Category: Case of the Month

History: A 76 year old man with a one year history of progressive right-sided hearing loss and tinnitus presented with a four month history of frequent falls.  A physical examination was essentially normal.  The tympanic membranes were clear, without drainage.  An MRI of the head revealed a 1.2 x 1.1 x 1.0 cm peripherally-enhancing lobulated mass involving the right internal auditory canal with extension into the right cerebellopontine angle.  The clinical impression was schwannoma vs. meningioma.

At surgery, two 0.2 cm fragments of red-tan tissue were removed from the right cerebellopontine angle.  They exuded “cheesy-white” material.

Microscopic sections revealed a papillary tumor (Fig. 1) with spaces lined by a single layer of bland cuboidal cells with acidophilic cytoplasm.  The supporting stroma was fibrovascular and showed focal calcifications and perivascular hyalinization (Figs. 2,3,4).  Neither significant pleomorphism nor mitotic activity was seen.

Diagnosis: “Low grade adenocarcinoma of endolymphatic sac origin (Heffner tumor)”

Hannah Wong MD, Norman Peckham MD, Donald Chase MD
Department of Pathology, Loma Linda University and Medical Center, Loma
Linda, California
California Tumor Tissue Registry, Loma Linda, California

Discussion: Low grade adenocarcinoma of endolymphatic sac origin (LGAE) is also referred to as endolymphatic sac papillary tumor, aggressive papillary tumor of temporal bone, endolymphatic sac adenoma, temporal-mastoid bone adenoma/adenocarcinoma, low grade adenocarcinoma of potential endolymphatic sac origin, and aggressive papillary tumor of the temporal bone.

LGAE is a rare tumor first described by Heffner in 1989 as an aggressive neoplasm arising in the region of the temporal bone.  There is no apparent gender predilection.  Of curiosity is that 11-30% of patients with LGAE also have von Hippel-Lindau (VHL) disease.  The average age of patients with LGAE (alone) is 52.5 years, but is younger (31.3 years) when associated with VHL disease.  Most tumors are unilateral, but patients with VHL have a higher incidence of bilateral disease.

Clinically, patients may present with sensorineural hearing loss, tinnitus, vertigo, serous otitis media, cranial nerve paralysis and/or jugular foramen syndrome.  The tumor may be found on physical examination as a blue or red mass behind an intact or ruptured tympanic membrane.  Imaging studies generally show soft tissue involvement with varying degrees of local destruction usually at the posterior aspect of the petrous portion of the temporal bone.  More advanced tumors may show intraosseous extension.

Histologically, the tumor is predominantly papillary with a variable degree of cystic change.  The papillae have fibrovascular cores lined by a single layer of cuboidal to columnar cells.  They may have a follicular appearance or be “crowded” into a solid mass.  Individual cells may show clear, vacuolated or acidophilic cytoplasmic features and usually have distinct cell borders.  The nuclei are oval, mildly irregular, centrally to apically located and have inconspicuous nucleoli.  Mitotic activity is generally absent.  The surrounding stroma is hypocellular with focal areas of fibrosis, hemorrhage, and/or cholesterol clefting.  PAS-positive proteinaceous material similar to colloid may be present.

LGAE generally displays one or both of two main histological patterns:
•    Follicular pattern consisting of colloid filled follicles.   This pattern is believed to be secondary to cystic dilation of the glands, resulting in a follicle-like appearance similar to that seen in thyroid tumors.
•    Papillary pattern consisting of a more cellular lesion made of papillary and solid areas.

Although histogenesis is still debated, most studies suggest that LGAE originates from the endolymphatic sac, which in turn was derived from neuroectoderm (otocyst) between the dura and the posterior surface of the petrous portion of the temporal bone.  The tumor strongly resembles normal endolymphatic sac tissue consisting of papillary epithelium composed of cuboidal or columnar cells arranged in villous folds overlying loose connective tissue.

LGAE expresses several cytokeratins including CAM5.2, 34βE-12, CK7, CK8 and CK19.  It also usually marks for epithelial membrane antigen and vimentin.  Expression of vascular endothelial growth factor and neuron specific enolase may also occur and increased Ki-67 expression has been reported.

The differential diagnoses for LGAE includes middle ear adenoma, middle ear carcinoma, paraganglioma, meningioma, squamous cell carcinoma and primary and secondary bone lesions.  Of these lesions, middle ear adenoma is the most common tumor with which LGAE can be confused with.  Middle ear adenomas are less aggressive neoplasms than LGAE and are typically confined to the middle ear.  Unlike LGAE they usually show glandular-trabecular growth patterns.

Despite local aggressiveness, clinical progression of LGAE is generally slow, allowing for initial local surgical resection without use of chemotherapy or radiotherapy.  Postoperative radiotherapy is generally reserved for recurrent disease or for cases of persistent disease due to previous incomplete excision.

