Approach to papillary lesions of the breast

The terminology can be confusing. I’ll try to add pictures/diagrams to clarify at a later date. Feel free to ask questions.

Intraductal papilloma – duct structures with broad fibrovascular cores lined by an myoepithelial and epithelial lining. May be solitary in the subareolar region (50-60 yrs typically) and multiple in the periphery ( 20-30 yrs typically). May be associated with UEH, ADH, DCIS, apocrine or squamous metaplasia. Surrounding fibrotic stroma may give the impression of pseudoinvasion and myoepithelial cells stains will be helpful in differentiating. DD includes papillary Dcis, encapsulated papillary ca and invasive ca. When there is an area of low grade atypical proliferation (adh vs lg dcis only – size criterion cut off of 3mm as per Page et al study can be used) But only for adh vs lg dcis distinction and not to be used for intermediate and hg dcis.

Entities: Benign papilloma, Papilloma with ADH, Papilloma with DCIS (care to differentiate from papillary dcis), carcinoma arising in a papilloma

Encapsulated/ encysted papillary carcinoma – a rare type of carcinoma which is relatively indolent. A well circumscribed papillary lesion with a fibrous rim and no evidence of stromal invasion however lacking a myoepithelial layer of the cells lining the fibrous cores and also lacks a myoepithelial layer at the peripheral rim compared to papillary carcinoma in situ which retains the myoepithelial layer at the rim. Encysted papillary carcinoma shows papillary cores lined by a single epithelial layer usually. This may be columnar but there may be unusual variants with a secretory endometrial appearance or an appearance of thyroid papillary carcinoma. To differentiate EPC myoepithelial markers will be negative at the fibrovascular cores and also at the periphery, and will usually show uniform ER positivity. The differential includes: benign papilloma, papillary carcinoma in situ, papilloma with dcis, papillary dcis, metastatic papillary carcinoma (thyroid and ovarian -check history), cystic degeneration of carcinoma (look for high nuclear grade and necrosis has a poor prognosis) and invasive papillary carcinoma (presence of desmoplastic stroma and mucin stains may help) (NB There can be encysted papillary carcinoma with pseudoinvasion especially due to fibrosis from needle core biopsies – care to withhold diagnosis of nst which is more common than invasive papillary)! EPC considered as a carcinoma with a pushing border and with a low risk of lymph node and visceral metastasis.

Solid papillary carcinoma– what a solid variant of EPC would look like. Carcinoma with a pushing border. Solid papillary carcinoma is characterized by well-circumscribed expansile nodules consisting of sheets of malignant epithelial cells supported by papillae, although these are often inconspicuous. The epithelial cells are typically ovoid or spindle-shaped and polarize around the fibrovascular cores. They may exhibit a streaming pattern similar to that seen with usual epithelial hyperplasia. Intracellular and extracellular mucin is commonly present and when accompanied by invasive carcinoma, the latter is often invasive mucinous carcinoma. The cells may exhibit neuroendocrine features and staining with chromogranin and synaptophysin can be seen. As with encapsulated papillary carcinomas, myoepithelial cells are typically not identified with immunohistochemical stains at the periphery of these tumors or lining the fibrovascular cores. This raises the possibility that these tumors represent invasive carcinomas with pushing borders rather than in situ processes; however, they tend to follow an indolent course, especially when there is no evidence of unequivocal stromal invasion.

Papilloma with focal atypia and atypical papilloma are unhelpful terms – not specific.

References:

Breast Pathology: O Malley, Pinder and Mulligan

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Benign Sclerosing Lesions of the Breast

The 3 entities are sclerosing adenosis, radial scar (complex sclerosing lesion) and microglandular adenosis.

Sclerosis adenosis:

A lobulocentric lesion (arise in association with the terminal duct lobular unit) with distorted obliterated glands with a myoepithelial layer in a fibrotic or sclerotic stroma. May show pseudoperineural invasion. May show apocrine metaplasia and atypia which is often seen with apocrine change. May be assoc with DCis, LCis and ADH! Myoepithelial markers p63 and SMM helpful to distinguish difficult cases that may look like carcinoma. May form a mass lesion (nodular sclerosing adenosis). Can sometimes be difficult to distinguish from tubular carcinoma. Tubular carcinoma tends to have more angulated glands compared to the lobulocentric architecture of SA and the stroma more desmoplastic than fibrous/sclerotic, also look for myoepithelial cells.

