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Breast malignant, males, children

Superpage - Other

Revised: 12 December 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Sarcoma

General


Reviewer: Monika Roychowdhury, M.D (see Reviewers page)
Revised: 24 September 2012, last major update September 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Epidemiology
=========================================================================

● Rare, < 0.1% of breast malignancies
● Median age 45-55 years
● Sarcomas rarely occur post-radiation therapy for breast cancer (Cancer 2005;104:856)
● Most common subtype is angiosarcoma (40%)

Treatment and prognosis
=========================================================================

● Treatment is similar as other sarcomas - excision with negative margins (J Clin Oncol 2003;21:2583)
● Axillary dissection not indicated
● 5 year overall survival is 67% (83% for tumors <5 cm and 42% for tumors >5 cm (Am J Surg 2008;196:559, Br J Cancer 2004;91:237)
● Angiosarcoma has worst prognosis (Radiother Oncol 2007;85:355, J Clin Oncol 2003;21:2583)

Gross description
=========================================================================

● Median size 4 cm

Micro description
=========================================================================

● Low grade: 0-5 mitotic figures/10 HPF and low grade nuclei
● High grade: 5+ mitotic figures/HPF and marked nuclear atypia or 6+ mitotic figures/HPF and moderate nuclear atypia



Sarcoma

Angiosarcoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 29 September 2012, last major update September 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Tumor composed of malignant cells with endothelial features

Terminology
=========================================================================

● Also called lymphangiosarcoma, less preferred term is “malignant hemangioendothelioma”

Epidemiology
=========================================================================

● Rare, < 0.2% of primary breast tumors (Ann Diagn Pathol 2009;13:147), 3-9% of breast sarcomas
● (a) young women with no prior history
● (b) women 5-10 years post-radiation therapy for breast carcinoma (in skin or breast, (Cancer 2009;115:4055), or
● (c) skin of chronically edematous arm after axillary lymph node dissection (Stewart-Treves syndrome, incidence has decreased dramatically due to use of more conservative surgery, Am J Surg Pathol 1983;7:329)
● Note: post-radiation and post-axillary dissection cases have more prominent cutaneous involvement

Clinical features
=========================================================================

● Clinically forms bulky mass associated with bruise-like cutaneous changes
● Estimated incidence of 0.14% after breast conserving therapy (J Am Acad Dermatol 2006;54:499)
● Precursor lesion is “atypical vascular lesion”, which occurs after surgery and radiation of the breast (Am J Surg Pathol 2008;32:943)
● May resemble recurrent breast carcinoma clinically (Clin Breast Cancer 2008;8:94)

Xray
=========================================================================

● Solitary mass on mammography without calcifications or skin thickening, at site of prior surgical incision

Case reports
=========================================================================

● Tumor post-radiation therapy #1 (Arch Pathol Lab Med 2002;126:989), #2 (Univ Oklahoma), #3 (Int Semin Surg Oncol 2006;3:26), #4-low grade tumor (Hum Pathol 1992;23:710), #5 - bilateral tumor with Paget’s disease (Mod Pathol 1995;8:1)
● 26 year old woman with epithelioid angiosarcoma (Am J Surg Pathol 1997;21:599)

Treatment and prognosis
=========================================================================

● Treatment is complete excision
● Post-radiation cases have shorter latency period and no edema, compared to Stewart-Treves syndrome cases (Am J Surg Pathol 2004;28:781)
● Tumors have similar behavior with or without prior radiation therapy (Cancer 2005;104:2682)
● Median survival of 3-6 years (Am J Clin Oncol 2009;32:582)
● Often recurs locally
● Grading may not have prognostic significance (Am J Surg Pathol 2008;32:1896, but see Am J Surg Pathol 1983;7:53)

Clinical images
=========================================================================

   

Hemorrhagic lesion

Post-radiotherapy

Erythema and ulceration

51 year old woman with high grade tumor

Gross description
=========================================================================

● Soft, spongy, hemorrhagic
● May have blue nodules at site of prior scar
● Mean 5cm
● Usually poorly circumscribed

Gross images
=========================================================================

Well circumscribed mass (AFIP)

Infiltrative mass with hemorrhage

Intermediate grade tumor with hemorrhage

High grade tumor

Contributed by anonymous pathologist:

Mastectomy post radiation and chemotherapy for ductal carcinoma

Microscopic description
=========================================================================

● Anastomosing vascular channels lined by atypical endothelial cells with pleomorphic, hyperchromatic nuclei
● Infiltrative margins
● Microscopic heterogeneity common within same tumor, so sample thoroughly
● Variable mitotic activity
● Usually no fibrous septae, no epithelial component
● Post-radiation tumors are typically high grade

Grade I (well differentiated):
● Anastomosing vascular channels dissect interlobular stroma
● Vessels have wide lumina with red blood cells
● Endothelium lining vessels have prominent and hyperchromatic nuclei, may resemble benign vascular tumors

Grade II (moderately differentiated):
● 75% of tumor is well differentiated, but solid foci are also found (Am J Surg Pathol 1981;5:629)

Grade III (poorly differentiated):
● Interanastomosing vascular channels are intermingled with solid endothelial or spindled areas, with necrosis and mitotic figures
● At least 50% of tumor is composed of solid or spindled areas without vascular channels

Micro images
=========================================================================


Neoplastic vascular channels

Solid areas and neoplastic vascular channels

Markedly pleomorphic tumor cells, mitotic figures and apoptotic cells

Focal spindle cells

Various images

Fig 1: Infiltrating vascular lesion with spindle cell proliferation in dermis
Fig 2/3: Pleomorphic spindle cells with “blood lakes” and brisk mitotic activity


       

Low grade tumor recurring as high grade tumor

Low grade angiosarcoma:
       

   

           

Low grade angiosarcoma (contributed by anonymous pathologist)

Intermediate grade angiosarcoma:

Dilated vascular spaces contain endothelial cells and red blood cells

Focal solid neoplastic vascular proliferation in fat

Focal spindle cell and small vessel proliferation

Focal complex capillary and endothelial cell proliferation

Spindle cells and mitotic figure

High grade angiosarcoma:

Irregular spaces resemble adenocarcinoma

Anastomosing vascular channels

   
High grade tumor

Anastomosing vascular channels with spindle and papillary foci

Solid growth and hemorrhagic necrosis

Spindle cells with indistinct vascular spaces

Plump spindle cells with mitoses

Blood lakes (foci of hemorrhagic necrosis

Post-mastectomy (AFIP):

Atypical vascular proliferation in dermis and subcutis and changes of chronic lymphedema

Vascular channels in superficial dermis with endothelial atypia

Anastomosing vascular channels with papillary proliferation of atypical endothelial cells

Focal solid pattern of atypical endothelial cells

Post-radiotherapy:
   

Skin tumor

Stains:
   
H&E, Ki-67 and Skp2

   
Left: CD31; right: Factor VIII-related antigen

Cytology description
=========================================================================

● Moderate to highly cellular with variable cellular aggregates
● Cells are epithelioid and spindled
● May have subtle angioformative changes (Cancer 2005;105:145)

Positive stains
=========================================================================

● Vimentin, Factor VIII
● CD31 and CD34 (well differentiated areas)
● High Ki-67 (Arch Pathol Lab Med 2007;131:538)
● ER (variable)

Negative stains
=========================================================================

● Keratin

Electron microscopy description
=========================================================================

● Prominent pinocytic vesicles and cell-cell junctions

Differential diagnosis
=========================================================================

Metaplastic carcinoma
Acantholytic squamous cell carcinoma: has at least focal areas of squamous differentiation, keratin+, negative for vascular markers
Hemangioma: well circumscribed, no atypia
Atypical vascular lesions: more circumscribed, less atypia than low grade angiosarcoma
Pseudoangiomatous stromal hyperplasia

Additional references
=========================================================================

Stanford University



Sarcoma

Leiomyosarcoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 14 October 2012, last major update October 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Malignant smooth muscle tumor
● Rare in breast as primary or metastases (< 1% of all breast tumors, ~25 cases reported in English literature (J Breast Cancer 2012;15:124)

Treatment
=========================================================================

● Excision with negative margin
● Radiation therapy suggested for large tumors with < 3 cm margin (Breast 2011;20:389)

Case reports
=========================================================================

● 18 year old woman (Breast 2011;20:389)
● 48 year old woman (J Breast Cancer 2012;15:124)
● 50 year old woman with 10 year history of cyclophosphamide for SLE (Cases J 2008 Nov 7;1(1):301)
● 52 year old woman (J Zheijiang Univ Sci B 2008;9:109)
● 53 year old man with leiomyosarcoma of nipple (Am J Surg Pathol 1978;2:299)

Clinical images
=========================================================================



Necrotic breast mass

Gross images
=========================================================================



Lobulated elastic tumor

Micro description
=========================================================================

● Intersecting fascicles of spindle cells with moderate eosinophilic cytoplasm, cigar shaped nuclei with blunt ends, moderate nuclear atypia, frequent mitotic figures

Micro images
=========================================================================

   
Dense cellularity and intersecting fascicles

       
48 year old woman

           
Tumor of nipple-areolar complex


Nuclear pleomorphism and mitotic activity (AFIP)


Cellular pleomorphic tumor

Cytology description
=========================================================================

● Large, dissociated round to spindle cells, medium to large, with abundant vacuolated cytoplasm with occasional intranuclear cytoplasmic invaginations; cells have pleomorphic nuclei, prominent nucleoli
● Also mitotic figures, osteoclast-like giant cells and stromal fragments (Diagn Cytopathol 2003;29:172, Acta Cytol 2008;52:485)

Cytology images
=========================================================================


Various images

Positive stains
=========================================================================

● Actin, desmin, vimentin

Negative stains
=========================================================================

● Keratin, S100, CD34

Molecular / cytogenetics
=========================================================================

● 10q-, 13q-
● Also 17p-, 1q+, 17p+ (Cancer Genet Cytogenet 2004;149:53)

Differential diagnosis
=========================================================================

● Metastatic tumor (Diagn Cytopathol 2007;35:508, Ir J Med Sci 2011;180:889)



Sarcoma

Liposarcoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 7 November 2012, last major update October 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Malignant tumor containing at least a few lipoblasts

Epidemiology
=========================================================================

● Rare, 100 cases reported through 2002
● 0.3% of all breast sarcomas, themselves only 1% of all breast malignancies
● Median age 47 years, range 19-76 years

Clinical
=========================================================================

● May be associated with radiation therapy
● Slow growing, painful breast mass, usually unilateral
● Axillary nodal metastases are rare, skin changes unusual
● Usually myxoid or pleomorphic subtype

Treatment and prognosis
=========================================================================

● Particularly aggressive when associated with pregnancy
● Death, when it occurs, is usually within 18 months of diagnosis
● Treatment is wide excision, axillary dissection not needed (Hum Pathol 1986;17:906)

Case reports
=========================================================================