Suggested reading:

1.    Mills SE, Faggey MJ and HF Frierson, Jr. Aggressive papillary tumor of temporal bone and endolymphatic sac (low-grade adenocarcinoma of endolymphatic sac origin). Tumors of the upper aerodigestive tract and ear. AFIP. Third series, fascicle 26; 436-438.

2.    Horiguchi H, Sano T, Toi H, Kageji T, Hirokawa M, Nagahiro S. Endolymphatic sac tumor associated with a von Hippel-Lindau disease patient: an immunohistochemical study. Mod Pathol. 14(7):727-732, 2001.

3.    Yilmaz I, Bolat F, Demirhan B, Aydin V, Ozluoglu LN. Endolymphatic sac papillary tumor: a case report and review. Auris Nasus Larynx. 35:276-281, 2007.

4.    Delisle MB, Uro E, Rouquette I, Yardeni E, Rumeau JL. Papillary neoplasm of the endolymphatic sac in a patient with von Hippel-Lindau disease. J Clin Pathol. 47:959-961, 1994.

5.    Ho VT, Rao VM, Doan HT, Mikaelian DO. Low-grade adenocarcinoma of probable endolymphatic sac origin: CT and MR appearance. AJNR. 17:168-170, 1995.

6.    Heffner DK. Low-grade adenocarcinoma of probable endolymphatic sac origin: a clinicopathologic study of 20 cases. Cancer. 64(11):2292-2302, 1989.

History: A previously healthy 80 year-old man presented with a one-month history of right axillary lymphadenopathy.  Physical examination revealed a mildly tender, firm, two cm lymph node in the right axilla.  No other lesions identified.

Imaging studies confirmed the presence of an enlarged lymph node in the right axilla.  There were no other radiological abnormalities.

Microscopic sections revealed complete effacement of lymph node architecture by a polymorphous lymphoid infiltrate consisting of large atypical lymphoid cells with open chromatin, prominent nucleoli, and moderate amounts of cytoplasm against a background of predominately small lymphocytes (Figs. 1,2,3).  Large atypical lymphoid cells were positive for CD20 and CD79a, while the smaller background lymphocytes were CD3, CD5 and PAX5 positive (Fig. 4).  Epstein-Barr virus genomes were detected in the large atypical lymphoid cells by EBER in situ hybridization.

Diagnosis: “EBV positive diffuse large B-cell lymphoma of the elderly”

Hannah Wong MD, Jun Wang MD, Donald Chase MD
Department of Pathology, Loma Linda University and Medical Center, Loma
Linda, California
California Tumor Tissue Registry, Loma Linda, California

Discussion: EBV positive diffuse large B-cell lymphoma of the elderly (EBV+ DLBCL, aka “age-related EBV-associated lymphoproliferative disorder”), is a rare B-cell lymphoproliferative disorder that occurs in elderly patients with no known history of immunodeficiency or lymphoma.  The entity was first described by Oyama et al. in 2003 and was added as a distinct entity in the newly published WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.

As the name suggests, EBV+ DLBCL of the elderly is a disease affecting patients over the age of 50 years.  There is a slight male predominance of 1.4:1.  Typically there is no history of immunodeficiency or lymphoma.  Presentation symptoms and signs include fever, night sweats, weight loss and lymphadenopathy.  Extranodal sites found at presentation include skin, lung, tonsil and stomach.

Histologically, the nodal or native tissue architecture is completely effaced by large atypical lymphoid cells/immunoblasts as well as Reed-Sternberg-like giant cells.  Accompanying these elements are variable numbers of small lymphocytes, plasma cells, histiocytes, centroblasts and immunoblasts.  Although EBV+ DLBCL of the elderly was originally separated into two subtypes; polymorphic lymphoproliferative disorder (PLPD) and large cell lymphoma (LCL) recent studies have shown the sub-classification to be clinically irrelevant.

The neoplastic large lymphoid cells show expression of pan-B cell markers (CD20, CD79a and PAX5), with variable expression of CD30, LMP-1 and EBNA-2.  Light chain restriction may be present but has been difficult to demonstrate in most cases. CD15, CD10 and Bcl-6 are generally negative.  Neoplastic cells showing EBER positivity and Ki-67 expression is generally high.

Differential diagnoses of EBV+ DLBCL of the elderly include other B-cell lymphoproliferative disorders such as Burkitt lymphoma, post-transplant lymphoproliferative disorder (PTLD), HIV-associated lymphoproliferative disorder, EBV- DLBCL, and EBV+ classical Hodgkin lymphoma (cHL).  It is important to differentiate these entities in order to provide the most targeted and effective treatment for the patients.

