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Pseudoneoplastic lesions: general considerations.

Pseudotumor is an imprecise term typically used to P indicate the presence of a mass that is thought to represent a neoplasm at some level of observation. In most circumstances, it is a misnomer because a mass actually exists, and hence, the term pseudoneoplasm would be more appropriate. However, there may still be circumstances in which the term pseudotumor is applicable, and some scenarios are presented below. This special section of the ARCHIVES is devoted primarily to those lesions that might better be termed pseudoneoplasms, in which a mass has been biopsied or resected but the slides do not show a neoplastic lesion.

From whence did the term arise? Ophthalmology has been cited as the first specialty that used the term pseudotumor in the literature (1); in 1930, Birch-Hirschfeld (2) employed that diagnosis in a discussion of orbital lesions that produced proptosis. Afterwards, other authors linked to it the adjectives inflammatory, lymphoid, granulomatous, xanthomatous, and fibrous, attempting to subdivide pseudotumors into pathologically recognizable categories. (3) The term pseudotumor is also synonymous with such alternative terms as postinflammatory tumor, (4,5) histiocytoma, (6) plasma cell granuloma, (7-9) mast cell granuloma (10) xanthoma, (11-14) xanthogranuloma (15) plasma cell/histiocytoma complex, (16) and, in some reports, (17) sclerosing hemangioma.

This brief introductory discussion considers definitions for the term pseudotumor further. Because this special section of the Archives is obviously intended for perusal by pathologists, such definitions will generally be based on the morphologic characteristics of the lesions being considered.


The case snapshots seen by clinicians, surgeons, radiologists, and pathologists are potentially quite different. For example, the surgeon may believe that he or she is palpating a definable mass in the breast, but the radiologist may see little or nothing on mammogram. similarly, a pathologist examining a fine-needle aspiration biopsy of the putative lesion may find nothing abnormal. In this scenario, the second and third physicians may question the claims of the surgeon, but unless they physically examine the patient themselves, they can never really determine whether a tumor is actually present at a clinical level. Nevertheless, the palpable lesion is certainly a pseudotumor in the mind of the surgeon.

Radiologists and pathologists are also subject to the same tricks of nature. For example, it is well known that hemorrhage in a hemophiliac patient may simulate neoplasms in radiographs, although no abnormality can be palpated. (18,19) Similar comments apply to roentgenographic images of tumefactive biliary sludge, (20) mucosal rosettes of the duodenal ampulla, (21) musculoskeletal anatomic variations, (22) and rounded atelectasis of the lung. (23-26) From the pathologist's perspective, adnexal nevi of the skin, (27-29) cutaneous reactions to Monsel solution (a styptic),30 and the presence of the organ of Chievitz (a carcinoma look-a-like) in biopsies of the oral mucosa (31,32) are singular pseudotumoral conditions with no clinical or radiographic corollaries. Only by face-to-face collegial interaction can all information on such cases be integrated to yield a clear assessment of the processes or anatomic variations in question. (33) In practical terms, interpretative disagreement between specialists--as stressful as that can be--is often the principal clue to the existence of a pseudotumoral condition.

Many pseudotumors can simulate neoplasms on all levels--clinical, radiologic, and pathologic--and they consequently represent real diagnostic pitfalls that can lead to real therapeutic missteps. Those are the entities to which this section is principally directed. In addition, other pathologic conditions are included that histopathologists alone may uniquely misinterpret as neoplasms.

Certain caveats are required to address this general topic. First, the group of lesions known as inflammatory pseudotumors is generally recognized as representing a neoplasm (inflammatory myofibroblastic tumors), although there may be difficulty in separating them from reactive processes.34 Similar comments apply to angiomyolipomas, melanocytic nevi, and many lesions formerly referred to as pseudolymphomas. After application of technologies such as immunohistochemistry, cytogenetics, and gene rearrangement analyses, most of these proliferations have been defined as neoplasms. Furthermore, as more knowledge continues to accrue, the classification of pseudoneoplasms presented here will undoubtedly undergo revision.