● 19 year old woman with pleomorphic liposarcoma mimicking abscess (Breast J 2010;16:537)
● 25 year old woman with myxoid liposarcoma diagnosed as fibroadenoma on FNA (Diagn Cytopathol 2008;36:674)
● 42 year old woman (JBR-BTR 2010;93:299)
● 47 year old woman with primary pleomorphic liposarcoma (Indian J Pathol Microbiol 2011;54:124)
● 75 year old woman (Arch Pathol Lab Med 2001;125:1503)

Gross description
=========================================================================

● Median 8 cm, well circumscribed, gelatinous to firm with yellow/tan cut surface; larger tumors may be necrotic

Gross images
=========================================================================



Circumscribed tumors

Micro description
=========================================================================

● Similar to soft tissue tumors
● Depending on subtype: mixture of pleomorphic bizarre giant cells, myxoid stroma, mature adipose cells, inflammatory cells, lipoblasts (scalloped, irregular, hyperchromatic nuclei and sharply defined intracytoplasmic vacuoles containing lipid) and capillaries
● Margins are usually at least focally infiltrative

Micro images
=========================================================================


       
Myxoid liposarcoma


Well differentiated liposarcoma

   
Lipoblast with vacuolated cytoplasm


Well circumscribed tumor (AFIP)

Positive stains
=========================================================================

● S100 (lipoblasts)

Differential diagnosis
=========================================================================

Adenolipoma: lipoma with eccrine sweat glands or other epithelial elements
Angiolipoma: prominent capillaries with hyaline thrombi; no atypia, no lipoblasts
Fibroadenoma with fat: no atypia, no lipoblasts
Lipoma: no atypia, no lipoblasts
Malignant phyllodes tumor with focal liposarcomatous differentiation: has distinctive phyllodes component
Pleomorphic lipoma: prominent floret cells, no atypia, no lipoblasts
Silicone implants: silicone is refractile, may have granulomas that resemble lipoblasts



Sarcoma

Low grade myofibroblastic sarcoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 7 November 2012, last major update November 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Rare malignant tumor of myofibroblasts (Am J Surg Pathol 1998;22:1228)

Terminology
=========================================================================

● Also called myofibrosarcoma
● Not part of WHO breast classification

Clinical features
=========================================================================

● Commonly recurs, only rarely metastasizes

Case reports
=========================================================================

● 55 year old woman with death due to metastatic tumor (Am J Surg Pathol 1997;21:489)

Gross description
=========================================================================

● Firm, pale, fibrous cut surface, ill defined margins

Micro description
=========================================================================

● Fascicles of spindle cells surrounded by dense collagen
● Cells have ill defined, pale, eosinophilic cytoplasm, fusiform and pleomorphic nuclei, numerous mitotic figures
● Also some giant cells
● Margins are infiltrative, often grossly (Pathol Res Pract 1999;195:1)

Micro images
=========================================================================



Fig 1A: fascicular growth
Fig 1B: alpha smooth muscle actin+, vimentin+ (insert)
Fig 1C: fibronectin+ matrix
Fig 1D: type IV collagen negative

Positive stains
=========================================================================

● At least one myogenic marker (desmin, alpha smooth muscle actin, muscle specific actin or calponin)

Negative stains
=========================================================================

● S100, EMA, h-caldesmon, ALK

Electron microscopy
=========================================================================

● Features of myofibroblasts: discontinuous basal lamina, abundant rough endoplasmic reticulum, intermediate filaments and myofilaments; indented and clefted nuclei

Electron microscopy images
=========================================================================



Fig 2A: arrows point to thin filaments at the cell surface suggestive of fibronexus junctions
Fig 2B: arrows point to fibronectin fibrils extending into the extracellular matrix

Molecular / cytogenetics description
=========================================================================

● Gains at 1p11-->p36.3 (66%), 12p12.2-->p13.2 (45%), 5p13.2-->p15.3 (31%), +22 (28%), loss at 15q25-->q26.2 (24%) (Am J Clin Pathol 2009;131:701)

Differential diagnosis
=========================================================================

Fibromatosis / myofibromatosis: irregular, nonencapsulated proliferation of spindle cells forming interlacing fascicles with variable collagen deposition and cellularity; no/rare mitotic figures
Fibrosarcoma: highly cellular fibroblastic proliferation in herringbone pattern
Inflammatory myofibroblastic tumor: more heterogeneous, less cellular, less hyperchromasia, less infiltrative, ALK+ (Hum Pathol 2008;39:846)
Leiomyosarcoma: alternating fascicular pattern, usually high grade
Myofibroblastoma: may have some pleomorphism, but low mitotic activity
Nodular fasciitis: not infiltrative, not deep, lacks chromosomal anomalies
Solitary fibrous tumor: patternless architecture of hypo- and hypercellular areas separated by thick, hyalinized collagen with cracking artifact and hemangiopericytoma-like vessels



Sarcoma

Malignant Fibrous Histiocytoma (MFH)


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 7 November 2012, last major update November 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Terminology
=========================================================================

● Not part of WHO breast classification
● Rare in breast or elsewhere under new WHO definition (see micro description)

Clinical features
=========================================================================

● Aggressive, with frequent distant metastases and death due to disease (Am J Surg Pathol 1992;16:667)

Case reports
=========================================================================

● 32 year old woman with recurrent primary MFH of breast (Acta Cytol 2010;54:985)
● 44 year old woman post-radiation therapy for invasive ductal carcinoma (Int Semin Surg Oncol;3:18)
● 46 year old woman post-radiation therapy for invasive ductal carcinoma (Cases J 2008 Nov 17;1(1):313)

Clinical images
=========================================================================


Cystic tumor with skin tethering

Gross images
=========================================================================


Tumor invades skin


Specimen includes ribs posteriorly

Micro description
=========================================================================

● High grade spindle cell tumor
● Excludes tumors with any recognizable line of differentiation other than fibroblasts or myofibroblasts
● May show various patterns such as storiform-pleomorphic, myxofibrosarcoma or giant cell type
● Entrapped breast ductal epithelium should not be misinterpreted as the epithelial component of a biphasic tumor
● A florid lymphoid response should not be confused with metaplastic carcinoma

Micro images
=========================================================================

           
Marked nuclear pleomorphism and giant cells


Tumor necrosis after neoadjuvant chemotherapy

Cytology description
=========================================================================

● May show cell clusters, fascicles, and dissociated cells displaying spindle cell morphology, marked pleomorphism, bizarre uninucleate/multinucleate giant cells, prominent mitotic activity

Cytology images
=========================================================================


stromal sarcoma with features of giant cell MFH

Positive stains
=========================================================================

● CD68 (71%), smooth muscle actin (36%), rare focal ER and PR (Ann Diagn Pathol 2011;15:407)

Negative stains
=========================================================================

● CD34, S100, desmin, keratins (CK7, CK20, CK5/6, CK18, Ann Diagn Pathol 2011;15:407)

Differential diagnosis
=========================================================================

● May resemble medullary carcinoma at FNA (Acta Cytol 2006;50:577)



Sarcoma

Malignant Peripheral Nerve Sheath Tumor (MPNST)


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 7 November 2012, last major update November 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Very rare in breast
● Most cases are not associated with neurofibromatosis

Terminology
=========================================================================

● Not part of WHO breast classification

Case reports
=========================================================================

● 19 year old woman (J Med Assoc Thai 2006;89:377)
● 38 year old woman (World J Surg Oncol 2007;5:142)
● 56 year old woman with 30 cm tumor (Br J Radiol 2007;80:e44)

Gross images
=========================================================================


30 cm tumor

Micro images
=========================================================================


Alternating hyper and hypocellular areas with palisading spindle shaped cells and intervening myxoid areas; cells are S100+ (inset)


Hyperchromatic and pleomorphic wavy nuclei with mitoses



Sarcoma

Osteosarcoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 13 November 2012, last major update November 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Malignant tumor of osteoid producing spindle cells

Epidemiology
=========================================================================

● Rare
● Median age 64 years, range 27-89 years

Case reports
=========================================================================

● 16 year old girl (J Pediatr Hematol Oncol 2012;34:e261)
● 40 year old woman (World J Surg Oncol 2006;4:90)
● 49 year old woman (APMIS 2006;114:581)
● 59 year old woman (Pathol Int 2009;59:111)
● 88 and 96 year old women (Arch Pathol Lab Med 2007;131:792)

Treatment and prognosis
=========================================================================

● Total excision without axillary dissection (Am J Surg Pathol 1998;22:925)
● Local recurrence, metastases and death from disease are common

Gross description
=========================================================================

● Mean 5 cm (1-13 cm)
● 60% are grossly circumscribed

Gross images
=========================================================================



Large, relatively well-circumscribed, necrotic tumor with cartilaginous and calcified foci (after tissue sampling)


Well circumscribed tumor with large areas of ossification (asterisks) and cystic or necrotic zones (stars)

Micro description
=========================================================================

● Resembles skeletal osteosarcoma, with fibroblastic, osteoclastic or osteoblastic subtypes
● By definition has spindle cells and neoplastic osteoid or bone, lacks an epithelial component and does not originate in bone
● Usually at least focally infiltrative

Micro images
=========================================================================


Neoplastic bone and spindle cells


Pleomorphic high-grade sarcoma with malignant osteoid (stars) and multinucleated osteoclastic giant cells (arrows)

Negative stains
=========================================================================

● ER, PR, HER2 (Arch Pathol Lab Med 2006;130:691)

Differential diagnosis
=========================================================================

Metaplastic carcinoma: has epithelial component
Metastases: need clinical history (Australas Radiol 1999;43:108)
Phyllodes tumor with osteosarcomatous differentiation: phyllodes component present (J Med Case Rep 2011;5:293)



Sarcoma

Rhabdomyosarcoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 15 November 2012, last major update November 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Malignant tumor with features of skeletal muscle differentiation
● Primary or secondary (Pediatr Hematol Oncol 1996;13:277)

Epidemiology
=========================================================================

● Very rare (Chin Med J (Engl) 2012;125:2618), usually teenager girls with alveolar subtype

Case reports
=========================================================================

● 13 year old girl (Surg Today 2007;37:38)
● 51 year old woman (Arch Pathol Lab Med 1998;122:747)

Gross description
=========================================================================

● Round or oval, well-demarcated but non-encapsulated masses
● Hard or soft; cut surface has homogeneous grayish yellow or white tissue with focal necrosis

Micro description
=========================================================================

● Primitive myoblasts and rhabdomyoblasts with cytoplasmic cross striations
● Usually alveolar subtype (Med Pediatr Oncol 1997;29:181)
● Poorly-differentiated small round or polygonal cells with sparse eosinophilic cytoplasm
● Nuclei are round/oval and densely stained
● Frequent mitotic figuresd
● “Racquet” and “strap” cells with peripherally placed nuclei are specific

Micro images
=========================================================================

       
Variable skeletal muscle differentiation

Positive stains
=========================================================================

● Vimentin, desmin, MyoD1, myogenin

Negative stains
=========================================================================

● Cytokeratin AE1/AE3

Differential diagnosis
=========================================================================

Malignant phyllodes tumor: may have rhabdomyosarcomatous differentiation, but also has phyllodes component
Metaplastic carcinoma: has epithelial component



Sarcoma

Sarcoma NOS


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 21 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● A diagnosis of exclusion
● Extensive tumor sampling and immunostaining are required before making this diagnosis