•    Burkitt lymphoma (BL) is a highly aggressive lymphoma with three clinical variants:

1. Endemic type mostly occurs in children between the ages of 4 – 7 in equatorial Africa.
2. Sporadic type  is more common in the United States and Western Europe, where the median age is 30 years.
3. Immunodeficiency-associated BL patients are virtually all immunocompromised, mostly due to HIV infection.

BL has a variable degree of EBV involvement with endemic types having the highest association.  Although the morphology of BL varies slightly in each type, the most common pattern is of medium-sized cells in a diffuse monotonous pattern with multiple benign macrophages having ingested apoptotic tumor cells resulting in the classic “starry-sky” pattern.  Multiple mitotic figures may be present.  Immunohistochemical stains can be helpful in differentiating BL from EBV+ DLBCL of the elderly since the malignant cells in BL are usually CD10 and BCL-6 positive while the malignant cells of EBV+ DLBCL are negative for those two markers.  BL is also unique in that t(8;22) involving the c-myc oncogene is a constant feature; however this translocation has not been investigated in EBV+ DLBCL of the elderly.

•    Post-transplant lymphoproliferative disorder (PTLD) is a lymphoid proliferation that arises in immunosuppressed recipients usually involving a solid organ or bone marrow allograft.  EBV has been found to be the driving force in PTLD, leading to early polyclonal proliferations and ultimately the development of lymphomas.  Four morphologic categories of PTLD are:

1. Early lesions resemble reactive hyperplasia and/or infectious mononucleosis. These lesions show an expanded paracortex filled with plasma cells and immunoblasts with a background of small T-cells with partial preservation of the underlying normal tissue architecture.
2. Polymorphic PTLD shows effacement of the normal nodal/extranodal architecture by a mixture of large immunoblasts and plasma cells with smaller lymphocytes.  Necrosis, mitoses and atypical immunoblasts may also be present.
3. Monomorphic PTLD has a monomorphic infiltrate effacing nodal/extranodal tissues with confluent sheets of atypical B-cells or plasma cells.
   The Hodgkin lymphoma (HL) variant is similar in morphology and immunophenotype to classical Hodgkin lymphoma.  It displays Reed-Sternberg (HRS)-like cells and variants, and are positive for CD30 and CD15, but not CD20.

Despite splitting PTLD variants into four morphologies, the distinction is of limited value.  The clinical history currently appears to be the most helpful criterion for differentiating PTLD from EBV+ DLBCL of the elderly.

•    HIV-related lymphomas display EBV presence about 60% of the time.  They are generally aggressive B-cell lymphomas related to other lymphoproliferative disorders which are associated with HIV infection such as BL, DLBCL, primary effusion lymphoma, plasmablastic lymphoma of the oral cavity and others.  Interestingly, other viruses such as Kaposi’s sarcoma-associated herpes virus/human herpes virus 8 (KSHV/HHV8) have also been found in several categories of immunodeficiency-associated lymphoma.  But despite the similar morphological and immunohistochemical features of HIV- associated LPD and EBV+ DLBCL of the elderly, a positive HIV serology usually separates the two.

•    EBV+ classical Hodgkin lymphoma (cHL).  Classical Hodgkin lymphoma accounts for 95% of all Hodgkin lymphomas.  cHL has a bimodal age distribution with the first peak at 15 to 35 years and a second peak later in life.  Approximately 30-50% of cHL have been found to be EBV positive.  Patients with EBV+ cHL have a more aggressive clinical course and worse prognosis in comparison to those with EBV- cHL.  Morphologically, EBV+ cHL has the classic morphology of cHL with HRS cells in a background of inflammatory cells.  The large HRS cells have abundant cytoplasm and at least two large round nuclei with prominent nucleoli.  These HRS cells are positive for CD30 and mostly positive for CD15 but are negative for CD45.  This is in comparison to EBV+ DLBCL of the elderly which is usually positive for CD45, CD20/CD79a, variably positive for CD30 but negative for CD15.  EBER has been found to be positive in the neoplastic cells of EBV+ DLBCL of the elderly more often than in the neoplastic HRS cells and their variants of EBV+ cHL.  Thus, immunohistochemical studies and EBER are the most useful tools to distinguish EBV+ cHL from EBV+ DLBCL of the elderly.

•    EBV- DLBCL is virtually the same as EBV+ DLBCL of the elderly except that it may occur in patients of any age and is not EBV+.  Morphologically, these two entities are virtually indistinguishable.  However, EBER positivity would help separate it from the EBV+ DLBCL of the elderly.

EBV+ DLBCL of the elderly has a highly aggressive behavior; the median survival for this disease is approximately two years.  Patients with EBV+ DLBCL of the elderly have been found to be less responsive to the standard chemotherapy regimens for large B-cell lymphoma compared with other forms of B-cell lymphoproliferative disorders.

