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Neoplasms: Benign and Malignant

ATYPICAL FIBROSARCOMA AND PLEOMORPHIC DERMAL SARCOMA (31084719,37634740)
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Terminology                                                                                                                                                                                                   ​​

  • Atypical fibroxanthoma (AFX), pleomorphic dermal sarcoma (PDS), and undifferentiated pleomorphic scarcoma (UPS), are related. AFX is the less aggressive counterpart, sort of BCC-like or cellular DF-like in behavior/risk for metastasis. They display less aggressive histologic features and are more superficial (confined to dermis). PDS and UPS may display more aggressive histologic features (atypical mitoses, LVI, PNI, extensive sub Q invasion, tumor necrosis, etc.) PDS describes tumors of pure cutaneous origin, compared to UPS which encompasses a heterogenous group of soft tissue tumors including those of osteoid or retroperitoneal origin. Malignant fibrous histiocytoma (MFH) is an outdated term that used to described deeper involved AFXs.

Natural History (37634740)                                                                                                                                                                           

  • Recurrence rate of 5-11%, metastatic rate of 1-2% (37634740, cit 9,10,12,15).

  • Danish National Health Registry experience:

    • Included patients treated with WLE (did not indicate if this included Mohs but assuming no.)​

    • Recurrence rate: AFX = 10%, PDS = 17%, vast majority occurring with 5 years

      • 10% of AFX recurrences were upstaged to PDS​

    • Metastasis rate: AFX = 0.8% (regional LNs or lungs), PDS = 15%​

      • local recurrence occured before metastasis in 5 of 8 AFX cases​

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Histopathologic DDX (36395448)                                                                                                                                                                 ​

  • Desmoplastic melanoma (SOX-10+), spindle cell SCC (CK+, p63+), leiomyosarcoma (desmin+).

  • Markers supporting diagnosis of AFX/PDS: CD10+, S100A6+, procollagen+.

  • Diagnosis made largely on H&E along with a few IHC markers to rule out the above.

Workup and Management                                                                                                                                                                             

  • Histopathology is sufficient (imaging and SLNBx does not have a valuable role).

  • Lower rate of local recurrence and greater tissue preservation with Mohs (31084719, citations 36-38, 43-46).

  • Adjuvant therapy not indicated unless tumor is recurrent, unresectable, or locally metastatic, then can consider radiation.

EXTRAMAMMARY PAGET'S DISEASE (30497678)

​​Background​​

  • EMPD is a pagetoid lesion (histologically) that typically affects sites with apocrine glands (groin, vulva, scrotum, perianal, penis, axilla, umbilicus, eyelid, external auditory canal) and is thought to be a malignancy of apocrine duct origin, or, when involving the vulva, derived from Toker cells.  Broadly speaking there is primary EMPD, which is EMPD arising intraepidermally and unrelated to another malignancy; and, there is secondary EMPD, the derivation of which is not clearly understood. You can consider secondary EMPD as having 2 subtypes: secondary to adjacent malignancy (an extension of an underlying adjacent visceral malignancy or adjacent cutaneous apocrine malignancy), or, secondary to a distant malignancy in which case it may be considered either a paraneoplastic-like phenomenon or a distant cutaneous metastasis.  Mammary Paget's disease involves the breast and is always associated with an underlying breast malignancy.  More broadly speaking, some (Andrews') divide EMPD into Four types:

    • Primary EMPD - arises intraepidermally and can be invasive or in situ​

    • Secondary EMPD, a/w [cutaneous] apocrine carcinoma

    • Secondary EMPD, a/w adjacent [visceral] malignancy

    • Secondary EMPD, a/w distant carcinoma

  • Morphology is identical regardless of subtype.  ​

Natural history

  • Usually unifocal lesion but can present as multifocal lesions in different anatomic locations.  

  • Association with other cancers is mixed, with reports ranging from a  minority of patients with EMPD to nearly half or more.   

  • Invasion portends poor prognosis.  

Diagnosis and Treatment 

Pathology

  • Primary EMPD - CK7+/CK20-/GCDFP15+​

  • Secondary EMPD - CK7+/CK20+/GCDFP15-

  • Vulvar and perianal EMPD:

    • Type 1 (endodermal pattern, a/w distant cancers) - CK7+/CK20+/GCDFP15-​

    • Type 2 (ectodermal pattern, a/w cutaneous origin) - CK7+/CK20-/GCDFP15+

    • Bladder Ca associated - uroplakin and p63 positive

    • Rectal Ca associated - CK7-/CK20+/CDX2+

    • Prostate Ca associated - PSA or P504S positive

  • Invasion of 1mm or more may portend poorer prognosis.  ​

Labs

  • Serum RCAS1 levels can be monitored in patients with invasive disease similar to how PSA is used for prostate cancer. 