Radial scar

A central zone of fibroelastosis from which ducts and lobules radiate which  appear to dilate and expand centrifugally. Has a myoepithelial layer assess with p63 and SMM. Assoc with other benign alterations such as microcysts, apocrine metaplasia, UEH. May be assoc with ADH, LCis, Dcis. On mammography may show a stellate/spiculated mass with a radiolucent centre. x2 general risk of breast ca. If assoc with atypia, other lesions an increased risk of breast ca therefore some centres will excise fully if there is atypia.

Microglandular adenosis

A rare entity showing small round tubules infiltrating haphazardly within hypocellular stroma or fat. Lacks a myoepithelial layer but has a basement membrane (p63, SMM neg, laminin & collagenIV & reticulin positive around the glands).  Epithelial cells s100 pos and Er, PR neg. The glands are lined by a single layer of flat or cuboidal epithelium with a round nucleus and inconspicuous nucleolus. Has a open lumen which may contain eosinophilic PAS or mucicarmine positive material. Other entities – atypical MGA and carcinoma arising in MCA.

References:

Breast Pathology. O’Malley, Pinder & Mulligan

 

 

 

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Approach to testicular tumors

Classified as Germ cell tumors & Non germ cell tumours – 90% are germ cell tumors. Consider the serum marker levels HCG, AFP.

Germ cell tumours are seminomatous and non seminomatous. Age is important when considering the differential. As a mneumonic it is said Seminomas occur is Sergeants (30-45) and teratomas in troops (20-35) age group.

Seminoma

Seminomas on macro show a creamy white homogenous appearance (an important differential when faced with this macro appearance is lymphoma). Micro on low power there is a monotonous diffuse often solid growth pattern. On high power the cells are evenly spaced with pale to clear cytoplasm, well defined cell borders, square boxed off nuclei with no overlapping and prominent nucleoli. There are fibrous septa and a scattered lymphocyte infiltrate. Variants include seminoma with an interstitial growth pattern which may be very subtle but on low power will appear as a area of vaguely increased cellularity but when viewed at higher power the tumour cells between the seminiferous tubules will be seen. Also seminoma with syncytiotrophoblasts – these appear as mulberry like multinucleated cells scattered in a multifocal pattern close to capillaries and should not be diagnosed as choriocarcinoma. With choriocarcinoma the hcg levels will be in the 1000s. Hcg will also be raised in seminoma and embryonal carcinoma but not to that extent. Anaplastic seminoma is described as a variant but is contraversial. Seminoma is Oct 3/4, PLAP and CD117 positive.

Regressed Germ cell tumor

When there are fibrous scars where the architecture of the seminoferous tubules appear to be retained consider a regressed germ cell tumour particularly seminoma. Look for evidence of residual seminoma or ITGCN – intratubular germ cell neoplasia. In such a case were regression is suspected it is important to put the entirety of the lesion through. The differential diagnosis would include infarction in which ghost outlines of the seminiferous tubules are identifiable. Important to correlate with the history ?torsion, ?vasculitis, tumour markers and there is no evidence of ITGCN. Regression can occur in embryonal carcinoma or teratoma.

Embryonal carcinoma

Occurs in the 20-30s age group and is more aggressive than seminomas. On macro may have a variable appearance with foci of haemorrhage and necrosis. On micro the tumor has a variable appearance with a papillary or glandular architecture. There are ugly cells with pleomorphism. There are clefted and indented nuclei with chromatin clumping and overlapping of nuclei. There maybe smudge cells/applique pattern at the periphery which represents degenerate cells and should not be mistaken for choriocarcinoma. CD30, Oct3/4, EMA positive. CD117 neg. DD to be aware of includes anaplastic large cell lymphoma.

Yolk sac tumor

Suspect if AFP is raised. Many patterns – reticular, microcystic, endodermal sinus pattern, macrocystic, papillary, glandular and hepatoid. Stroma may be myxoid, solid or blastema like cells. Characteristically show Schiller Duval bodies – a papillary core with a blood vessel ringed by epithelium in  a cystic space lined by flat cells and Hyaline globules in cytoplasms. Positive for AE1/3 and AFP. Also glycipan 3.