Suggested reading:

1.    Nakamura S, Jaffe E.S, Swerdlow S.H.EBV+ Diffuse large B-cell of the elderly.. In: Swerdlow S.H., Campo E., Harris N.L., Jaffe E.S., Pileri S.A., Stein H., Thiele J., Vardiman J.W. (Eds.): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC: Lyon, 243-244 2008.
2.    Shimoyama Y., Yamamoto K., Asano N., Oyama T., Kinoshita T., Nakamura S. Age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorders: Special references in lymphomas surrounding this newly recognized clinicopathologic disease.  Cancer Sci  9:1085-1091, 2008.
3.    Shimoyama Y., Oyama T., Asano Net al. Senile Epstein-barr virus-associated B-cell lymphoproliferative disorders: a mini review. J Clin Exp Hematopathol  46:1-4, 2006.
4.    Oyama T., Ichimura K., Suzuki R., et al . Senile EBV+ B-cell lymphoproliferative disorders: a clinicopathologic study of 22 patients. Am J Surg Pathol  27;16-26. 2003.
5.    Mueller S., Aigner T., Haag J., Schwartz R., Niedobitek G. Senile EBV-associated B-cell lymphoproliferative disorder of prepatellar bursa in elderly patient with multifocal urate arthropathy. Hematol Oncol  25:140-142, 2007.
6.    Oyama T., Yamamoto K., Asano N., et al . Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: A study of 96 patients. Clin Cancer Res  13:5124-5132,  2007.

History: An 8 year old otherwise healthy boy was found to have a left scrotal mass. An ultrasound showed the left testis to be “inhomogeneous” and surrounded by a tumor confined to the scrotum. The right testis was normal. Regional inguinal lymph nodes were not enlarged and an abdominal CT scan was unremarkable.

A left orchiectomy specimen included a 7.0 x 3.5 x 2.5 cm grey-tan solid tumor that surrounded and compressed an uninvolved 1.5 cm testis.

Microscopically the tumor was solid, partly necrotic and highly cellular (Fig. 1). It was partially compartmentalized by fibrous bands separating two populations of cells which varied in amounts of cytoplasm (Fig. 2). Some regions showed spindling with occasional fusiform cells displaying cross striations (Fig. 3). Most of the tumor, however, consisted of areas of primitive small rounded hyperchromatic cells with limited cytoplasm, and other regions having an admixture of primitive cells with larger, more differentiated cells containing abundant eosinophilic cytoplasm and concentric cytoplasmic striations (Fig. 4,Fig. 5). Immunohistochemical stains showed the tumor to have moderate nuclear staining for myogenin (“myogen”) and strong cytoplasmic decoration for desmin (“des”) (Fig. 6).

Diagnosis: “Paratesticular Embryonal Rhabdomyosarcoma”

Krishna Ahuja MD, Donald R. Chase MD, Anwar Raza MD, Craig Zuppan, MD
Department of Pathology, Loma Linda University and Medical Center, Loma Linda, California
California Tumor Tissue Registry, Loma Linda, California

Discussion: Rhabdomyosarcoma (RMS) is a malignant mesenchymal tumor, usually of childhood, showing striated muscle differentiation. It generally arises in body regions with skeletal muscle, though it may also occur in locations lacking these elements such as the prostate or nasopharynx. As a result, RMS is currently felt to devolve not from myocytes, but from primitive mesenchyme having myogenic tendencies. Although the etiology is not known, it is associated with:

Genetic Disorders:
Neurofibromatosis type 1
Adenomatous polyposis coli
Beckwith-Wiedemann syndrome
Gorlin nevoid basal cell carcinoma syndrome

Developmental Disorders:
Congenital lung cyst
Central nervous system malformations
Genitourinary malformations
Fetal alcohol syndrome

Traditionally the morphological classification of RMS includes three main types, each having slightly different ages of occurrence:

• Embryonal rhabdomyosarcoma (infants, children, adolescents, young adults)
• Alveolar rhabdomyosarcoma (adolescents, young adults)
• Pleomorphic rhabdomyosarcoma (adults)

The WHO, however, currently recommends a classification by subtype which emphasizes prognosis.