Terminology
=========================================================================

● Not part of WHO breast classification

Micro description
=========================================================================

● Spindle cells with markedly pleomorphic nuclei and abundant mitotic figures (Am J Surg Pathol 2006;30:450)
● By definition, no evidence of carcinoma or a specific type of sarcomatous differentiation

Positive stains
=========================================================================

● CD10, vimentin
● EGFR (often)

Negative stains
=========================================================================

● Keratin, CD34, desmin, h-caldesmon

Differential diagnosis
=========================================================================

Sarcomatoid metaplastic carcinoma: keratin+
Stromal sarcoma: CD34+, no severe atypia



Sarcoma

Stromal sarcoma


Reviewer: Monika Roychowdhury, M.D., (see Reviewers page)
Revised: 21 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare lesion with sarcomatous stroma, benign ductal elements, no phyllodes architecture (Am J Surg Pathol 2003;27:343)

Terminology
=========================================================================

● Also called periductal stromal sarcoma

Epidemiology
=========================================================================

● Mean age 55 years, range 37-89 years

Treatment and prognosis
=========================================================================

● Excision with negative margin
● May recur

Case reports
=========================================================================

● 14 year old boy (J Med Case Rep 2011;5:249)
● 29 year old woman (Surg Today 2011;41:1145)
● 47 year old woman with primary stromal sarcoma of the breast with MFH like features (Diagn Cytopathol 2011;39:223)
● 52 year old woman whose tumor had myxoid features (Pathol Int 2009;59:588)
● Tumor involving entire breast with axillary nodal metastases (Asian J Surg 2004;27:339)
● Two cases (Gan To Kagaku Ryoho 2011;38:2171)

Gross description
=========================================================================

● Mean 3 cm, solid, gray-white, homogenous

Micro description
=========================================================================

● Circumferential cuffs of predominantly uniform plump spindle cells with variable cellularity and atypia surrounding open tubules and ducts, but no phyllodes pattern
● May have multiple nodules separated by adipose tissue
● >3 stromal mitotic figures per 10 HPF
● Stromal infiltration into adjacent breast tissue
● May have osseous metaplasia or resemble fibrosarcoma
Periductal stromal hyperplasia if no/minimal atypia and 0-2 stromal mitotic figures/10 HPF

Micro images
=========================================================================


           
14 year old boy

Positive stains
=========================================================================

● CD34
● Variable CD117

Negative stains
=========================================================================

● ER, PR, myoepithelial markers

Electron microscopy descriptions
=========================================================================

● Immature cells with abundant free ribosomes, profiles of rough ER, variable microfilaments
● Often prominent cell nesting and a variety of cell junctions, including desmosomes (Cancer 1979;43:209)



Other malignancies

Lymphoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 16 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Criteria for primary breast lymphoma: (a) sufficient tissue for diagnosis; (b) close interaction between lymphoma infiltrate and breast tissue; (c) no evidence of widespread lymphoma at time of diagnosis; (d) no prior diagnosis of nonbreast lymphoma (Cancer 1972;29:1705)
● Secondary breast lymphoma has similar incidence as primary breast lymphoma and is most common metastatic disease to breast

Epidemiology
=========================================================================

● Rare, < 1% of all breast malignancies are primary breast lymphoma
● Usually ages 30-35 years (diffuse large B cell) or 55-60 years (diffuse large B cell or MALT-type)
● Screening mammography may be increasing detection of low-grade lymphoma
● No association between implants and lymphoma (Plast Reconstr Surg 2009;123:790), but see anaplastic lymphoma below

Prognostic features
=========================================================================

● Low stage is favorable prognostic factor
● Unfavorable factors are young age and high stage (Leuk Lymphoma 2009;50:918)
● CNS is common site of relapse (BMC Cancer 2008;8:86)

Treatment
=========================================================================

● Radiation therapy, chemotherapy and Rituximab
● No advantage to mastectomy (Ann Surg 2007;245:784)

Gross description
=========================================================================

● Soft, gray-white
● 25% bilateral
● No skin retraction, no nipple discharge

Micro description
=========================================================================

● Varies by subtype - see lymphoma chapters for more detail

Cytology images
=========================================================================



Dyscohesive cells - subtype not specified

Positive stains
=========================================================================

● CD45, B or T cell markers
● Other markers vary by subtype

Negative stains
=========================================================================

● Keratin (may stain lymphoepithelial lesions)

Differential diagnosis
=========================================================================

Lobular carcinoma: usually linear or targetoid patterns, keratin+ and CD45-
Lymphoid hyperplasia: may resemble low grade B cell lymphomas
Lymphocytic mastitis: may be difficult to differentiate on core biopsy (Breast Cancer 2009;16:141)

Additional references
=========================================================================

Am J Surg Pathol 1993;17:574, Mod Pathol 2000;13:599 (T cell lymphomas), Am J Surg Pathol 1994;18:288, Arch Pathol Lab Med 1999;123:1208


Subtypes
=========================================================================

● 94% B cell and 4% T cell lymphomas in one study (Br J Radiol 2012;85:e195)


Anaplastic large cell lymphoma:
● Associated with implants, particularly if ALK negative: odds ratio is 18.2, although absolute risk is low (JAMA 2008;300:2030)
● Median age 52 years (Arch Pathol Lab Med 2009;133:1383)
● 33 year old woman with silicon implant and ALK negative tumor (Arch Pathol Lab Med 2003;127:e115)
● 92 year old woman with sarcomatoid variant (Arch Pathol Lab Med 2002;126:723)


           
Large cells with abundant cytoplasm  Associated with silicon implant

           
ALK- cases                 Various images

   
Sarcomatoid variant  TIA+ and ALK+


Burkitt’s lymphoma:
● In African patients, may present with massive bilateral breast involvement
● Patients may be pregnant or lactating
● Less common than other subtypes
● 12 year old girl in Africa with giant bilateral tumors (Arch Gynecol Obstet 2009;279:743)


      
Lymphocytic infiltrate    Ki-67 staining is diffuse and strong


Large cells with deeply basophilic cytoplasm and multiple intracytoplasmic lipid vacuoles, high N/C ratio and hyperchromatic round nuclei


CLL / SLL:

               
Xray, H&E, CD5, CD20
Contributed by Dr. Julia Braza, Beth Israel Deaconness Medical Center, Boston, Massachusetts



Diffuse large B cell lymphoma:
● Most common subtype of primary breast lymphoma (Am J Hematol 2009;84:133, Cancer 2007;110:25)
● Typically poorer prognosis if high proliferative (Ki-67) activity and nongerminal center B cell phenotype (CD10-, MUM1+, Mod Pathol 2005;18:398); better prognosis if germinal center phenotype (Leuk Res 2008;32:1837)
● 40 year old woman with bilateral tumors, diagnosed by FNA (Arch Pathol Lab Med 2005;129:694)
● 55 year old woman whose tumor exhibited clear cell change (Case of the Week #217)



Rapidly growing mass

   
Large cells with 1    Diffuse proliferation of large centroblasts
or more nucleoli    and starry sky macrophages

   
H&E and CD20     Weak BCL10+

   
Various images     Mixed with MALT

   
Various images


Follicular lymphoma:
● Usually stage I (65%), but 20% are stage III/IV
● 56 year old woman a non-palpable BI-RADS 4B lesion without microcalcifications, diagnosed by biopsy (J Med Case Rep 2007;1:113)



Bulging and fleshy tumor

   
Follicular lymphoma  BCL2+


Mantle cell lymphoma:


Various images


Marginal zone / MALT lymphoma:
● Usually stage I, 10% bilateral, survival > 90% at 5 years and no MALT1 gene rearrangement (Mod Pathol 2006;19:1402)
● Relatively indolent behavior compared to other sites (Ann Oncol 2009;20:1993)
● Bilateral MALT lymphoma (57 year old woman-World J Surg Oncol 2008;6:52, 64 year old woman-Arch Pathol Lab Med 2000;124:1233)
● 62 year old woman (Breast Care (Basel) 2011;6:391)
● 79 year old woman with collision tumor of invasive ductal NOS and MALT lymphoma (Arch Pathol Lab Med 2004;128:99)
● 87 year old woman with CD5+ marginal zone / MALT lymphoma (Arch Pathol Lab Med 2004;128:99)


H&E, CD20, BCL10


NK lymphoma, nasal type:
● 20 year old woman with post-transplant lymphoproliferative disorder (Mod Pathol 2004;17:125)

       
Lobular pattern of        Tumor cells have abundant cytoplasm
infiltration           and irregular nuclei

       
Pan-keratin immunostain high- TIA+ and CD56+
lights lymphoepithelial lesions


Peripheral T cell lymphoma:
● 37 year old woman with palpable breast mass (Case of the Week #192)

   
CD4+ large cell tumor   Cells have clear cytoplasm and mitotic activity

   
CD8+ tumor



Other malignancies

Myeloid sarcoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● See also leukemia-acute chapter
● Neoplasm of myeloid cells associated with acute myeloid leukemia (usually as relapse), myeloproliferative or myelodysplastic disorder

Terminology
=========================================================================

● Also called granulocytic sarcoma or chloroma
● Not part of WHO breast classification

Epidemiology
=========================================================================

● Uncommon (< 100 cases reported)
● Almost always women
● Median age 52 years, range 31-73 years

Clinical features
=========================================================================

● Rarely occurs as an isolated mass (Arch Pathol Lab Med 2005;129:32)
● Need immunostains to diagnose and to prevent misdiagnosis as lymphoma or sarcoma (Breast J 2004;10:48)
● In patients with leukemia, diagnosis is typically followed by bone marrow relapse after mean 7 months (range, 1-19 months) and poor outcome (Chin Med J (Engl) 2008;121:1854)

Case reports
=========================================================================

● 25 year old woman with AML without maturation (Coll Antropol 2010;34:641)
● 40 year old woman with synchronous granulocytic sarcoma of the breast and spine (Chin Med J (Engl) 2008;121:1854)
● Elderly woman with isolated breast myeloid metaplasia 16 years after initial diagnosis (Am J Surg Pathol 1980;4:281)
● Bilateral myeloid sarcoma of breast (J Clin Oncol 2012;30:e199)
● Other cases: Eur J Gynaecol Oncol 2011;32:435, Breast J 2004;10:48

Treatment
=========================================================================

● Systemic chemotherapy (similar to acute leukemia), possibly radiation therapy (Ann Hematol 2003;82:431)

Micro description
=========================================================================

● Well to poorly differentiated to blastic tumor of immature and mature granulocytes or monocytes
● Also immature eosinophilic precursors
● Usually preserves ductal and lobular structures
● No / minimal necrosis
● Dissection of collagen by tumor cells is common (Chin Med J (Engl) 2008;121:1854)

Micro images
=========================================================================


   
Various images


Myeloperoxidase+ and CD43+

Positive stains
=========================================================================

Varies by type of myeloid leukemia:
● Naphthol AS-D chloroacetate esterase, myeloperoxidase, lysozyme, CD43, CD68
● Variable CD117, CD45, TdT, CD79a and PAX5

Negative stains
=========================================================================