Virtually all topographic sites in the human body harbor lesions that simulate neoplasms. Perhaps because they are especially susceptible to etiologic events that cause pseudoneoplasms, some locations appear particularly prone (eg, the lung, urinary tract, and gut). In addition, partially overlapping and partly distinct groups of pseudoneoplasms are observed in various anatomic sites. This phenomenon may again reflect the relative influences of pathogenetic factors, but other variables likely affect them as well. The following sections consider putative etiologic categories of pseudoneoplasms. Pictorially, they are paired with the true neoplasms with which they might be confused (Table).




Idiopathic Pseudoneoplasms

The true inflammatory pseudotumor has an unknown cause, in most cases, and is most commonly encountered in the pulmonary parenchyma. (34-57) It may represent unresolved or organizing pneumonia, infectious or otherwise. (58)

There are several other inflammatory pseudotumor variants that represent etiologically heterogeneous entities, with at least one variant of each being idiopathic. Examples include nodular lymphoid hyperplasias of the lung, gut, skin, mucosal surfaces, soft tissue, and lymphoreticular system (59-66) (Figure 1, A through D); and fibroosseous lesions of the craniofacial and small tubular bones. (67-70) In these groups of disorders, some identifiable pathogenetic factors include viral infection or autoimmune diseases66 and fibrous dysplasia or familial cherubism. (69,71) However, some morphologically identical inflammatory pseudotumors are associated with no explanatory factors and must be classified as idiopathic.




Still other conditions are quasineoplastic because they feature causally unknown and, to some extent, autonomous, cellular proliferations in various locations, without definable stimuli. Radial scar of the breast, (72,73) urethral (prostatic utricular) polyp, (74) tumefactive fibroinflammatory lesions of soft tissue, (75,76) metaphyseal fibrous defects (nonossifying fibromas) of bone, (77,78) and aneurysmal bone cysts (79,80) (Figure 2, A through D) belong to this category. They differ from true neoplasms because they are self-limited or even spontaneously regress.

Other pseudoneoplasms in this section do have a linkage with underlying disease processes, but the etiology of the latter conditions may be idiopathic. Proliferative Paget disease of bone, (80-82) tumorlike plaques of active multiple sclerosis, (83) and lymphoma-like Hashimoto thyroiditis (84,85) (Figure 3, A through C) are representative examples.

Reparative/Posttraumatic Pseudoneoplasms

Exaggerated host responses to injury comprise the most common sources of pseudoneoplasms. Sometimes, the insult may have been trivial and subclinical, and the resulting reparative process might, therefore, be regarded as idiosyncratic. That situation likely applies to nodular fasciitis, (86-88) proliferative myositis, (88,89) giant cell reparative granuloma of bone (80,90,91) (Figure 4, A through D), fibrohyaline pleuritis (92,93) (Figure 5, A and B), and xanthogranulomatous inflammation in several sites. (94-96)

Still other pseudoneoplasms are caused by documented episodes of injury, but again, with an amplified and individualistic reparative response. Pseudocarcinomatous hyperplasias of the skin (97,98) (Figure 6, A and B), acroangiodermatitis, (99) myositis ossificans (100,101) (Figure 7, A through D), atypical (ischemic) decubital fibroplasia, (102) tumefactive synovial chondrometaplasia, (103) necrotizing sialometaplasia, (104) gliosis, (105) nephrogenic urothelial metaplasia (106) (Figure 8, A and B), inflammatory polyps of the anorectal region, (107) colitis cystica profunda, (108) florid reactive mesothelial proliferations (109) (Figure 9, A and B), tumorlike chronic pancreatitis, (110) and radiotherapy-induced tissue reactions (111) (Figure 10, A and B) are all examples of this category. Why some individuals develop exaggerated repair mechanisms and others do not is an unsettled question.