Prognostic Group and Type % of Cases 5-year Survival
Superior:
Botryoid embryonal RMS 6% 95%
Spindle cell embryonal RMS 3% 88%
Intermediate:
Embryonal RMS, NOS 49% 66%
Poor:
Alveolar RMS 31% 54%
Undifferentiated sarcoma 3% 40%

*(From Newton, 1995 and CTTR seminar of June, 2008 by Cheryl Coffin)

Embryonal RMS

ERMS accounts for approximately 50 % of all RMS mostly affecting children younger than 10 years of age, it also occurs in adolescents and young adults and is uncommon in patients older than 40 years of age. The tumor seems to display various stages of myogenesis and its patterns are variable, ranging from poorly differentiated tumors that are difficult to diagnose without immunohistochemical or electron microscopic examination, to well-differentiated neoplasms that resemble fetal or even adult muscle. The percentage of differentiated rhabdomyoblasts serves as a rough estimate of differentiation. Tumors with mostly primitive small cells tend to do worse than those dominated by larger, rounded rhabdomyoblasts. Two important sub-types with more favorable prognoses are:

Spindle cell RMS: Usually involves paratesticular soft tissue, followed by the head and neck area. Histologically it is composed almost exclusively of elongated fusiform cells with cigar-shaped nuclei and prominent nucleoli. Cross striations are more readily discernible in this subtype than in others.

Botryoid RMS (BRMS): Most commonly found in mucosa-lined hollow organs such as nasal cavity, nasopharynx, bile duct, urinary bladder and vagina. According to ICR criteria, a “cambium layer”, characterized by a subepithelial condensation of tumor cells separated from an intact surface epithelium by a zone of loose stroma, must be present to recognize this variant.

Alveolar RMS

This tumor occurs more often in limb girdles than does BRMS and usually arises in adolescents. The classic alveolar pattern consists of anastomosing fibrovascular septa lined by discohesive tumor sometimes accompanied by multinucleated cells. The neoplasm is aggressive and may present with distant metastasis. Curiously, in addition to lung, it may metastasize to breast or the bone marrow where it can cause a leukemic-like presentation.

Pleomorphic RMS

Accounting for no more than 10% of the tumors, the “adult form” of RMS is rare. It usually arises in the limbs and appears to be less chemosensitive than the other variants. The histology is that of a pleomorphic sarcoma (nos) showing positivity for muscle markers such as myogenin, desmin, etc. The expected 5-year survival is only around 20%. Of interest is that it may be associated with prior radiation to or near the primary site.

With combination therapy, especially improved chemotherapy, the prognosis of RMS has greatly improved through the years. Despite the dramatic improvement in treatment of RMS, early diagnosis and accurate classification remains vital. Continued therapeutic success is expected as we enter the molecular era with the potential for targeted therapies.

Suggested Reading:

Stout AP. Rhabdomyosarcoma of the skeletal muscles. Ann Surg 123:447, 1946.

Newton WA Jr, et al. Classification of rhabdomyosarcomas and related sarcomas. Pathologic aspects and proposal for a new classification – an Intergroup Rhabdomyosarcoma Study. Cancer 76:1073, 1995.

Parham DM: Pediatric Neoplasia: Morphology and Biology, Chapter 5, pp 87-100, Lippincoot-Raven Publishers, Philadelphia 1996.

Cheryl M. Coffin: “The New International Rhabdomyosarcoma Classification, Its Progenitors, and Considerations beyond Morphology.” Advan Anat Pathol, Vol 4, No 1, pp1-16, 1997.

Enzinger and Weiss’: Soft Tissue Tumors 5th Ed. Editors SW Weiss, JB Goldblum. Mosby, Inc. pp 595-632, 2008.

History: A 55-year-old man with a ten year history of swollen eyes presented with asthmatic symptoms. He was found to have enlarged upper and lower eyelids with ocular secretions that prevented him from seeing properly. The clinical differential included inflammatory pseudotumor of the orbits, proptosis from Grave’s disease and multiple myeloma. The workup showed an elevation of free kappa light chains. A periocular biopsy was performed.

The examined tissue consisted of a diffuse infiltration of lymphocytes admixed with lipid-laden histiocytes (xanthoma cells). They had small rounded nuclei and abundant clear or vacuolated cytoplasm (Fig. 1). There were also scattered multi-nucleated giant cells of the Touton type (Fig. 2). Within the lymphoid component were prominent follicles with parafollicular fibrosis (Fig. 3). Immunohistochemically, the foamy histiocytes were strongly positive for CD68 and negative for S100. The lymphoid infiltration had a reactive profile with the germinal cells being CD20 positive and negative for Bcl-2. The parafollicular T cells were CD3 positive (Fig. 4).