Excision​

  • Mohs, with significantly better cure rates if CK7 IHC is used; excision with 2-5cm margins.

SLNBx

  • indicated when invasion is present

Non-surgical treatment modalities

  • Radiation treatment with a variety of dosing regimens have been utilized both as primary and adjuvant treatment with varying success.

  • Imiquimod has been utilized with varying response rates and long term maintenance therapy may be needed. 

  • 5-FU has weaker evidence than imiquimod.​

Screening for Underlying Malignancy 39401611

Malignancy Rates

  • 18% of extramammary Paget’s disease (EMPD) cases were associated with an internal adenocarcinoma, with the risk varying by anatomic subtype: perianal EMPD (25%) had the highest risk (mainly colorectal cancer), while penoscrotal (6%) and vulvar EMPD (6%) were primarily linked to genitourinary, breast, and gynecologic malignancies.

Screening Recommendations

  • Screening should be tailored by anatomic subtype:

    • Perianal EMPD: Colonoscopy, urine cytology, and CT of the chest, abdomen, and pelvis.

    • Penoscrotal EMPD: Urine cytology, fecal occult blood test, and PSA test (if <70 years old).

    • Vulvar EMPD: Mammography and urine cytology, with additional imaging for high-risk cases.

Other Literature

Herrel LA, Weiss AD, Goodman M, Johnson TV, Osunkoya AO, Delman KA, Master VA. Extramammary Paget's disease in males: survival outcomes in 495 patients. Ann Surg Oncol. 2015. PMID: 25384700.​​​

- Case serious of 495 male patients with good descriptive statistics.

PILOMATRIX CARCINOMA (28914451)

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Background                                                                                                                                                                                                   ​​

  • Malignant variant of pilomatrixoma (also spelled pilomatricoma), but uncertain if it arises de novo or from malignant transformation. 

  • Alternate names: calcified epithelial carcinoma, matrical carcinoma, malignant matricoma.  

  • In one review of literature of 36 cases (including one pilomatrical carcinomsarcoma): mean age 57yo (range 8-85; bimodal distribution with >90% occurring in the 0-29yo and 50-69yo age groups), M:F 1.4:1, 2/3rds in caucasian.  Of note, NO patients in this cohort had an associated genetic condition. 28914451 

Natural history                                                                                                                                                                                               

  • Tendency for local recurrence and need for multiple excisions to attain clear margins (6 of 35 cases requiring 2 or more excisions). 28914451

  • In this cohort, 31% of patients had a recurrence of some type at an average of 6.5mo post-op.  3 of 35 patients presented with metastatic disease, and 11 ultimately ended up with locoregional or metastatic recurrences.  Sites included local lymph nodes, vertebrae, lungs, and intracranial involvement. 28914451

Diagnosis and Treatment                                                                                                                                                                              

Pathology

  • Ki-67, CK14, beta-catenin, cyclin D1, and p53 have been used in conjunction with routine histopathology

Excision​

  • No gold standard for margins, with 4mm up to 3cm being reported.

Imaging​

  • Over half of patients in this cohort received pre or post-op imaging with contrast CT or MRI.  28914451

Adjuvant Radiation

  • Typically reserved for recurrent metastatic disease, locoregional disease, or when clear margins cannot be obtained.  

  • External beam radiation therapy or combined EBRT/high-dose-rate brachytherapy 

Other Literature                                                                                                                                                                                             

  • A more recent review of the literature demonstrated similar findings to the above. 36826070

SEBACEOUS CARCINOMA (31797796)

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Background                                                                                                                                                                                                   ​​

  • Periocular and extraocular tumors behave differently with different genetic signatures. ​Periocular sebaceous carcinoma arise from sebaceous glands; the origin of exgtraocular SebCa is indeterminate.

  • Consider SC in atypical chalazion or chronic unilateral blepharitis in patient >60yo. 

  • Average age for both periocular and extraocular is ~68yo. 

  • Extraocular occurs slightly more in males and periocular slightly more in females, both around 60:40.

Clinical Presentation​

  • Extraocular - typical presentation is a red-yellow-brown painless ulcerated papule on head and neck.  Average diameter of 1.4cm. 

  • Periocular - Mean lesion size 1.4cm.  Upper eyelid is most common location, occurring about 2:1 compared to lower eyelid. 

Natural history/Risk Factors                                                                                                                                                                        

  • Periocular is 5x more likely to metastasize compared to extraocular, but survival seems similar between the two.