Developmental Pseudoneoplasms

The most straightforward group of pseudoneoplasms result from individual developmental quirks or, alternatively, from ignorance regarding details of normal organogenesis and embryology. Choristomas, (112) hamartomas (113,114) (Figure 11, A through D), and cutaneous nonmelanocytic nevi (27-29) are members of the first of those categories and are classified as flaws of morphogenesis. Tissue remnants or heterotopias relating to embryologic development constitute another large group, including examples of vaginal adenosis, (115-117) cervical mesonephric remnants (118) (Figure 12, A and B), adenomyoma (Brunner gland hamartoma) of the duodenum, (119) cutaneous rudimentary meningocele (120) (Figure 13, A and B), and glial heterotopias. (121)




On the other hand, the oral organ of Chievitz is a normal structure rather than an embryologic vestige, (31,32) but it is so uncommonly seen in mucosal biopsies that some observers fail to recognize it and confuse this inclusion with a malignant neoplasm (usually squamous carcinoma).

Malformations related to congenital or Mendelian syndromes can also resemble neoplasms. The tumefactive lesions of osseous fibrous dysplasia (82,90,122) and the paraventricular glial nodules of tuberous sclerosis (105) are examples.

"Functional" Pseudoneoplasms

Some pseudoneoplasms are caused by a dysfunctional pathophysiologic state, often relating to endocrine abnormalities. Dominant nodules often arise in parenchymal hyperplasias of the thyroid or parathyroid glands, (85) and those lesions can simulate adenoma or even carcinoma, microscopically. Comparable comments apply to localized unilateral nodular adrenocortical hyperplasia. (123) Other pseudotumors with an endocrine underpinning include prostatic hyperplasias, (124,125) focal nodular hyperplasia of the liver (126) (Figure 14, A through D), ovarian stromal hyperthecosis, (127) the endometrial Arias-Stella reaction, (128) osteitis fibrosa cystica (brown tumor of hyperparathyroidism) (129,130) (Figure 15, A through D), and uterine cervical microglandular hyperplasia. (131)




Iatrogenic Pseudoneoplasms

Several medical procedures can produce tissue reactions that mimic neoplasms. Most are reparative in nature and might also have been included in the corresponding section above. However, because of their clearly iatrogenic nature, they deserve special recognition. Instrumentation or surgery of the genitourinary tract may cause an idiosyncratic tumefaction comprising spindle cells, known simply as postoperative spindle cell nodule (132,133) (Figure 16, A and B). Similarly, application of an iron salt-based cutaneous styptic (Monsel solution) has caused idiosyncratic dermal proliferations resembling spindle-cell tumors of the skin. (30)

Other pseudoneoplasms in this category are able to imitate an infiltrative or in situ neoplasm. For example, urothelial cytotoxicity caused by cyclophosphamide can simulate in situ urothelial carcinoma (134) (Figure 17, A and B), and florid vaginal adenosis is found in women whose mothers took diethylstilbestrol during pregnancy. (116) Iatrogenic pseudoneoplasms are particularly problematic for pathologists because we are seldom supplied with pertinent (sometimes crucial) information on prior treatments or interventions.

Infectious Pseudoneoplasms

Particularly because of the acquired immunodeficiency syndrome, tissue reactions to several infectious pathogens capable of simulating neoplasms have been recognized. Conjointly cytopathic and reparative responses to cytomegalovirus, Epstein-Barr virus, papovavirus, selected species of mycobacteria, and other bacilli can produce proliferations in several organs with a histologic likeness to sarcomas, gliomas, or lymphomas (66,135-138) (Figures 18, A and B, and 19, A through D).




That phenomenon is not restricted to individuals with acquired immunodeficiency syndrome. It also underlies the genesis of malakoplakia (139,140) (Figure 20, A and B), histoid cutaneous infections caused by Mycobacterium leprae, (141) and florid lymphoid hyperplasia of the terminal ileum in patients infected with Yersinia. (142)


As outlined in the foregoing material, pseudoneoplastic proliferations are potentially encountered in virtually all the topical areas of anatomic pathology, including cytopathology. Thus, they represent a truly protean challenge with many possible implications for patient care and case outcome. All pathologists must bear those facts in mind in day-to-day practice, to guard against misinterpretations. We hope that this special section of the Archives will help to forewarn because to be forewarned is to be forearmed!
Representative Pseudoneoplastic Lesions by Organ
System With Related Neoplastic Mimes