Diagnosis: “Adult-Onset Asthma and Periocular Xanthogranuloma”

Jin Guo MD, Jun Wang MD and Donald R. Chase MD
Department of Pathology, Loma Linda University and Medical Center, Loma Linda, California
California Tumor Tissue Registry, Loma Linda, California

Discussion: Adult-onset asthma with periocular xanthogranuoloma (AAPOX) was first described by Jakobiec et al in 1993 when they reported 6 patients with periocular xanthogranulomatous disease associated with adult onset asthma, but lacking necrobiosis. The entity has now been placed into a heterogeneous group of syndromes called adult xanthogranulomatous disease (AXGD) that are rare and poorly understood. AXGD has variable clinical features which have resulted in subclassification into:
• Adult onset xanthogranuloma
• Necrobiotic xanthogranuloma
• Erdheim-Chester disease, and
• AAPOX

Histopathologically, each of these four entities is characterized by infiltration of “hallmark cells” specifically foamy histiocytes and Touton-type giant cells, both of which are negative for S100 and CD1. The infiltration along with accompanying lymphocytes can replace the normal lacrimal gland architecture, causing mass effects and loss of tear production.

Adult onset xanthogranuloma is an isolated xanthogranulomatous lesion without significant systemic involvement.

Necrobiotic xanthogranuloma is characterized by subcutaneous skin lesions that tend to ulcerate and become fibrotic. Associated systemic findings frequently include paraproteinaemia and multiple myeloma.

Erdheim-Chester Disease is an idiopathic condition of lymphohistiocytic infiltration of the heart, lungs, retroperitoneum, bones, and other tissues. The elements are xanthogranulomatous with Touton giant cells and are accompanied by regional fibrosis.. The condition is often fatal, with death due to cardiomyopathy, severe lung disease, or chronic renal failure.

AAPOX often presents with bilateral yellow-orange, elevated, indurated and non-ulcerated xanthomatous eyelids and/or orbital masses. It typically extends into the anterior orbital fat, and sometimes involves the extraocular muscles and/or the lacrimal gland(s). Most patients experience adult-onset asthma within a few months to a few years of onset. Even when asthmatic symptoms are severe enough to require systemic corticosteroids and/or inhalation therapy, a chest X-ray may be negative.

AAPOX is rare with only 21 previous reported cases. Like other AXGDs, it usually has sheets of mononucleated foamy histiocytes, with lymphocytes, plasma cells and Touton giant cells. The cells characteristically infiltrate the orbicularis muscles and the anteriorbital tissues. Their Touton cells have a ring of nuclei about a central eosinophilic zone which is surrounded by a zone of pallor extending to the periphery of the cell. Lymphoid follicles are commonly scattered throughout. Unlike Erdheim-Chester Disease, fibrosis is usually minimal to moderate and unlike necrobiotic xanthogranuloma there is no necrobiosis of collagen. Because the eyelids remain intact and the process does not reach the deep orbital and perioptic connective tissues, visual acuity may not be affected and ocular motility is generally well preserved unless the extraocular muscles are involved. Only rarely are the corneas exposed to the infiltrate, but in rare cases where lacrimal gland involvement causes punctuate corneal epitheliopathy the patient may suffer from a dry eye condition. CT scanning may reveal preseptal and anterior orbital involvement with occasional posterior tracking along or within the orbital muscles and fat, usually sparing the perioptic nerve connective tissues. Facial bones are usually not involved.

Systemic evaluations are usually normal except for rare reports of elevated alpha high-density cholesterol and/or M-protein (IgG) on serum immunoelectrophoresis. The latter suggests that the inflammatory infiltrates have stimulated B cell populations.

The main differential diagnoses of AAPOX include other AXGDs including the aforementioned adult onset xanthogranuloma, necrobiotic xanthogranuloma, and Erdheim-Chester Disease. These conditions all share similar lymphogranulomatous infiltrates but have subtle differences in the amount of lymphoid follicles, number of Touton giant cells, degree of fibrosis and presence of necrosis. Curiously, these features may vary within the same specimen and change with time and treatment. Based upon morphology alone, therefore, the AXGDs are difficult to sub-classify on histomorphologic grounds alone and usually require correlation with patterns of systemic involvement.

Necrobiosis with palisading epithelioid histiocytes is most often seen in necrobiotic xanthogranuloma whereas large lymphoid aggregates with germinal centers are often found in cases of AAPOX. Whereas orbit/adnexal xanthogranulomas tend to be anterior in adult-onset xanthogranuloma, AAPOX, and in necrobiotic xanthogranuloma, in Erdheim-Chester disease the disease is often diffuse (and posterior) leading to visual loss. Bone involvement is common and death may occur despite aggressive therapies.

While the majority of cases can be classified as one of the four syndromes, there are cases that fall in between. These patients have varying combinations of periocular xanthogranuloma and other blood dyscrasias including thrombocytopenia, paraproteinaemia and/or monoclonal gammopathy of undetermined significance (MGUS).

In addition to AXGDs, AAPOX should also be differentiated from other non-Langerhans disorders of histiocytes, including juvenile xanthogranuloma (JXG). This tumor is usually manifested as a self-limited, corticosteroid-sensitive skin tumor that rarely has systemic manifestations. Infants and small children are mainly affected with head and neck lesions. Many extracutaneous sites, however, have been reported, particularly the eye where JXG may cause spontaneous hyphema and result in secondary glaucoma and eventual blindness. Approximately one half of patients with ocular involvement also have skin lesions.