● CD3, CD20

Molecular description
=========================================================================

● May demonstrate mutations of primary hematopoietic neoplasm / leukemia (J Clin Pathol 2010;63:558)

Differential diagnosis
=========================================================================

● Small round cell tumors (in children)
Lymphoma
Lobular carcinoma



Other malignancies

Plasmacytoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Neoplasm of plasma cells, either primary to breast or secondary (most cases) to a systemic process or another plasmacytoma

Terminology
=========================================================================

● Not part of WHO breast classification

Clinical features
=========================================================================

● Rare
● May progress to multiple myeloma after years of remission
● Frozen section diagnoses are often incorrect - resembles lobular or poorly differentiated tumor, but with a grossly well circumscribed appearance

Case reports
=========================================================================

● 27 year old woman with coexisting ductal carcinoma (World J Surg Oncol 2009;7:43)
● 37 year old woman with only breast involvement (Arch Pathol Lab Med 2001;125:1078)
● 70 year old woman with recurrence of mediastinal disease in bilateral breasts (World J Surg Oncol 2004;2:29)
● 78 year old man with breast and axillary nodal involvement (Clin Breast Cancer 2006;7:81)
● Patient with disease free survival of 9+ years (Arch Pathol Lab Med 1984;108:676)

Clinical images
=========================================================================



Well-defined mass with irregular borders

Micro description
=========================================================================

● Immature and mature plasma cells with nuclear pleomorphism
● Also binucleated and multinucleated forms, mitotic figures and necrosis

Micro images
=========================================================================


         
Plasma cells, some binucleated,   Nuclear pleomorphism, binucleated and
surrounding benign lobules     multinucleated plasma cells with enlarged nucleoli


Tumor in HIV+ man

         
Plasma cells (long arrows),      Dense infiltrate of plasma cells
Russell bodies (short arrow)    and lymphocytes (AFIP)
and lymphocytes

         
With ductal carcinoma       Her-2 negtive

         
Plasma cells are IgA+        Monoclonal lambda staining
and kappa light chain+

         
Kappa staining            Diffuse Ki-67 nuclear staining

Cytology description
=========================================================================

● Dispersed population of plasmacytoid cells at various stages of maturation (Acta Cytol 2003;47:1107)
● Mature plasma cells have an eccentric nucleus and abundant deep basophilic cytoplasm with a paranuclear halo
● Plasmablasts (immature plasma cells) have a prominent eccentric nucleus with a single large nucleolus and abundant deep basophilic cytoplasm with no paranuclear halo
● Also binucleate and multinucleate forms (Acta Cytol 1997;41:364)

Differential diagnosis
=========================================================================

Plasma cell mastitis: no light chain restriction
Melanoma
MALT lymphoma



Other malignancies

Rosai-Dorfman disease


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Typically massive lymph node involvement that may also involve extranodal sites
● Associated with systemic symptoms (fever, leukocytosis, anemia)

Terminology
=========================================================================

● Not part of WHO breast classification
● Also called sinus histiocytosis with massive lymphadenopathy

Clinical features
=========================================================================

● Very rare in breast, < 25 cases reported
● May have disease confined to breast or disseminated disease
● Most common sites are skin, subcutis, upper respiratory tract, bone, eye, adnexae and CNS
● Usually resolves spontaneously, although systemic cases may cause death

Case reports
=========================================================================

● 35 year old man (Acta Cytol 2010;54:349)
● 43 year old woman with enlarging breast mass (Univ Pittsburgh Case #338)
● 50 year old woman with disease confined to breast mimicking cancer (Pathol Res Pract 2007;203:741)
● 65 year old woman with multiple breast nodules (Am J Surg Pathol 1999;23:359)
● 67 year old woman (Gac Med Mex 2010;146:212)
● 75 year old woman with 2 breast tumors (Ned Tijdschr Geneeskd 2011;155:A3176)
● Breast mass and axillary lymphadenopathy (Breast J 2011;17:516)
● Bilateral breast involvement by disseminated Rosai-Dorfman disease (Breast J 2011;17:309)
● Three patients with Rosai-Dorfman disease confined to breast (Ann Diagn Pathol 2010;14:81)
● With recurrence after excision (Am J Med Sci 2010;339:282)

Gross description
=========================================================================

● Circumscribed, often multinodular masses in breast stroma
● Dermis and subcutis uninvolved

Micro description
=========================================================================

● Large histiocytes with abundant pale eosinophilic cytoplasm, mildly atypical round vesicular nuclei (Am J Surg Pathol 1997;21:664)
● Lymphocytophagocytosis (emperipolesis) in background of mature lymphocytes and plasma cells

Micro images
=========================================================================


                    
Lymphoplasmacytic infiltrate             Histiocytes with emperipolesis (arrowhead) with
with histiocytes (fig 1)                  lymphocytes, plasma cells and fibrosis

AFIP images:
                    
Erythrophagocytosis                 With marked sinusoidal edema

           
Emperipolesis        CD68+ histiocytes (fig 2)  Sinusoids distended by histiocytes

Cytology description
=========================================================================

● Large pale cells with enlarged irregular nuclei, lymphocytes and plasma cells, also fragments of fibrous tissue and calcific debris
● Only rare lymphophagocytosis (emperipolesis, Diagn Cytopathol 1999;21:287)

Positive stains
=========================================================================

● S100, CD68

Negative stains
=========================================================================

● CD1a

Differential diagnosis
=========================================================================

Idiopathic granulomatous mastitis
Tuberculosis or other infectious granulomas
Langerhans’ cell histiocytosis
Erdheim-Chester disease
Benign fibrous histiocytoma
Melanoma



Childhood tumors

Breast tumors in children - general


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 17 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

See also thelarche, pubertal macromastia, and other topics in Breast-nonmalignant chapter

Clinical features
=========================================================================

● Malignant disease is rare; most patients require only clinical examination and reassurance
● Fine needle aspiration or core biopsy is usually adequate (Eur J Pediatr Surg 2006;16:303, Acta Cytol 2008;52:681)
● Most common benign lesions are fibroadenoma, juvenile fibroadenoma and virginal hypertrophy (J Indian Med Assoc 2001;99:619)
● Masses may also be due to normal or abnormal breast development (physiological masses usually regress, Zhonghua Yi Xue Za Zhi 2008;88:2556), infection, trauma or cysts

Unilateral breast development:
● Common
● May resemble a mass
● May exist as long as 2 years before other breast becomes palpable

Fibrocystic disease:
● Rare

Carcinoma:
● Very rare



Childhood tumors

Juvenile fibroadenoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 18 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Terminology
=========================================================================

● Also called giant fibroadenoma
● Not a distinct entity in WHO breast classification

Epidemiology
=========================================================================

● Usually adolescents, often African-American, often bilateral and with rapid growth to > 10 cm

Clinical features
=========================================================================

● May have atypical ductal hyperplasia suggestive of DCIS - low risk of carcinoma, but follow-up is recommended (Am J Surg Pathol 1987;11:184)

Prognostic features
=========================================================================

● Patients with multiple bilateral tumors should anticipate recurrence but not malignant change (Am J Surg Pathol 1985;9:730)

Case reports
=========================================================================

● 12 year old girl with Beckwith-Wiedemann syndrome and bilateral tumors (Ann Plast Surg 2010;64:803)
● 12 year old girl with bilateral giant tumors (Patholog Res Int 2011;2011:482046)
● 12 year old girl with bloody nipple discharge (Pediatr Neonatol 2010;51:190)
● 13 year old girl with hemihypertrophy and recurrent giant tumors (Breast Dis 2011;33:41)
● 13 year old girl with tumor exhibiting fibroadenomatoid hyperplasia (The Internet Journal of Surgery 2007;12:1)
● 15 year old girl with 3 kg tumor (J Pediatr Adolesc Gynecol 2009;22:e25)

Treatment
=========================================================================

● Excise but conserve as much breast tissue as possible (Breast J 2000;6:418)

Clinical images
=========================================================================



Various images

Gross images
=========================================================================



Various images

   
Bilateral giant juvenile fibroadenoma


Gray-white mass (fig 4)

Micro description
=========================================================================

● Stromal and epithelial hyperplasia, but no stromal atypia and no / rare stromal mitotic figures
● No periductal increase in cellularity, no stromal overgrowth, no cytologic atypia, mitotic rate < 3 / HPF (Stanford University)

Micro images
=========================================================================


               
Stromal and epithelial hyperplasia

   
Bilateral giant juvenile fibroadenoma

           

Cytology images
=========================================================================


         
Cluster of epithelial cells with    Epithelial cells and stromal fragments
mild pleomorphism        with few spindled cells


Branching sheets of epithelial cells with many bare nuclei and myxoid stromal fragments

Differential diagnosis
=========================================================================

Phyllodes tumor: rare in young patients, leaf-like growth pattern



Childhood tumors

Juvenile papillomatosis (swiss cheese disease)


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 18 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Grossly distinct multinodular mass with clustering of cystic formations resembling swiss cheese, composed of epithelial proliferation and clustered cysts
● First described by Rosen in 1980 (Am J Surg Pathol 1980;4:3)

Terminology
=========================================================================

● Not part of WHO breast classification

Epidemiology
=========================================================================

● Mean age 19 years
● 2/3 are less than age 20 years

Clinical features
=========================================================================

● Resembles fibroadenoma clinically
● 10% develop breast carcinoma, higher risk if recurrent, bilateral disease and family history of breast cancer (Am J Clin Pathol 1990;93:599)
● 26-58% have positive family history of breast cancer (Cancer 1982;49:2591, Am J Clin Pathol 1986;86:745), 15% have bilateral disease
● May be associated with secretory carcinoma (Jpn J Clin Oncol 1985;15:457)

Case reports
=========================================================================

● Infant boy with Noonan syndrome and family history of breast cancer (Pediatr Blood Cancer 2005;45:991)
● 6 year old girl with coexisting secretory carcinoma (J Pediatr Surg 1987;22:637)
● 16 year old girl with ER-, PR+, HER2+ tumor and recurrences (Breast Cancer 1998;5:187)
● 17 year old boy (G Chir 2011;32:374)

Gross description
=========================================================================

● Localized multinodular mass with clustering of cystic formations resembling swiss cheese

Gross images
=========================================================================



Multiple cysts resembling swiss cheese

Micro description
=========================================================================

● Florid epithelial hyperplasia and papillomatosis, cysts with foamy histiocytes and sclerosing adenosis
● Variable apocrine metaplasia, atypia and necrosis

Micro images
=========================================================================



Various images

   
Clustered cysts  Epithelial hyperplasia

AFIP images:
              
Multiple cystically dilated ducts      Hyperplastic epithelium in dilated duct

              
Intraductal epithelial proliferation     Apocrine metaplasia of hyperplastic
with necrosis                intraductal epithelium

              
Hyperplastic epithelium and         With sclerosing adenosis and apocrine
foam cells                metaplasia adjacent to cystically dilated ducts

              
Multiple small intraductal papillomas     #2-high power shows hyperplastic intraductal
in 15 year old girl             epithelium, myoepithelial cells are associated with
                     the delicate fibrovascular stalks