  • Immunosuppression, prior radiation (ie for acne) but only for periocular, poor differentiation, high androgen receptor staining index (>50%) again only for periocular.  

Diagnosis                                                                                                                                                                                                       

Pathology (extraocular)

  • DDX - BCC with focal sebaceous dx, clear-cell SCC

  • Histopathology - infiltrative, uniformly nested or lobular, vacuolated nested neoplasm in the dermis (rarely penetrates to subcutis). Mitoses frequent. In situ or pagetoid spread is often present in addition to deeper component.  Fairly equally split between well, mod, and poor differentiation (33:28:39). Perineural and lymphovascular invasion are very uncommon (both <0.5%).  

  • Positive markers - XIIIa (AC-1A1), androgen receptor (present in 88% of SebCa, 22% of BCC, and 3% of SCC, ref 33478823), adipophilin and perilipin, EMA (also pos in SCC 83%, BCC 0%, ref 27039776), CK AE1 and AE3 (also pos in SCC); PGRMC1, ABHD5, SQS, CA15-3, CA19-9, CK8, CK19

  • Negative markers - BerEP4 (BCC), CEA (in contrast to sebaceous glands), S100, HMB45, SOX10, CD5, GCDFP-15, D2-40

Pathology (periocular)

  • Histopathology - much more variable than extraocular: lobular, comedo-acinar, papillary, and mixed variants.  21:47:32 well:mod:poor dx.  PNI more common than in extraocular (2.7%) as well as LVI (3.9%).   

  • Positive markers - CK7,  EMA, adipophilin, BerEP4 (usually negative but occ. positive, in contrast to extraocular), BRST1, CAM5.2

Risk Stratification​

  • High ALDH1 or androgen receptor index may predict increased chance of recurrence or mets, but data is poor.  Perineural invasion does not seem to have a significant impact, but is still often considered when risk stratifying.  ​

Muir-Torre

  • Primarily a concern with extraocular SC below the neck, in which case it is recommended if Mayo M-T score is 2 or higher:

    • Age of onset: 1 point if the first sebaceous neoplasm was diagnosed before age 60, 0 points otherwise

    • Number of sebaceous neoplasms: 0 points for one, 2 points for two or more

    • Personal history of Lynch-related cancer: 1 point if yes, 0 points if no

    • Family history of Lynch-related cancer: 1 point if yes, 0 points if no 

    • The risk score ranges from 0–5, and a score of 2 or higher has a high positive predictive value for MTS. A score of 1 or lower is less likely to be MTS. 

  • Can also consider testing if <50 yo, first sebaceous carcinoma, and loss of MMR expression on immunohistochemistry (essentially a score of 1 on Mayo M-T score). ​

  • Screening for periocular SebCa is generally not recommended. 

  • MMR loss on IHC has a 81-85% sensitivity and 48% specificity for M-T syndrome; for colorectal cancer loss of MMR on IHC has a 92-94% sensitivity and 88-100% specificity. ​

Treatment                                                                                                                                                                                                       

Superficial and Destructive Therapies

  • Not generally recommended for extraocular, but positive focal surgical margins of periocular SebCa have been treatd with cryotherapy or topical miotmycin.  

Excision​

Extraocular

  • Complete circumferential margin assessment (ie Mohs or PDEMA)

  • WLE with 1cm margin down to facial plane

Periocular

  • Even stronger recommendation for complete circumferential margin assessment (ie Mohs or PDEMA)

  • WLE with up to 2cm margins needed to clear 95% of tumors (54% at 1cm margins).  

Sentinel Node/LN dissection​

Extraocular

  • Metastatic rate to LN ~1%.

  • Routine SLNBx is not recommended for extraocular SebCa.  

  • Mult-D discussion should be had regarding utility of CLND after positive node identified. CLND is usually pursued, but benefit is unclear.  

Periocular

  • Metastatic rate to LN = ?

  • Routine SLNBx can be considered for periocular SebCa AJCC T2c or higher.  

  • Consider CLND for positive nodes.

Imaging​

  • Generally, recommend for clinically palpable nodes (extrocular or periocular), or periocular tumors AJCC T2c or higher, poorly differentiated pathology, pagetoid spread, or PNI​

Radiation

  •  Unclear benefit/effectiveness, but may be used as an adjuvant or primary therapy for inoperable tumors. 

External Medicine

 Conceived 2016

DISCLAIMER: This website is a collection of primary literature and the opinions of the website creators on that literature.  It is not intended to be used for the practice of medicine or the delivery of medical care in the absence of other appropriate credentials (like a medical degree).  Discuss any information with your doctor before pursuing treatments mentioned on this site.  

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