non-neoplastic B-cells. Ultrastructural examination revealed elongated cells with prominent nucleoli, interdigitating cell processes and frequent desmosomes. These features are typical of FDC sarcoma. However, immunohistochemical stains showed no expression of antigens characteristic of FDCs, including CD21, CD23 and CD35. Cytogenetic characterization of this tumor, by conventional G-banding and multicolor spectral karyotyping, revealed multiple clonal chromosomal aberrations, including del(X)(p11.4) and add (21)(p11.2). Gene expression analysis by cDNA microarray of RNA obtained from short-term tumor cultures revealed high-level expression of a set of genes (including PDGF receptor- and -ß, certain metalloproteinases, and CD105) that were also highly expressed in cultures of nodal FRC cultured from non-neoplastic lymph nodes.

We propose that this tumor represents a nodal sarcoma with intermediate differentiation between FDCs and FRCs. This case adds to the diversity of tumors that may arise from lymph node stroma and supports a possible relationship between the FDC and FRC lineages.


A survey of clusterin and fascin expression in sarcomas and spindle cell neoplasms: strong clusterin immunostaining is highly specific for follicular dendritic cell tumor.

Grogg KL, Macon WR, Kurtin PJ, Nascimento AG.

1Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Mod Pathol. 2005;18:260-266 Abstract quote

Clusterin, a glycoprotein implicated in many cellular functions including apoptosis, has recently been shown to be strongly expressed in follicular dendritic cell tumors, and to be absent or only weakly expressed in other dendritic cell tumors. Fascin has also been investigated as a potential marker of dendritic cell neoplasms.

We evaluated staining for antibodies directed against these two antigens in 202 spindle cell tumors, including cases of follicular dendritic cell tumor (n=14), interdigitating dendritic cell tumor (n=7), leiomyosarcoma (n=17), inflammatory myofibroblastic tumor (n=13), inflammatory pseudotumor (n=2), spindle cell thymoma (n=17), synovial sarcoma (n=11), fibrosarcoma (n=14), liposarcoma (n=27), gastrointestinal stromal tumor (n=13), malignant fibrous histiocytoma (n=18), angiomatoid fibrous histiocytoma (n=4), angiosarcoma (n=10), malignant peripheral nerve sheath tumor (n=8), malignant melanoma (n=16), and spindle cell carcinoma (n=11). Among these spindle cell neoplasms, strong diffuse clusterin staining had an overall specificity of 93% and a sensitivity of 100% for follicular dendritic cell tumor.

Clusterin staining was least reliable in distinguishing follicular dendritic cell tumor from spindle cell thymoma or malignant fibrous histiocytoma, but these are entities that usually can be distinguished by clinical and morphologic data. Rare cases of leiomyosarcoma, fibrosarcoma and angiosarcoma may show strong clusterin staining. Fascin staining was very nonspecific among spindle cell tumors and thus does not imply a dendritic cell lineage.

Clusterin expression distinguishes follicular dendritic cell tumors from other dendritic cell neoplasms: report of a novel follicular dendritic cell marker and clinicopathologic data on 12 additional follicular dendritic cell tumors and 6 additional interdigitating dendritic cell tumors.

Grogg KL, Lae ME, Kurtin PJ, Macon WR.

Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Am J Surg Pathol. 2004 Aug;28(8):988-98. Abstract quote  

While tumors of dendritic cell lineage may have overlapping histomorphologic features, most but not all cases can be classified using an immunohistochemical panel, including CD21, CD23, CD35, CD1a, and S-100.

Based on observations that clusterin is expressed in benign follicular dendritic cells, clusterin expression in 32 dendritic cell tumors was evaluated. Diffuse strong staining for clusterin was seen in 12 of 12 follicular dendritic cell tumors. Two of these cases were negative for traditional markers (CD21, CD23, CD35); they were classified based on characteristic ultrastructural features. Three of 6 interdigitating dendritic cell tumors were negative for clusterin and 3 showed focal weak positivity. Clusterin staining in Langerhans cell histiocytosis ranged from negative (6 of 14) to weak/moderate (8 of 14). Follicular dendritic cell tumors behaved as benign tumors or low-grade sarcomas. Interdigitating dendritic cell tumors demonstrated a widely variable behavior, ranging from benign to rapidly fatal disease.

Based on this initial study, strong clusterin staining supports a diagnosis of follicular dendritic cell tumor. Thus, staining for clusterin is useful in classification of dendritic cell tumors, particularly when the more common markers of follicular dendritic cells are not expressed.


LOCATION Intraabdominal, especially liver and spleen Lymph nodes and various extranodal sites
HISTOLOGY Dispersed tumor cells; many plasma cell and lymphocytes More compact tumor cells; light sprinkling of lymphocytes
BEHAVIOR Indolent Variable; intraabdominal ones are aggressive
EBV Always present Rare <4%
Peripheral T-cell lymphoma with extensive dendritic cell network mimicking follicular dendritic cell tumor: a case report with pathologic, immunophenotypic, and molecular findings. Starkey CR, Corn AI, Porensky RS, Viswanatha D, Wilson CS.

Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.