Cytology description
=========================================================================

● Difficult to diagnose
● Cystic fluid, but mass persists after aspiration
● Sheets of hyperplastic breast epithelium with areas resembling fibroadenoma, macrophages and apocrine cells (Diagn Cytopathol 1993;9:457)

Additional references
=========================================================================

Stanford University



Childhood tumors

Breast cancer in children


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 18 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Clinical features
=========================================================================

● Rare; incidence of malignant pediatric breast tumors is 0.08 cases per 100K population
● Most common malignant breast lesions in children are metastases (Radiographics 2009;29:907)
● Of primary breast malignancies, carcinomas represent 55% (usually ductal) and sarcomas represent 45% (85% of these are malignant phyllodes tumors, J Surg Res 2008;147:182)
● 7% of childhood carcinoma patients present with metastatic disease compared to 0% of sarcoma patients
● 5/10 year survival is 63%/54% for carcinoma, 90%/90% for sarcomas

Case reports
=========================================================================

● 13 year old boy with secretory breast cancer (Breast Cancer Res Treat 2012;133:813)

Gross images
=========================================================================



Maligant phyllodes tumor



Male tumors

General breast disease in males


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 8 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

See also gynecomastia,   papilloma,   myofibroblastoma,   carcinoma,   metastases

Clinical features
=========================================================================

● Rare - usually fibrocystic disease, fibroadenoma, phyllodes tumor (Mod Pathol 1992;5:114) or pseudoangiomatous stromal hyperplasia

Case reports
=========================================================================

● 23 year old man with synovial cyst post-surgery (Ann Diagn Pathol 2005;9:219)
● 48 year old man with neurofibroma (World J Surg Oncol 2007;5:23)
● 49 year old man with solitary fibrous tumor (World J Surg Oncol 2008;6:16)
● 49 and 50 year old men with granular cell tumor (J Ultrasound Med 2011;30:1295)
● 66 year old man with fibroadenomas with digital fibroma-like inclusions (Arch Pathol Lab Med 2007;131:1126)
● 75 year old man with pleomorphic hyalinizing angiectatic tumor (Pathol Res Pract 2009;205:69)
● 76 year old man with undifferentiated pleomorphic sarcoma (J Breast Cancer 2011;14:241)
● Factitious disease due to injection of liquid plastic (Int J Dermatol 2001;40:743)
● Granular cell tumor of nipple (Acta Chir Belg 2008;108:112)
● Sclerosing adenosis at autopsy in man with pulmonary small cell carcinoma (Hum Pathol 1986;17:861)

Micro images
=========================================================================



Fibroadenomas


Granular cell tumor

              
Epithelial inclusion cyst  Neurofibroma      Solitary fibrous tumor  Undifferentiated pleomorphic sarcoma



Male tumors

Gynecomastia in males


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 8 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Enlargement of male breast due to hypertrophy and hyperplasia of glands and stroma
● Multifactorial etiology: physiological (puberty or aging), endocrine tumors, endocrine dysfunctions, non-endocrine diseases, drug induced, idiopathic

Clinical features
=========================================================================

● Most common lesion of male breast
● Usually bilateral, but may be more distinct in one breast
● Caused by increase in estrogen to androgen ratio (Sao Paulo Med J 2012;130:187)
● Occurs at birth, puberty or associated with Kleinfelter’s syndrome, functioning testicular tumors (Leydig, Sertoli), lung tumors, cirrhosis (hyperestrinism), neurofibromatosis (Plast Reconstr Surg 2008;121:34e alcohol, anabolic steroids, other drugs (digitalis, dilantin, highly active antiretroviral therapy for HIV, isoniazid-J Bras Pneumol 2008;34:978, methotrexate-Mod Rheumatol 2007;17:511, spironolactone-CMAJ 2007;176:620, lavender and tea tree oils-N Engl J Med 2007;356:479)

Prognostic features
=========================================================================

● May recur

Case reports
=========================================================================

● 69 year old man with fibroadenomatoid nodules associated with spironolactone (Am J Surg Pathol 1990;14:774)

Treatment
=========================================================================

● Observation / reassurance (often reversible, eMedicine), tamoxifen (Rev Med Chil 2007;135:1558), surgery with liposuction (Plast Reconstr Surg 2008;121:740) or endoscopic subcutaneous mastectomy (Surg Laparosc Endosc Percutan Tech 2009;19:e85)
● Folate for methotrexate associated disease (Rheumatol Int 2010;30:1371)

Clinical images
=========================================================================


           
Grades I-IV


Spironolactone induced

Gross description
=========================================================================

● Button or disk-like subareolar enlargement
● Oval, elastic and with well-circumscribed borders
● Unilateral (more common) or bilateral
● Firm, gray-white cut surface

Micro description
=========================================================================

● Proliferation of ducts without lobules
● Dense, periductal stromal fibrosis or edema with micropapillary hyperplasia and mild lymphocytic infiltrate
● Epithelium may be surrounded by prominent swollen stroma giving “halo” effect
● Over time, less hyperplasia and more stromal fibrosis
● May have pseudoangiomatous stromal hyperplasia, focal squamous metaplasia (Arch Pathol Lab Med 1986;110:971)

Micro images
=========================================================================


               
Gynecomastia

           
Periductal stromal edema        Solid form with microlumina, different
with mild epithelial hyperplasia       cell types in central and peripheral duct

           
Post-estrogen treatment for       With atypical duct hyperplasia
prostatic carcinoma

           
Fig 1: dense fibrous stroma       Micropapillary pattern of slender strands
and dilated ductules without lobules  of cells with hyperchromatic nuclei (AFIP)

Virtual slides
=========================================================================



Gynecomastia

Cytology images
=========================================================================



Clusters of bland, cohesive epithelial cells

Positive stains
=========================================================================

● ER and PR are associated with Kleinfelter’s syndrome
● PSA is associated with antiandrogen therapy (but PSAP negative)

Electron microscopy description
=========================================================================

● Proliferation of epithelial and myoepithelial cells, intracytoplasmic lumina and squamous metaplasia
● Stroma shows fibroblasts, myofibroblasts and some pericytes (Arch Pathol Lab Med 1979;103:624)



Male tumors

Myofibroblastoma of breast


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 8 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Rare benign spindle cell tumor of mammary stroma composed of myofibroblasts
● First described in 1987 (Am J Surg Pathol 1987;11:493)

Terminology
=========================================================================

● Also called benign stromal spindle cell tumor with predominant myofibroblastic differentiation

Epidemiology
=========================================================================

● Although initially considered male predominant, now equal gender frequency (older men and post-menopausal women, Mod Pathol 1996;9:786)
● Incidence appears to be increasing, but probably an artifact of mammographic screening (Arch Pathol Lab Med 2008;132:1813)

Etiology
=========================================================================

● May derive from CD34+ vimentin+ fibroblasts of mammary stroma capable of multidirectional differentiation (Histopathology 2003;42:233)
● Probably related to spindle cell lipoma and solitary fibrous tumor (Virchows Arch 2002;440:249, Am J Surg Pathol 2001;25:1022, Breast J 2008;14:287)

Clinical features
=========================================================================

● Solitary, slow growing nodule
● Benign behavior

Case reports
=========================================================================

● 10 month old boy (Fetal Pediatr Pathol 2012;31:164)
● 25 year old man with bilateral gynecomastia (Int J Surg Pathol 2001;9:331)
● 40 year old woman (Indian J Pathol Microbiol 2008;51:395)
● 59 year old woman (University of Pittsburgh, Case #249)
● 65 year old man with 15 cm rapidly growing tumor (J Med Case Rep 2008;2:157)
● 72 year old man (Arch Pathol Lab Med 2003;127:e415)
● 73 year old man with cellular tumor (Am J Mens Health 2012;6:344)
● 83 year old man with 10 cm tumor (Am J Surg Pathol 1994;18:1170)
● Post-radiation tumor (Breast J 1999;5:136)

Treatment
=========================================================================

● Excision is curative

Clinical images
=========================================================================



15 cm tumor

Gross description
=========================================================================

● Well-circumscribed nodule or multilobar mass
● Bulging, gray-pink and 1-4 cm
● Resembles fibroadenoma

Gross images
=========================================================================



Firm, circumscribed, tan-gray lobulated nodule

Micro description
=========================================================================

● Well-circumscribed
● Uniform, bland spindle cells haphazardly arranged in fascicles with pushing borders, separated by broad bands of hyalinized collagen (Stanford University)
● Spindle cells have abundant eosinophilic cytoplasm, round / oval nucleus with 1-2 small nucleoli
● May have mild nuclear pleomorphism
● Prominent mast cells
● Variants include cellular, collagenized, epithelioid (Am J Surg Pathol 2009;33:1085), fatty (J Clin Pathol 2001;54:568) and infiltrative (no atypia or mitotic activity)
● May have histiocytoid cells, prominent vessels, focal cartilaginous differentiation (Virchows Arch 1999;434:547), smooth muscle and multinucleated floret-like giant cells
● No / rare mitotic activity
● Usually no entrapment of ducts or lobules
● Usually no necrosis

Micro images
=========================================================================


       
Epithelioid type

   
Well circumscribed              Spindle cells and hyalinized collagen


Fascicles of spindle cells separated by dense collagen

       
Classic type       Cellular variant     Other variants


Predominantly fatty variant


CD34+


H&E, CD34, SMA



Fig 1: sharply circumscribed tumor with fibrous pseudocapsule
fig 2: bland spindle cells in collagenous or myxoid stroma
fig 3A: CD34+; fig 3B: bcl2+; fig 4: desmin+ (focal)

Cytology description
=========================================================================

● May appear malignant
● Cohesive and single spindle cells without atypia
● Scant cytoplasm and oval nuclei with fine granular chromatin, occasional nuclear grooves and small nucleoli (Diagn Cytopathol 2004;30:406)
● Tumor cells may be intimately associated with extracellular matrix material
● Also mast cells, hyaline bands between tumor cells (Diagn Cytopathol 2002;26:290)
● May have features of solitary fibrous tumor or pleomorphic lipoma (Pathol Res Pract 1999;195:257)

Cytology images
=========================================================================



Fig 2: loose groups of cells with abundant eosinophilic granular cytoplasm and bland nuclei

Positive stains
=========================================================================

● ER, PR (Histopathology 2000;36:515), vimentin and CD34 (often)
● bcl2
● Variable desmin, caldesmon and androgen receptors (Hum Pathol 1998;29:347)

Negative stains
=========================================================================

● S100, cytokeratin
● Ki-67 (or low)

Molecular description
=========================================================================

● 13q-, 16q- (similar to spindle cell lipoma, J Pathol 2000;191:282)

Electron microscopy description
=========================================================================

● Features of smooth muscle and myofibroblasts: rough endoplasmic reticulum, bundles of myofilaments with focal densities, intermediate filaments and attachment plaques (Ultrastruct Pathol 1999;23:249, Pathol Res Pract 1999;195:1)

Differential diagnosis
=========================================================================