Other entities involving ocular adnexal or orbital tissue that may require distinction from adult xanthogranulomatous disease include:
• Langerhans histiocytosis
• Rosai-Dorfman syndrome
• Inflammatory MFH
• Inflammatory myofibroblastic tumor (inflammatory pseudotumor)
• Graves disease
• Multiple myeloma, and
• Lymphoma.

Despite surgical debulking, AAPOX often recurs within 6-12 months. Although systemic prednisone treatment may cause temporal shrinkage, it alone is usually not successful in causing a lasting resolution. Combined prednisone and systemic chemotherapy for paraproteinaemia may result in more complete resolution of the xanthogranulomatous eyelid deposits. Radiotherapy has also been successfully employed, but the results are more anecdotal than statistical. The eyelid lesions in necrobiotic xanthogranuloma can be successfully be treated with radiotherapy or systemic prednisalone and chlorambucil unless extensive destruction has occurred. Patients without detectable systemic disease at the time ocular adnexal lesions appear should be spared surgical debulking because of possible scarring. In this setting high doses of systemic corticosteroids and low doses of periobital radiotherapy may be given with hope of protection of the globe. If this approach fails, systemic corticosteroids and light chemotherapy may be tried. In patients with MGUS, follow-up should include serial serum protein immunoelectrophoresis and bone biopsy as needed.

A recent study evaluated the efficacy of methotrexate in the treatment of the periorbital changes in adult-onset xanthogranuloma with or without asthma. With follow-up of over 3 years, 10-20 mg/weeks of methotrexate with folate supplementation and a course of corticosteroids showed promising results in significantly reducing inflammation and ptosis.

In summary, AAPOX as well as other entities in the adult xanthogranulomatous disease are rare and pose challenges in daily clinical practice. Recognizing their clinical and histopathological features will facilitate early diagnosis and appropriate therapeutic management.

Suggested reading:

Sivak-Callcott JA, Rootman J, Rasmussen SL, Nugent RA, White VA, Paridaens D, Currie Z, Rose G, Clark B, McNab AA, Buffam FV, Neigel JM, Kazim M. Adult xanthogranulomatous disease of the orbit and ocular adnexa: new immunohistochemical findings and clinical review. Br J Ophthalmol 90(5):602-8, 2006.

Jakobiec FA, Mills MD, Hidayat AA, Dallow RL, Townsend DJ, Brinker EA, Charles NC. Periocular xanthogranulomas associated with severe adult-onset asthma. Trans Am Ophthalmol Soc 91:99-125, 1993.

Hammond MD, Niemi EW, Ward TP, Eiseman AS. Adult orbital xanthogranuloma with associated adult-onset asthma. Ophthal Plast Reconstr Surg 20(4):329-32, 2004.

Hayden A, Wilson DJ, Rosenbaum JT. Management of orbital xanthogranuloma with methotrexate. Br J Ophthalmol 91(4):434-6, 2007.

Vick VL, Wilson MW, Fleming JC, Haik BG. Orbital and eyelid manifestations of xanthogranulomatous diseases. Orbit 25(3):221-5, 2006.

Rayner SA, Duncombe AS, Keefe M, Theaker J, Manners RM. Necrobiotic xanthogranuloma occurring in an eyelid scar Orbit 27(3):191-4, 2008.

Chaudhry IA, Al-Jishi Z, Shamsi FA, Riley F. Juvenile xanthogranuloma of the corneoscleral limbus: case report and review of the literature. Surv Ophthalmol 49(6):608-14. Review, 2004

Elner VM, Mintz R, Demirci H, Hassan AS. Local corticosteroid treatment of eyelid and orbital xanthogranuloma. Trans Am Ophthalmol Soc 103:69-73, 2005

History: A 53 year old woman presented with acute abdominal pain assumed to be diverticulitis. A right hemicolectomy was performed.

The resected colon showed extensive serosal fibrinopurulent exudate. There was also an 8 x 7 x 4 cm mass in the cecum and ascending colon which narrowed the lumen by approximately 70%. It ulcerated the overlying mucosal and perforated into the underlying fat. The attached portion of ileum was uninvolved.

Microscopically, the tumor involved the submucosa with upward extension into the mucosa and more deeply into the muscularis and serosa (Fig. 1). The tumor was composed of sheets of fairly uniform large cells with a faint organoid growth pattern (Fig. 2). The cells were round to oval with moderate amounts of cytoplasm, vesicular nuclei and prominent nucleoli (Fig. 3). Numerous mitotic figures (up to 30/10 HPFs) were accompanied by apoptotic bodies as well as large areas of necrosis (Fig. 4). Immunohistochemically, the tumor cells were strongly positive for synaptophysin and CD56 and moderately positive for chromogranin (Fig. 5). They were negative for cytokeratins, CDX2, TTF1, CD45 and CD117.