Am J Clin Pathol. 2006 Aug;126(2):230-4. Abstract quote

Peripheral T-cell lymphoma (PTCL) with a nodular pattern of growth is uncommon and may be misdiagnosed initially as a B-cell lymphoma or reactive process. We report a case of a rapidly growing PTCL with a distinctly nodular pattern in an axillary lymph node from an 89-year-old man. Immunohistochemical stains for CD21, CD23, and CD35 highlighted an extensive dendritic cell network that imparted the nodular appearance and, in addition, was associated intimately with the neoplastic cells. The neoplastic cells otherwise had an immunophenotype similar to previously reported cases of PTCL with a nodular pattern and germinal center origin (CD3+, CD4+, CD5+, bcl-6+, CD31+, subset CD10+, subset CXCL13+, and subset CD79a+). Molecular studies confirm a clonal T-cell receptor g gene rearrangement. This case emphasizes unusual morphologic features in a PTCL that may be mistaken for follicular lymphoma or a tumor of follicular dendritic cell origin.



Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases.

Pileri SA, Grogan TM, Harris NL, Banks P, Campo E, Chan JK, Favera RD, Delsol G, De Wolf-Peeters C, Falini B, Gascoyne RD, Gaulard P, Gatter KC, Isaacson PG, Jaffe ES, Kluin P, Knowles DM, Mason DY, Mori S, Muller-Hermelink HK, Piris MA, Ralfkiaer E, Stein H, Su IJ, Warnke RA, Weiss LM.

Service of Pathologic Anatomy and Hematopathology, Institute of Haematology and Clinical Oncology L.e A. Seragnoli, Bologna University, Italy.

Histopathology 2002 Jul;41(1):1-29 Abstract quote

Neoplasms of histiocytes and dendritic cells are rare, and their phenotypic and biological definition is incomplete. Seeking to identify antigens detectable in paraffin-embedded sections that might allow a more complete, rational immunophenotypic classification of histiocytic/dendritic cell neoplasms, the International Lymphoma Study Group (ILSG) stained 61 tumours of suspected histiocytic/dendritic cell type with a panel of 15 antibodies including those reactive with histiocytes (CD68, lysozyme (LYS)), Langerhans cells (CD1a), follicular dendritic cells (FDC: CD21, CD35) and S100 protein.

This analysis revealed that 57 cases (93%) fit into four major immunophenotypic groups (one histiocytic and three dendritic cell types) utilizing six markers: CD68, LYS, CD1a, S100, CD21, and CD35. The four (7%) unclassified cases were further classifiable into the above four groups using additional morphological and ultrastructural features.

The four groups then included: (i) histiocytic sarcoma (n=18) with the following phenotype: CD68 (100%), LYS (94%), CD1a (0%), S100 (33%), CD21/35 (0%). The median age was 46 years. Presentation was predominantly extranodal (72%) with high mortality (58% dead of disease (DOD)). Three had systemic involvement consistent with 'malignant histiocytosis'; (ii) Langerhans cell tumour (LCT) (n=26) which expressed: CD68 (96%), LYS (42%), CD1a (100%), S100 (100%), CD21/35 (0%). There were two morphological variants: cytologically typical (n=17) designated LCT; and cytologically malignant (n=9) designated Langerhans cell sarcoma (LCS). The LCS were often not easily recognized morphologically as LC-derived, but were diagnosed based on CD1a staining. LCT and LCS differed in median age (33 versus 41 years), male:female ratio (3.7:1 versus 1:2), and death rate (31% versus 50% DOD). Four LCT patients had systemic involvement typical of Letterer-Siwe disease; (iii) follicular dendritic cell tumour/sarcoma (FDCT) (n=13) which expressed: CD68 (54%), LYS (8%), CD1a (0%), S100 (16%), FDC markers CD21/35 (100%), EMA (40%).

These patients were adults (median age 65 years) with predominantly localized nodal disease (75%) and low mortality (9% DOD); (iv) interdigitating dendritic cell tumour/sarcoma (IDCT) (n=4) which expressed: CD68 (50%), LYS (25%), CD1a (0%), S100 (100%), CD21/35 (0%). The patients were adults (median 71 years) with localized nodal disease (75%) without mortality (0% DOD). In conclusion, definitive immunophenotypic classification of histiocytic and accessory cell neoplasms into four categories was possible in 93% of the cases using six antigens detected in paraffin-embedded sections. Exceptional cases (7%) were resolvable when added morphological and ultrastructural features were considered.

We propose a classification combining immunophenotype and morphology with five categories, including Langerhans cell sarcoma. This simplified scheme is practical for everyday diagnostic use and should provide a framework for additional investigation of these unusual neoplasms.


Aggressive neoplasm, generally unresponsive to conventional therapy and leading to widespread disease

Of the 24 cases with follow-up, 9 patients died of disease and 7 were alive with persistent or progressive disease after therapy

Eight of the nine patients died within one year of diagnosis

One died at 16 months after diagnosis


GENERAL Surgical excision of the mass lesion with multiagent, systemic chemotherapy. Radiation therapy, alone or with multiagent chemotherapy, was used in several cases

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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