Fibromatosis: not circumscribed, more diffuse fibrosis and no thick bands of collagen
Nodular fasciitis: more infiltrative, mucoid stroma
Low grade myofibroblastic sarcoma: marked cellular pleomorphism, infiltrating margins and high mitotic rate
Myoepithelioma: S100+, keratin+



Male tumors

Male papilloma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 18 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● Usually presents with bloody nipple discharge

Terminology
=========================================================================

● Classified in WHO breast classification as central, peripheral or atypical papilloma (PubCan)

Case reports
=========================================================================

● 14 year old boy with enlarging breast mass (J Pediatr Surg 2011;46:e33)
● 57 year old man with intracystic papilloma associated with phenothiazine (Breast Cancer 2006;13:84)

Micro description
=========================================================================

● Identical to papillomas in women: multiple papillae in complex arborizing pattern with well-developed vascular connective tissue core surrounded by epithelial and myoepithelial cells; benign nuclei, frequentapocrine metaplasia, inflammationIdentical to papillomas in women

Micro images
=========================================================================



Various images

AFIP images:

Complex intraductal papilloma


Papillary tumor with fibrovascular core

Electron microscopy description
=========================================================================

● Epithelial cells, myoepithelial cells and intermediate cells with intranuclear helioid inclusions
● Squamous metaplasia (Ultrastruct Pathol 1994;18:601)



Male tumors

Male breast carcinoma - general


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 18 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Epidemiology
=========================================================================

● Very rare
● Have higher risk for second primary (breast, stomach and melanoma, Breast Cancer Res 2007;9:R10)
● In US, males have 1% the rate of breast carcinoma of women; 1000-1500 new cases per year in US
● Mean age 60 years at diagnosis
● Histology similar to women, mostly ductal and most ER+
● Incidence may be increasing in US, Canada and UK (World J Surg Oncol 2008;6:58)

Risk factors
=========================================================================

● Breast carcinoma in first degree relatives
● BRCA2 > BRCA1 mutation carriers (J Natl Cancer Inst 2007;99:1811, Ann Saudi Med 2009;29:288)
● Older age
● Infertility
● Obesity
● Ionizing radiation
● Klinefelter’s syndrome (50x risk)
● Estrogen treatment for prostate carcinoma or cirrhosis

Clinical features
=========================================================================

● Typically firm, painless mass in subareolar breast or upper, outer quadrant
● Nipple discharge in men is strongly suggestive
● Often presents at high stage since minimal breast substance (Saudi Med J 2009;30:1060)
● Axillary nodes in 50% at presentation
● Luminal A and B subtypes are most common (Breast Cancer Res 2009;11:R28)

Prognostic factors
=========================================================================

● Male patients with early stage disease may have poorer prognosis than similar stage female patients (Cancer 2007;109:1471)
● HER2+ patients have poorer survival stage by stage (Mod Pathol 2002;15:853, Am J Surg Pathol 2006;30:1292)
● Nodal metastases are an important, negative prognostic factor (Cancer Radiother 2009;13:103)
● Treatment is similar for men and women (US National Cancer Institute)

Case reports
=========================================================================

● 47 year old man with bilateral breast cancer and hypogonadism (World J Surg Oncol 2007;5:60)
● 54 year old man with synchronous bilateral male breast cancer (J Breast Cancer 2012;15:248)
● 59 year old man with pure mucinous carcinoma (Breast Cancer 2012;19:365)
● 75 year old man with intracystic papillary carcinoma (Arch Pathol Lab Med 1985;109:858)
● 76 year old man with oncocytic carcinoma (Arch Pathol Lab Med 1989;113:1396)
● 82 year old man with in situ and invasive lobular carcinoma (Hum Pathol 1989;20:1220)
● Tubulolobular carcinoma (Am J Surg Pathol 2005;29:980)

Treatment
=========================================================================

Similar to female breast cancer treatment:
● Surgery
● Sentinel node biopsy (J Am Coll Surg 2008;206:616)
● Radiation therapy
● Tamoxifen (Breast 2007;16 Suppl 2:S147)
● Adjuvant systemic therapy (Cancer 2005;104:2359)

Gross images
=========================================================================



Intracystic papillary carcinoma

Micro description
=========================================================================

● Similar to female tumors
● Invasive ductal carcinoma is most common, papillary is #2 (Virchows Arch 2006;449:507); invasive lobular / LCIS is rare

Micro images
=========================================================================


   
DCIS-various      DCIS and invasive carcinoma

   
Infiltrating ductal carcinoma

       
Androgen receptor+  PSA+         Invasive ductal carcinoma (A),
                       solid papillary carcinoma (B)

       
Intracystic papillary DCIS

       
Nodal metastases   HER2+         p53+

       
Moderately differentiated ductal carcinoma

       
ER+           PR+           HER2 negative

       
Luminal B tumor     Various subtypes    Intracystic papillary carcinoma

Invasive lobular carcinoma

AFIP images:

DCIS-solid type after estrogen for prostate cancer

              
Invasive carcinoma with cribriform pattern

              
Intracystic papillary carcinoma        Cystic papillary carcinoma with invasion

Cytology description
=========================================================================

● Reliable but underutilized (Acta Cytol 2009;53:369)

Papillary tumors:
● Papillary clusters of epithelial cells with variable fibrovascular cores
● Also single epithelial cells with high N/C ratio and eccentric nuclei, hemosiderin-laden macrophages (Cancer 2006;108:222)

Cytology images
=========================================================================



Poorly cohesive groups of large, pleomorphic cells with
increased N/C ratios, irregular membranes and macronucleoli


Loosely cohesive malignant cells

Positive stains
=========================================================================

● ER (95%), PR (70%) and androgen receptors (Eur J Surg Oncol 2006;32:44)
● Ki-67 (20-40%)

Negative stains
=========================================================================

● p53, HER2 (usually, Arch Pathol Lab Med 2003;127:36)

Differential diagnosis
=========================================================================

● Gynecomastia with chemoradiation induced atypia (Arch Pathol Lab Med 2002;126:613, micro image)

Additional references
=========================================================================

eMedicine



Male tumors

Metastases to male breast


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 18 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Clinical features
=========================================================================

● 2% of all nonhematologic breast malignancies
● Most common primary is melanoma; also prostate (Urology 1978;11:641), colon, lung and bladder (Virchows Arch 2006;449:507)
● Prostate metastases are often bilateral, usually after estrogen therapy in background of gynecomastia; PSA+, PAP+ (note that the normal male breast and gynecomastia may be PSA+ but PAP-, Breast Cancer Res 2004;6:R18, Hum Pathol 1991;22:242)
● Need strong index of suspicious to diagnose, may need immunostains to distinguish primary and metastatic disease

Radiology
=========================================================================

● Single, round, discrete lesions without spiculation (Acta Cytol 2002;46:377)

Case reports
=========================================================================

Primaries from:
● Bladder (Br J Radiol 2000;73:1326)
● Lung (Australas Radiol 1998;42:16, South Med J 2007;100:850)
● Prostate (Hinyokika Kiyo 1999;45:269, Arch Pathol Lab Med 2001;125:1101)
● Skin eccrine adenocarcinoma (J Cutan Pathol 2007;34:934)

Micro description
=========================================================================

● Usually no DCIS or elastosis (J Clin Pathol 2007;60:1333)

Micro images
=========================================================================



Prostatic carcinoma metastases to male papillary breast cancer


Prostate primary



Miscellaneous

Treatment effect - chemotherapy


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 18 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Clinical features
=========================================================================

● With post-chemotherapy specimens, sample extensively before concluding “no invasive carcinoma” (Hum Pathol 2004;35:781)
● May have disseminated apoptotic or non-apoptotic tumor cells in bone marrow (Breast Cancer Res 2006;8:R60)
● Histologic changes do not correlate with clinical or pathologic response to chemotherapy (J Surg Oncol 2002;80:4), although tumor cell necrosis may have some predictive value (Am J Surg Pathol 2005;29:354)

Case reports
=========================================================================

● 46 year old woman with xanthomatous pseudotumor after preoperative chemotherapy for invasive ductal carcinoma (Arch Pathol Lab Med 2003;127:739)

Micro description
=========================================================================

● Smaller tumor size, reduced cellularity, generally same morphology and tumor markers (may change rarely)
● Extensive cytoplasmic vacuolization causing tumor cells to resemble histiocytes
● Also tumor necrosis, atrophy and marked nuclear atypia (enlarged, bizarre shapes) in a background of chronic inflammation with hemosiderin laden macrophages and fibrosis; similar changes in lymph nodes (Histopathology 1996;29:63, Pathol Res Pract 1997;193:187)
● May show distortion of glandular architecture, eosinophilic change, decreased mitotic activity (Arch Pathol Lab Med 2009;133:633)

Micro images
=========================================================================



Residual tumor cells have bizarre shapes with enlarged hyperchromatic nuclei and cytoplasmic vacuoles


Various images


Post-chemotherapy specimen has only scattered tumor cells in collagenous stroma (AFIP)

Post-chemotherapy fibrosis   scar and foamy histiocytes   foamy histiocytes and lymphocytes

Additional references
=========================================================================

Ann Surg Oncol 2003;10:734, Breast 2001;10:492, Arch Pathol Lab Med 2009;133:633



Miscellaneous

Treatment effect - cryoprobe


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 18 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Clinical features
=========================================================================

Cryoprobe: uses cryotherapy to makes nonpalpable carcinomas well-defined and palpable by creating an ice ball, leading to removal of less tissue (Am J Surg 2006;192:462)
● Alters tumor morphology making it difficult to grade tumor, distinguish DCIS and invasive tumor, and identify angiolymphatic invasion or mitotic figures (Am J Clin Pathol 2007;128:239)
● Alternative to excision of fibroadenomas (Radiology 2005;234:63)
● Normal breast parenchyma in cryozone shows dense fibrosis, fat necrosis, xanthogranulomatous reaction, endovascular fibrosis and hemorrhage (Cryobiology 2007;55:44)
● Causes reduction in ER/PR receptors, but does not affect Ki-67 staining or margin evaluation

Micro images
=========================================================================


               
Post-cryoprobe ablation shows coagulative   Residual invasive ductal carcinoma
necrosis and amorphous eosinophilic staining

               
Cryoprobe related artifact (fig B)        Cellular shrinkage, smudgy nuclei
compared to core biopsy (fig A)         and prominent retraction artifact


Acellular central hyaline background
without residual fibroadenoma



Miscellaneous

Treatment effect - hormonal therapy


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 14 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Micro description
=========================================================================

● Causes stromal fibrosis and elastosis (Br J Cancer 1979;39:536), hyalinization and degenerative changes in tumor cells with cytoplasmic vacuoles, nuclear aberrations and necrosis
● Letrozole, an aromatase inhibitor (Wikipedia), produces central scarring (Histopathology 2007;51:219)



Miscellaneous

Treatment effect - radiation therapy


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 18 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

See also atypical or benign vascular proliferations post-radiation of breast

Case reports
=========================================================================

● 57 year old woman with radiation induced morphea (J Med Case Rep 2008;2:136)

Micro description
=========================================================================