  Adnexal nevi (adnexal neoplasms)
  Lymphoid hyperplasias (lymphomas)
  Reactions to Monsel solution (sarcomas; sarcomatoid
  Acroangiodermatitis (Kaposi sarcoma)
  Proliferating scars and posttraumatic spindle cell nodules
    (sarcomas; sarcomatoid carcinomas)
  Intravascular papillary endothelial hyperplasia (Masson
    lesion) (angiosarcoma)
  Pseudocarcinomatous epithelial hyperplasia (squamous cell
  Rudimentary meningocele (angiosarcoma)
  Mycobacterial pseudotumors (mesenchymal neoplasms)
  Bacillary angiomatosis (hemangiomas)

Soft tissue

  Neuromuscular choristoma (peripheral nerve sheath
  Fibrolipomatous hamartoma (lipomas)
  Nodular fasciitis (sarcomas)
  Proliferative myositis (sarcomas)
  Myositis ossificans (osteosarcoma)
  Tumefactive fibroinflammatory lesions (eg, idiopathic
    retroperitoneal fibrosis) (fibromatoses)
  Florid (tumefactive) lymphocytic myositis (lymphoma)
  Atypical decubital (ischemic) fibroplasia (sarcomas)

Bones and joints
  Bizarre osteochondromatous proliferations (Nora lesion) of
    digits (cartilaginous neoplasms)
  Synovial chondrometaplasia/chondrocalcinosis (cartilaginous
  Fibrous dysplasia and fibroosseous lesions (osteosarcoma and
  Proliferative-phase Paget disease of bone (osteosarcoma)
  Aneurysmal bone cyst (telangiectatic osteosarcoma)
  Giant-cell reparative granuloma (giant-cell tumor)
  Avulsion fractures of ischial tuberosities (osteosarcoma)
  Brown tumor of hyperparathyroidism (osteitis fibrosa cystica)
    (giant-cell tumor)


  Radial scar (low-grade ductal adenocarcinoma)
  Choristoma (hamartoma) (metaplastic carcinoma)
  Proliferative adenosis (low-grade ductal adenocarcinoma)
  Extramedullary hematopoiesis (invasive lobular carcinoma)
  Collagenous spherulosis (adenoid cystic carcinoma or
    intraductal carcinoma)
  Pseudoangiomatous stromal hyperplasia (angiosarcoma)

Nervous system
  Gliosis (low-grade gliomas)
  Active-phase plaques of multiple sclerosis (gliomas)
  Progressive multifocal leukoencephalopathy (gliomas)
  Paraventricular glial nodules of tuberous sclerosis (gliomas;
  Viral encephalitides (lymphoma)

Endocrine system
  Sclerosing and proliferative Hashimoto thyroiditis
    (differentiated and paucicellular anaplastic carcinomas)
  Nodular thyroid hyperplasia (thyroid adenomas and
    differentiated thyroid carcinomas)
  Nodular parathyroid hyperplasia (parathyroid adenoma)
  Nodular adrenal hyperplasia (adrenocortical adenoma)
  Adrenal myelolipoma (liposarcoma)
  Chronic tumefactive pancreatitis (low-grade pancreatic
    ductal adenocarcinoma)

Lymphoreticular system

  Selected lymphoid hyperplasias (lymphomas)
  Florid unilinear hyperplasia in bone marrow recovery
    (myelodysplasia; leukemia)
  Infection-related hemophagocytic syndrome (T-cell
  Epstein-Barr virus-related atypical lymphoid hyperplasias
    (large-cell lymphoma)
  Mycobacterial pseudotumors (dendritic-cell tumors)

Upper airway
  Pseudocarcinomatous epithelial hyperplasia (squamous cell
  Oral organ of Chievitz (low-grade squamous or
    mucoepidermoid carcinoma)
  Necrotizing sialometaplasia (squamous or mucoepidermoid
  Radiation effects on mucosal epithelia (squamous carcinoma)
  Benign lymphoepithelial lesion of salivary gland (lymphomas)
  Traumatized antral/choanal polyps (polypoid sarcomatoid
  Glial heterotopias (peripheral nerve sheath tumors)
  Benign fibroosseous lesions (low-grade fibrosarcoma or