Diagnosis: Large Cell Neuroendocrine Carcinoma of the Cecum
Yvonne Noronha MD, Donald R Chase, MD
Department of Pathology and Human Anatomy,
Loma Linda University and Medical Center, Loma Linda, CA
California Tumor Tissue Registry, Loma Linda, CA.

Discussion: Originally described in the lung, large cell neuroendocrine carcinoma (LCNEC) has subsequently been reported in other organs. Because of its rarity, clear-cut criteria were originally lacking and the tumor was graded as if it was of pulmonary origin. But it is now recognized that unlike carcinoid tumors/atypical carcinoids, LCNEC is high grade, supported by their high mitotic rates, generally >10/10 HPF and aggressive clinical behavior.

Recently, in a study of 65 high grade neuroendocrine carcinomas of the GI tract, Shia et al used the WHO/ International Association for the Study of Lung Cancer criteria for pulmonary neuroendocrine tumors as a guideline to classify neuroendocrine carcinoma of the GI tract. To be classified as high grade neuroendocrine carcinoma, the tumor had to have >10 mitoses/10 HPF and had to fulfill criteria from one of the following three sub-groups:

1) Small cell carcinoma:
• Tumors with typical small cell morphology: markedly high nuclear to cytoplasmic ratio, hyperchromatic nuclei, finely granular chromatin with absent or faint nucleoli and frequent nuclear molding.
• Immunohistochemical evidence of epithelial differentiation: Positive staining for AE1:AE3.
• Positive staining for neuroendocrine markers helps but was not a requirement for diagnosis.

2) Large cell neuroendocrine carcinoma:
• Tumor with large cell neuroendocrine morphology: diffuse growth pattern/ neuroendocrine architecture (organoid growth pattern, trabeculae, and rosette formation); monotonous round to oval cells with moderate amounts of cytoplasm, granular or vesicular nuclei, with or without prominent nucleoli. Focal intracytoplasmic mucin or lumen formations were not criteria for exclusion.
• Positive immunohistochemical staining for chromogranin or synaptophysin in > 20% of tumor cells.

3) Mixed neuroendocrine carcinoma:
• Tumors showing histologic features in between small and large cell neuroendocrine carcinoma with immunohistochemical evidence of neuroendocrine differentiation.

The differential diagnosis of LCNEC is broad and should include (apart from carcinoids and small cell neuroendocrine carcinomas) lymphomas, plasma cell myelomas, poorly differentiated carcinomas and sarcomas. The correct diagnosis is based on the recognition of the typical morphology on H&E staining and is supported by the use of a limited immunohistochemical panel (synaptophysin and chromogranin). CD56 can be used but may not clarify the diagnosis since it can be positive with lymphomas, plasma cell myelomas, synovial sarcomas and rhabdomyosarcomas which are part of the differential diagnoses of LCNEC on H&E.

LCNECs are aggressive tumors. In one study of 83 cases of LCNEC of lung, the median survival was 17 months. The clinical significance of these tumors has yet to be fully evaluated. Their recognition, however, is of potential therapeutic significance since their neuroendocrine nature links them to classic small cell carcinomas which are sensitive to chemotherapy. Reports available to date regarding the chemosensitivity of LCNECs are contradictory. Although there are no prospectively controlled data, surgical resection when feasible, followed by combination chemotherapy similar to that employed for small cell carcinoma, appear to offer the best chance for improved survival in patients with early stage disease.

Suggested Reading:

1. Hamilton S.R and Aaltonen L.A. World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Digestive System. Lyon: IARC Press; 2000.
2. Travis WD, Colby TV, Shimosato Y, et al. in association with Sobin LH and pathologists from 14 other countries. WHO/IASLC Classification of Lung and Pleural Tumors. Berlin: Springer; 1999.
3. Shia J, Tang LH, Weiser MR et al. Is Nonsmall Cell Type High-Grade Neuroendocrine Carcinoma of the Tubular Gastrointestinal Tract a Distinct Disease Entity? Am J Surg Pathol 32(5): 719-731, 2008.
4. Bernick PE, Klimstra DS, Shia J et al. Neuroendocrine Carcinomas of the Colon and Rectum. Dis Colon Rectum 47: 163-169, 2004.
5. Gaffey MJ, Mills Se, Lack EE. Neuroendocrine Carcinoma of the Colon and Rectum. A clinicopathologic, ultrastructural and immunohistochemical study of 24 cases. Am J Surg Pathol; 14: 1010-1023, 1990.