● Giant tumor cells with bizarre nuclear changes (J Clin Pathol 1990;43:152), naked nuclei and abnormal mitotic figures
● Extensive tumor necrosis demarcated by thick fibrous walls
● Changes in non-neoplastic breast include atypia, lobular sclerosis and atrophy (may distort lobular architecture and obscure myoepithelial cells, Hum Pathol 1984;15:545), intimal thickening in small muscular arteries (Radiother Oncol 2009;92:477) and fat necrosis, but usually no mitotic activity or loss of polarity
● Changes do not regress over time (Am J Surg Pathol 2004;28:47)

Micro images
=========================================================================


       
Fibrotic stroma, DCIS and atrophic glands   Atypical stromal cells, lymphocytic infiltrate
                       and increased collagen bundles

                
Large stromal fibroblasts may          Thickened basement membranes
also occur In NON-irradiated tissue

                
Atypical stromal fibroblasts            LCIS unchanged by radiation compared
                       to atrophic normal glands

                
Atypia in normal duct              Atypia within normal lobule

                
Fat necrosis post-iridium implant         Vessel shows reduplicated elastic lamina
                        and intimal thickening (elastin stain)


Collagenization of intralobular stroma and glandular atrophy (AFIP)

Radiation induced epithelial atypia   #2   #3

Virtual slides
=========================================================================



Post-therapy

Differential diagnosis
=========================================================================

Pleomorphic lobular carcinoma



Miscellaneous

Frozen sections


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 18 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

See also sentinel lymph nodes

Uses by pathologists
=========================================================================

● Historically used for primary diagnosis, not anymore (Pathologica 2011;103:325)
● Now used to evaluate margins at lumpectomy and reduce need for subsequent surgery (Ann Surg Oncol 2007;14:2953, J Am Coll Surg 2005;201:194, Scand J Surg 2009;98:34)
● Diagnosis of non-core specimens, although limitations include artifacts, sampling or interpretation errors, and in situ carcinoma only; recommended to use FNA, core biopsy or imaging as preoperative diagnostic tools (Tumori 1999;85:15)
● Frozen sections for ultrasound guided core needle biopsies may reduce patient stress waiting for paraffin results (BMC Cancer 2009;9:341)

Questions to ask prior to frozen section or intraoperative assessment (if any answer is no, don’t do frozen section):
● Is tumor > 1.0 cm?
● Will there be adequate essential diagnostic material after frozen section?
● Will additional material be sent after a biopsy is evaluated?
● Will diagnosis have immediate and relevant impact on operative management of patient?

Note: some specimens may not be diagnostic at frozen section, including adenosquamous carcinoma-low grade (Histopathology 2006;49:603)

Gross images
=========================================================================



Tumor with positive margins (Fig 1A/1B)

Micro images
=========================================================================



Infiltrating ductal carcinoma (Fig 1A/1B)

Additional references
=========================================================================

Arch Pathol Lab Med 2005;129:1565, Ann Surg Oncol 2012;19:3236



Miscellaneous

Grossing (histologic sampling) of breast lesions


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 18 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● For grossly benign biopsies, focus on fibrous tissue, since unlikely to detect carcinoma or atypia exclusively in unremarkable adipose tissue (Am J Surg Pathol 1989;13:505)
● Clinical outcomes of positive shaved and inked margins may differ (Cancer 1997;79:1568)
● Grossly negative margins may be histologically positive in up to 25% of specimens (Am Surg 2005;71:22)

Grossing the biopsy or excision of a palpable breast mass
=========================================================================

● Measure and (optionally) weigh specimen
● Take radiograph, if indicated
● Blot dry, ink margins and blot dry again
● If multiple orientations obtained, may want to ink in multiple colors to identify tumor proximity to specific margins
Example: superior margin-blue, inferior margin-green, anterior margin-yellow, posterior margin-black, section and submit from medial to lateral
● Palpate specimen for masses and correlate with radiograph
● Section specimen as thin as possible (3-4 mm slices, may need to fix first)
● May want to photograph / make drawing and indicate where sections came from
Describe: tumor (size in three dimensions, color, distance from margins, consistency, necrosis), fibrosis, cysts (number, size, content) and calcifications, if margins are submitted as shaved or perpendicular
● Submit entire specimen, if possible, in 3-5 sections; otherwise, at least 3 sections of tumor or 1 section per cm of tumor diameter (whichever is more), any suspicious areas and surgical margins; include center and periphery of tumor and adjacent tissue, areas of mammographic abnormality; Rosai suggests at least 2/3 of nonadipose breast tissue
Note: resection by surgeon of 4-5 additional tumor cavity margins during breast conserving surgery for early stage invasive breast cancer is recommended (Ann Surg Oncol 2010;17:228)

Grossing re-excision for residual disease
=========================================================================

● Either submit entire specimen or submit 2 blocks per cm if grossly benign, remaining tissue if carcinoma identified (Am J Surg Pathol 1999;23:316)

Grossing a needle localization specimen
=========================================================================

● Review radiograph to confirm that calcified areas have been excised
● Measure and (optional) weigh specimen
● Blot dry, ink margins and blot dry again
● If multiple orientations obtained, may want to ink in multiple colors to identify tumor proximity to specific margins
Example: superior margin-blue, inferior margin-green, anterior margin-yellow, posterior margin-black, section and submit from medial to lateral
● Palpate specimen for masses and correlate with radiograph
● May want to photograph / make drawing and indicate where sections came from
● Section specimen as thin as possible (3-4 mm slices, may need to fix first)
● Some recommend radiographs of sections to confirm that the calcified areas are being submitted
Describe: tumor (size in three dimensions, color, distance from margins, consistency, necrosis), fibrosis, cysts (number, size, content) and calcifications, if margins are submitted as shaved or perpendicular
● Submit entire specimen, if possible, in 3-5 sections; otherwise, at least 3 sections of tumor or 1 section per cm of tumor diameter (whichever is more), any suspicious areas and surgical margins; include center and periphery of tumor and adjacent tissue, areas of mammographic abnormality; Rosai suggests at least 2/3 of nonadipose breast tissue
● Make sure to submit area of specimen containing radiographic microcalcifications; if carcinoma or atypical hyperplasia is found, submit additional sections (Am J Surg Pathol 1990;14:578)

Grossing a mastectomy specimen
=========================================================================

Radical mastectomy: rare procedure currently; removal of entire breast, underlying and adjacent adipose tissue, pectoralis major and minor muscles and axillary contents en bloc
Supraradical mastectomy: not performed today, radical mastectomy, chest wall, various ribs, sternum, internal mammary vessels and nodes, variable pleura
Modified radical mastectomy: common, preserves pectoralis muscles, some skin is preserved (but nipple, areola and surrounding areas are excised), some lymph nodes containing fat from lower axilla
Simple mastectomy: most / all mammary tissue, nipple and variable adjacent skin
Subcutaneous mastectomy: most of mammary tissue, no skin or nipple and variable axillary tail
Quadrantectomy: one of four anatomic breast quadrants, usually with axillary content
Tylectomy / lumpectomy / excisional biopsy: removal of mass and variable amount of adjacent breast tissue
Cavity margin sampling: surgeon biopsies entire wall of residual cavity created by prior procedure; results supercede lumpectomy margins, which are often falsely positive (i.e. positive when cavity margin is negative, Am J Surg Pathol 2005;29:1625)

● Measure and weigh specimen
● Ink margins (deep, superior, inferior, lateral, medial) - can use different colors to establish tumor distance to margins microscopically
● Palpate specimen for masses and correlate with radiograph (if present)
● Orient by using axillary fat as lateral
● If possible, separate axillary nodes into level I (low - inferior to lower border of pectoralis minor muscle in radical mastectomy specimens), level II (middle - between upper and lower borders of pectoralis minor muscle) and level III (high - superior to upper border of pectoralis minor muscle)
● If pectoralis minor muscle not present, separate lymph nodes into upper and lower half
● Should be 20 lymph nodes in usual radical mastectomy
● Recommended to fix overnight with Carnoy’s solution to clear the fat (although this is not often done)
● Section nipple and areola
● Divide breast into quadrants (with marker or mentally)
● Section entire breast into 2 cm thick slices, examine for tumor or suspicious areas
● May want to photograph / make drawing and indicate where sections came from

Describe: specimen, tumor (size in three dimensions, color, distance from margins, consistency, necrosis), fibrosis, cysts (number, size, content), calcifications, gross abnormalities of skin, nipple, scar, biopsy site / cavity and lymph node findings, if margins are submitted as shaved or perpendicular

Sections: nipple (perpendicular cuts to maximize cross sectional area), scar, tumor (at least 3 sections or 1 per cm of diameter, whichever is greater, include center and periphery of tumor and adjacent tissue), other gross lesions, areas of mammographic abnormality, closest tumor margin, other margins, representative sections of nonadipose tissue from each quadrant (upper-outer, lower-outer, upper-inner, lower-inner, Breast J 2003;9:307) and all lymph nodes (separate into upper and lower half or levels (for radical mastectomy), recommended to submit entire node unless grossly involved by tumor, Mod Pathol 1999;12:781)

Grossing a microdochectomy specimen
=========================================================================

Definition: removal of diseased duct system to investigate nipple discharge
● Surgeon marks apex of specimen with suture and leaves probe in affected duct
● Duct may also be wire marked (BMC Cancer 2009;9:151)
● Dissect by making serial slices across duct lumen (or can open duct with fine scissors)
● Should report whether cause for nipple discharge was demonstrated
Additional references: Breast 2008;17:309, BMC Cancer 2006;6:164

Microdochectomy images
=========================================================================


     
Insertion of ductoscope  Selective lactiferous duct sample

Protocols
=========================================================================

● CAP protocol for excision of DCIS (Arch Pathol Lab Med 2009;133:15)
● CAP protocol for excision of breast cancer (Arch Pathol Lab Med 2000;124:1026)
● CAP protocol: updated regularly - visit http://www.cap.org, then type cancer protocols and checklists into search box
RCPA, Drexel University

Additional references
=========================================================================

Ann Diagn Pathol 2011;15:291



Miscellaneous

Features to report for breast carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 18 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Editor’s note

Required features to report
=========================================================================

● Specimen type / procedure
● Lymph node sampling (specify)
● Specimen size (third dimension is not required)
● Laterality (if known)
● Tumor site (if known)
● Invasive tumor size (at least one dimension is required)
● Invasive tumor histologic type
● Invasive tumor grade (Nottingham modification of Bloom-Richardson), including tubule formation, nuclear pleomorphism and mitotic activity (should grade lobular carcinoma and colloid carcinoma, don’t need to grade medullary carcinoma)
Note: if another grading system is used, must still specify mitotic count
● TNM staging
● Number of lymph nodes examined, number involved by tumor, maximal metastasis size and presence of extracapsular spread
● Margins (distance of invasive and in-situ tumor from closest margin, specify margin)

Optional features to report, but recommended
=========================================================================