Choriocarcinoma

Early dissemination therefore generally present with metastasis. Hcg in 1000s. Haemorrhagic mass grossly. Biphasic pattern – syncytiotrophoblast and cytotrophoblast with well defined cytoplasmic borders and mononuclear cells present. hcg positive in synctiotrophoblasts, mononuclear cells positive for cytokeratin – CK7, 8, 18, 19, EMA.

Teratoma

May show mature, immature blastema or neuroepithelium. All postpubertal teratomas are considered malignant. Prepubertal teratomas are benign. There may be sarcomatoid transformation, also malignant transformation of mature components very rarely. The differential diagnosis includes an epidermoid cyst and a dermoid cyst which does not show ITGCN. Important to sample the specimen well and if necessary put the testis through in its entirety.

Non germ cell tumours (Sex-Cord-Stromal tumors) include sertoli cell and leydig cell tumors.

Sertoli cell tumour

Characterised by tubules or chords of cells with large eosinophilic cells with large vesicular nuclei. Tumour markers negative. S100, Ck variable, calretinin and inhibin positivity.

Leydig cell tumor

Polygonal eosinophilic cells with a syncytial pattern with a round nucleus. Characteristically rod shaped crystalloids of Reinke seen. Endocrine manifestations such as gynaecomastia and precocious puberty. Inhibin positive. Focal cytokeratin positivity.

In elderly patients spermatocytic seminoma, lymphoma and metastases more common.

Spermatocytic Seminoma

Arises from spermatogonia B. So different tumourgenesis pathway to other germcell tumours which have ITGCN as a precursor. Older age group but 1/3 can occur in the seminoma age group. Diffuse pattern, oedematous with eosinophilic to basophilic fluid, macrocysts. Tri-lineage population – mononuclear cells, cells with plasmacytoid appearance and spiream cells. All germ cell markers – Oct 3/4, PLAP, CD30 neg. variable CD117 positivity. PASD neg. Can rarely show sarcomatoid transformation.

N.B. When spindle cell areas are seen in a testicular tumor consider teratoma with sarcomatoid transformation or spermatocytic seminoma with sarcomatoid transformation.

Non-Hodgkins lymphoma

Most common- diffuse large B cell NHL. Lymphoma can be intertubular.

Other scenarios:

Tubercular like epididymo-orchitis following bcg therapy

Metastasis

Melanoma!

References:Chaudri, Testicular tumours teaching seminar

Robbins and Cotran. Pathologic Basis of Disease

Boswick. Urological Pathology

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Soft tissue tumours with a myxoid appearance

Myxoid liposarcoma:

  • Myxoid background
  • Chicken wire like curvilinear blood vessels
  • Lipoblasts
  • Mucin pools
  • When >5% round cell component- Myxoid round cell liposarcoma,
  • t(12;16)(q13;p11) karyotype leading to fusion of DDIT3 (CHOP) with FUS (TLS).
  • S100 positive
  • younger patients

Low grade fibromyxoid sarcoma

  • on low power appearance of lobular areas of myxoid stroma seperated by collagenous septae, myxoid areas may have a more whorled appearance
  • Vessels more distended
  • vague appearance of collagen within myxoid area between cells
  • Areas of higher cellularity
  • Difficult to find mitoses
  • MUC4 gene unregulation
  • any age also younger patients
  • sometimes giant collagen rosettes

Myxoid fibrosarcoma

  • Pleomorphic
  • Myxoid
  • atypical mitotic figures
  • areas of high cellularity
  • pseudolipoblasts
  • mostly in elderly, in limb girdles, abdominal and retroperitoneal extremely rare

Other rarer cases in the malignant myxoid spindle cell DD include Extraskeletal myxoid chondrosarcoma, acral myxoinflammatory fibroblastic sarcoma

Extraskeletal myxoid chondrosarcoma

  • deep soft tissue of proximal extremities
  • multilobulated with myxoid matrix with small uniform round cells with minimal atypia finely granular eosinophilic cytoplasm arranged in clusters, cords and delicate networks within a prominent myxoid matrix
  • EWRS – NR4A3 fusion

Nodular fasciitis

  • Benign
  • Encapsulated
  • slit like spaces
  • extravasated rbcs
  • assoc with infection, trauma