Lower airway

  Pseudocarcinomatous epithelial hyperplasia (squamous cell
    carcinoma and adenocarcinoma)
  Fibrohyaline plaques of pleura (desmoplastic mesothelioma)
  Florid mesothelial hyperplasia (epithelial mesothelioma)
  Localized tumefactive organizing pneumonia (inflammatory
    sarcomatoid carcinoma)
  Selected examples of lymphocytic interstitial pneumonia
  Pulmonary chondroid/lipomatous/muscular hamartomas
    (metaplastic carcinomas)


  Sclerosing mediastinitis (sclerosing carcinomas, lymphomas,
   or germ-cell tumors)
  Thymic dysplasia (thymoma)
  Benign mesothelial inclusions in mediastinal lymph nodes
   (metastatic carcinoma)

Alimentary tract

  Pseudocarcinomatous epithelial hyperplasia
  Enteritis/colitis cystica profunda (adenocarcinoma)
  Adenomyoma of duodenum (well-differentiated
  Tumefactive chronic pancreatitis (well-differentiated ductal
  Mycobacterial pseudotumors (sarcomas)
  Bacillary angiomatosis (hemangiomas)
  Florid lymphoid hyperplasia (lymphomas)
  Hepatic bile duct hamartoma (metastatic adenocarcinoma)
  Hepatic focal nodular hyperplasia (fibrolamellar
    hepatocellular carcinoma)
  Inflammatory cloacogenic polyp (tubulovillous adenoma)
  Xanthogranulomatous cholecystitis (sarcomatoid carcinoma)

Genitourinary tract (M/F)

  Pseudocarcinomatous epithelial hyperplasia
    (adenocarcinoma and urothelial carcinoma)
  Postoperative spindle cell nodules (sarcomas; sarcomatoid
  Drug effects (eg, cytoxan cystitis mimicking carcinoma in
    situ) (urothelial carcinoma)
  Prostatic urethral (utricular) polyp (adenocarcinoma)
  Paratesticular mycobacterial pseudotumor (sarcomas)
  Xanthogranulomatous nephritis/cystitis/orchitis/endometritis/
    oophoritis (sarcomatoid carcinomas)
  Adenomatous and basal-cell prostatic hyperplasia
  Cribriform intraductal prostatic hyperplasia
  Nodular stromal prostatic hyperplasia (low-grade sarcoma)
  Prostatic sclerosing adenosis (adenocarcinoma)
  Radiation effect on prostatic epithelium (residual
  Granulomatous prostatitis/orchitis (sclerosing high-grade
    adenocarcinoma;sclerosing seminoma)
  Vaginal adenosis (adenocarcinoma)
  Uterine cervical mesonephric remnants (adenocarcinoma)
  Uterine cervical microglandular adenosis (adenocarcinoma)
  Ovarian stromal hyperplasia/hyperthecosis (ovarian stromal
  Nephrogenic metaplasia of bladder and urethra
  Endometriosis (adenocarcinoma)

Cardiovascular system

  Rhabdomyomatous hamartomas of myocardium (true adult
  Endodermal choristoma of interatrial cardiac septum
   (metastatic adenocarcinoma)
  Lipomatous hypertrophy of the heart (lipoma)
  Mesothelial-monocytic intracardiac excrescences (metastatic
    adenocarcinoma or mesothelioma)
  Endocardial and myocardial lymphocytic infiltrates post
    transplant (aka quilty lesions) (lymphomas)
  Florid pericardial mesothelial hyperplasia (epithelial


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Mark R. Wick, MD; Henry D. Tazelaar, MD

Accepted for publication July 17, 2009.

From the Department of Pathology, University of Virginia Medical Health Sciences Center, Charlottesville, Virginia; and Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Arizona (Dr Tazelaar).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Mark R. Wick, MD, Department of Pathology, Rm 3020, University of Virginia Health Sciences Center, 1215 Lee St, Charlottesville, VA 22908-0214 (e-mail:
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Title Annotation:Special Section--Pseudoneoplasms
Author:Wick, Mark R.; Tazelaar, Henry D.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Geographic Code:1USA
Date:Mar 1, 2010
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