● Angiolymphatic invasion (note: tumor in dermal lymphatics may be due to benign mechanical transport, Hum Pathol 2005;36:310)
● Perineural invasion
● Involvement of nipple, skin (epidermis or dermis) and chest wall
● Multifocality
● Presence of microcalcifications and correlation with mammography
● Correlation of other findings with mammography
● Extent of margin involvement (if positive)
DCIS (particularly if no invasive carcinoma present): size, morphologic type (architectural pattern), nuclear grade (high, intermediate, low), presence of comedocarcinoma (necrosis) and % of carcinoma represented by DCIS (25% or more is “extensive”); also margin involvement (focal or diffuse and distance to margin), presence of microcalcifications (within DCIS or elsewhere) and correlate with mammographic findings
● For invasive carcinoma: % of cells staining for ER and PR and intensity of staining (weak, moderate, strong)
● For invasive carcinoma: HER2 staining (0/negative, 1+/weak, 2+/partial circumferential staining and 3+/strong circumferential staining visible at low power)
● Fibrocystic disease
● Presence of ADH, ALH or LCIS

Optional features to report
=========================================================================

Fibrotic focus
● Presence of extensive tumor necrosis
● Host lymphocytic response (Am J Surg Pathol 2003;27:194)

Quality of reporting
=========================================================================

● Improved in Australia after guidelines were issued; synoptic reports are more complete (Pathology 2009;41:361)

Templates
=========================================================================

Michigan Cancer Consortium

Micro images
=========================================================================


AFIP images:
        
DCIS close to inked margin     DCIS with a positive margin


DCIS at (or a basement membrane away from) the inked margin

Additional references
=========================================================================

Arch Pathol Lab Med 2000;124:1026, Association of Directors of Anatomic and Surgical Pathology (2004), Arch Pathol Lab Med 2009;133:15



Miscellaneous

Staging of breast carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 18 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
=========================================================================

● T and M (not N) are similar for clinical and pathologic staging
● Numerous changes were made in AJCC 7th edition - AJCC Cancer Staging Manual (7th ed)

Primary tumor (T)
=========================================================================

● Same definitions for clinical and pathologic classification, although T1 subclassification requires more than clinical examination

TX: primary tumor cannot be assessed (includes cases with tumor present at margin by macroscopic examination, because total extent of tumor cannot be assessed)
T0: no evidence of primary tumor
Tis: carcinoma in situ
Tis (DCIS): ductal carcinoma in situ
Tis (LCIS): lobular carcinoma in situ
Tis (Paget’s): Paget’s disease of the nipple NOT associated with invasive carcinoma or carcinoma in situ (DCIS or LCIS) in the underlying breast parenchyma; carcinomas in the breast parenchyma associated with Paget’s disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget’s disease should still be noted
T1: tumor 2 cm (20 mm) or less in greatest dimension
T1mic: tumor 1 mm or less in greatest dimension (if multiple foci of microinvasion, use largest focus and add a comment, don’t add sizes of individual foci)
T1a: tumor more than 1 mm, but 5 mm or less in greatest dimension
T1b: tumor more than 5 mm, but 10 mm (1 cm) or less in greatest dimension
T1c: tumor more than 1 cm, up to 2 cm in greatest dimension
T2: tumor more than 2 cm, up to 5 cm in greatest dimension
T3: tumor more than 5 cm in greatest dimension
T4: tumor of any size with direct extension to chest wall or skin as described below (invasion of dermis alone does not qualify as T4)
     ●T4a: extension to chest wall, not including only pectoralis muscle adherence / invasion
     ●T4b: ulceration or ipsilateral satellite nodules or edema (including peau d’orange) of the skin, which do not meet the criteria for inflammatory carcinoma
     ●T4c: both T4a and T4b
     ●T4d: inflammatory carcinoma (clinical diagnosis characterized by diffuse erythema and edema [peau d’orange] involving a third or more of the skin of the breast; skin changes are due to lymphedema caused by tumor emboli within dermal lymphatics, which may not be obvious in a small skin biopsy; however, tissue diagnosis is necessary to demonstrate an invasive carcinoma in the underlying breast parenchyma or at least in the dermal lymphatics; note that either tumor emboli in dermal lymphatics or locally advanced breast cancers directly invading the dermis or ulcerating the skin, without the clinical skin changes described above, do NOT qualify as inflammatory carcinoma; dimpling of the skin, nipple retraction or any other skin changes except those described under T4b and T4d may occur in T1-3 without changing the classification

Notes:
● Measure invasive component only, not DCIS
● T classification traditionally assumes there was no prior treatment; can stage after preoperative (neoadjuvant, primary) chemotherapy, but should indicate that prior treatment was received (J Natl Cancer Inst 2005;97:1137)
● pT classification requires pathologic examination of a primary carcinoma with no gross tumor at resection margins (but can classify if only microscopic tumor is present at resection margin)
● If tumor size is slightly less than or greater than a cutoff for a given T classification, it is recommended that the size be rounded to the millimeter reading that is closest to the cutoff
● Can attempt to reconstruct original tumor size if multiple biopsies / excisions; due to difficulties in adding sizes from two resections, may want to report “at least pT_, a more accurate estimate may be based on imaging studies”
● If there are multiple simultaneous, macroscopically measurable, ipsilateral invasive tumors, use largest size, don’t sum sizes (but add a comment)
● If there are multiple invasive carcinomas, the size, grade, histologic type and results of ER, PgR and HER2 should pertain to largest invasive carcinoma; if smaller invasive carcinomas differ in any of these features, include this information in “Comments”
● Tumor in pectoralis muscle should be measured with the breast tumor to determine the tumor size and T category
● Simultaneous bilateral breast carcinomas are staged as separate primaries in separate organs
● Gross measurement is recommended (either fresh or fixed); however if significant in situ disease is present or invasive tumor extends microscopically beyond the grossly measured mass, then microscopic measurements may be more accurate; using microscopic measurements only is discouraged because processing artifact may cause significant tissue expansion or shrinkage (Hum Pathol 2005;36:756)
● If a prior biopsy showed a larger area of invasion than excisional specimen, use dimension of invasive carcinoma in the prior specimen for T classification
● If patient received prior treatment and no invasive carcinoma is present in current specimen, classified as Tis if residual DCIS and T0 if there is no remaining carcinoma (but add comment)
● Grade corresponds to largest area of invasion; if there are smaller foci of invasion of a different grade, include this information under “Additional Pathologic Findings”
● Margin status is “positive” if there is ink on carcinoma (ie, the distance is 0 mm); if the margin is not positive, then a distance from the margin may be listed; distances can be specific measurements or expressed as greater than or less than a measurement

Regional lymph nodes (pN)
=========================================================================

Note: IHC means immunohistochemistry, ITC means individual tumor cells

pNX: regional lymph nodes cannot be assessed (e.g., previously removed or not removed for pathologic study)
pN0: no regional lymph node metastasis identified histologically
pN0 (i-): no regional lymph node metastases histologically, negative IHC
pN0 (i+): malignant cells in regional lymph node(s) no greater than 0.2 mm (detected by H&E or IHC including ITC)
pN0 (mol-): no regional lymph node metastases histologically, negative molecular findings (RT-PCR)
pN0 (mol+): positive molecular findings (RT-PCR), but no regional lymph node metastases detected by histology or IHC
pN1: micrometastases; or metastasis in 1-3 axillary lymph nodes; OR in internal mammary nodes with metastases detected by sentinel lymph node biopsy, but not clinically detected apparent
pN1mi: micrometastasis (greater than 0.2 mm or more than 200 cells, but none greater than 2.0 mm)
pN1a: metastasis in 1-3 axillary lymph nodes, at least one metastasis greater than 2.0 mm
pN1b: metastasis in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy, but not clinically detected
pN1c: metastasis in 1-3 axillary lymph nodes and in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy, but not clinically detected
pN2: metastasis in 4-9 axillary lymph nodes; or in clinically detected internal mammary lymph nodes in the absence of axillary lymph node metastasis
pN2a: metastasis in 4-9 axillary lymph nodes (at least one tumor deposit larger than 2.0 mm)
pN2b: metastasis in clinically detected internal mammary lymph nodes in the absence of axillary lymph node metastases
pN3: metastasis in 10 or more axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes; or in clinically detected ipsilateral internal mammary lymph nodes in the presence of one or more positive level I or II axillary lymph nodes; or in more than 3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy, but not clinically detected; or in ipsilateral supraclavicular lymph nodes
pN3a: metastasis in 10 or more axillary lymph nodes (at least one tumor deposit greater than 2.0 mm); or metastasis to the infraclavicular (level III axillary) lymph nodes
pN3b: metastases in clinically detected ipsilateral internal mammary lymph nodes in the presence of 1 or more positive axillary lymph nodes; or in 4 or more axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy, but not clinically detected
pN3c: metastasis in ipsilateral supraclavicular lymph nodes

Notes:
● Requires resection and examination of at least the low axillary lymph nodes (level I)
● “i” stands for isolated tumor cells (ITC); “i+” means small clusters of tumor cells detected by H&E or IHC that are 0.2 mm or less (Am J Surg Pathol 2005;29:136) or fewer than 200 cells in a single histologic cross-section); isolated tumor cells are not counted as a positive node below
● In practice, the distinction between ITC and micrometastases is often difficult and without prognostic significance (Cancer 2008;112:1672)
● Classification based solely on sentinel lymph node biopsy, without subsequent axillary lymph node dissection, is designated (sn) for “sentinel node”, for example: pN0(sn)
● “Clinically detected” is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy, or a presumed pathologic macrometastasis based on fine needle aspiration biopsy with cytologic examination
● Tumor in axillary fat without evidence of residual lymph node tissue is classified as a positive axillary lymph node
● Lymph node ratio (LNR, the ratio of positive over excised lymph nodes) is suggested as an alternative to pN staging (J Clin Oncol 2009;27:1062)

Diagrams
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Various possible difficulties

Additional references
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Cancer 2003;98:2740, CA Cancer J Clin 2006;56:37, Cancer 2005;103:1319 (problems with assessing ITCs)


Distant Metastasis (M)
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M0: no clinical or radiographic evidence of distant metastases; includes M0(i+)
cM0(i+): no clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow or other nonregional nodal tissue that are no larger than 0.2 mm in a patient without symptoms or signs of metastases
M1: distant detectable metastases as determined by classic clinical and radiographic means or histologically proven larger than 0.2 mm


Stage grouping
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Stage 0:   Tis   N0   M0
Stage IA:    T1   N0   M0
Stage IB:    T0-1   N1mi  M0
Stage IIA:   T0-1   N1   M0 or   T2 N0 M0
Stage IIB:   T2   N1   M0 or   T3 N0 M0
Stage IIIA:  T0-2  N2   M0 or   T3 N1-2 M0
Stage IIIB:  T4   N0-2  M0
Stage IIIC:  Any T   N3   M0
Stage IV:    Any T   Any N   M1

Notes:
● Stage designation may be changed post-surgery if (a) imaging studies within 4 months of diagnosis reveal the presence of distant metastases, (b) there has been no disease progression and (c) no preoperative therapy was given
● T1 includes T1mi
● T0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA and are classified as Stage IB
● The designation pM0 is not valid; any M0 should be clinical


Additional references
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Arch Pathol Lab Med 2006;130:287, National Cancer Institute (USA), Updated CAP staging

End of Breast malignant, males, children > Superpage > Other


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