DD of those with pleomorphic and myxoid appearance:

  • Myxoid fibrosarcoma
  • Pleomorphic liposarcoma

References:

WHO Soft tissue tumor classification.2002

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Endometrial Hyperplasia

Simple Hyperplasia

  • Normal to slightly increased gland to stromal ratio
  • Proliferative endometrium
  • Cystically dilated glands of variabe sizes (diffuse compared to a few in disordered proliferative endometrium)
  • Oval nuclei maintaining orientation to basement membrane

*simple hyperplasia is due to unopposed/prolonged oestrogen exposure. A diffuse process. Features of prolonged oestrogen exposure include pseudo-decidualisation and cystic dilatation of glands.

Complex Hyperplasia

  • Increase in the gland to stromal ratio with glandular crowding
  • More focal

Atypical Hyperplasia

  • Nuclear rounding
  • Presence of nucleoli
  • Nuclear stratification
  • Loss of polarity
  • Nuclear atypia should be assessed carefully in areas without metaplasia (ie ciliated cell metaplasia)

References:

My approach to the interpretation of endometrial biopsies and curretttings. McCluggage. J Clin Pathol. 2006 August; 59(8): 801–812.

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Breast Pathology: Ductal carcinoma in situ

Is a clonal non invasive proliferation in breast involving ducts (although may involve lobules termed cancerization). A precursor of invasive ca. Most commonly seen as microcalcifications – rod shaped, branching in high grade and granular in low grade. Tx WLE with rim of normal + DXT. ?completeness of excision – 10mm although some accept 2mm. Occasionally mastectomy. Smooth muscle myosin and p63 IHC to identify myoepithelial layer to differentiate from invasive malignancy. Homogenous expression of basal, luminal cytokeratins and ER due to it’s clonal nature compared to UEH. Recurrences at site of excision of dcis is thought to be residual dcis and often presents as invasive disease.

High grade Dcis

  • large, pleomorphic cells with course chromatin. Nuclei >x2.5 the size of rbc,
  • Prominent nucleoli, mitoses
  • necrosis

Low grade Dcis

  • evenly spaces, small regular cells with round nuclei x1.5-2 rbc in size
  • typically micropapillary, cribriform architecture
  • well defined cell boundaries
  • shows polarisation

Intermediate Dcis

When dcis cannot be assigned to low grade or high grade.

Rarer subtypes:

Apocrine Dcis: abundant granular cytoplasm and prominent nucleoli. Typically high grade with necrosis.

Neuroendocrine Dcis:

  • granular cytoplasm, cells may resemble carcinoid
  • solid or pseudorosette architecture
  • polygonal/spindle cells (spindle cells may mimic streaming of UEH)
  • assoc with papillary cis & Dcis
  • strong ER staining +/- neuroendocrine markers

Clear cell Dcis

Signet ring Dcis

Clinging Dcis (low grade termed flat epithelial atypia)

Microinvasive Dcis- <1mm invasive focus. Do myoepithelial markers to confirm also consider cancerisation of  lobules – do further levels.

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Breast Pathology: Intraductal epithelial proliferations

Usual type epithelial hyperplasia:

  • Peripheral slit like spaces
  • Streaming
  • Mixed population
  • Uneven distribution and overlapping of nuclei
  • Variation in appearances including oval nuclei
  • mosaic pattern of staining with Ck5, Ck14 and ER pos
  • punctate necrosis and ocasional nonatypical mitoses may be present
  • x2 risk of breast ca

Atypical ductal hyperplasia

  • Features of UEH & LGDcis
  • cells similar to LGDcis
  • <2 duct spaces with complete involvement or <2mm
  • CK5 & Ck14 neg, ER pos
  • x4 risk of breast ca

Low grade Dcis

  • uniformity
  • punched out spaces
  • rigid bars
  • micropapillae
  • evenly spaced
  • small, regular, round nuclei
  • CK5 & Ck14 neg, ER pos

Gynaecomastoid hyperplasia

  • rudimentary ill defined micropapillary clusters
  • taper towards lumen
  • small pyknotic nuclei arranged around outer edge of micropapillae
  • variable nuclei

References:

Breast Pathology: Francis, Pinder, Mulligan

Pathology Reporting of Breast Disease. Jan 2005. NHS Breast Screening Programme

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