Case of the Month ...

Clinical History:

A 78 year old male presented to the hospital with mental status change. He had multiple medical problems including chronic renal failure, Hashimoto's thyroiditis and prostatic adenocarcinoma. Physical examination at admission revealed a 3 cm enlarged right axillary lymph node. Imaging studies showed multiple brain metastases and diffuse lymphadenopathy. There were no other masses on CT scan. FNA of the right axillary lymph node was performed.


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Diagnosis & Discussion
click on image for larger version

Figure 1
Figure 2
Figure 3A
Figure 3B
Figure 3C
Figure 3D
Figure 3E
Figure 3F

Image Figs:

  1. Figure 1. FNA direct smear of lymph node, Diff Quik stain, 100X
  2. Figure 2. FNA direct smear of lymph node, H&E stain, 100X
  3. Figure 3 A-F. Synaptophysin (A), Chromogranin (B) , CD56 (C), TTF-1 (D), PSA (E), EG (F)


  1. Based on cytomorphological features in figures 1 to 2 and immunostaining in figure 3, what is the most likely diagnosis?
    1. metastatic prostatic adenocarcinoma
    2. metastatic squamous cell carcinoma (SCC), basaloid type
    3. lymphoma
    4. metastatic small cell carcinoma (SmCC)
    5. metastatic large cell neuroendocrine carcinoma (LCNEC)
    6. high grade sarcoma
  2. What is the value of immunostaining for TTF-1 in distinguishing the primary site?
    1. Positive supports lung primary
    2. Negative supports prostatic primary
    3. Positive support prostatic primary
    4. Negative supports lung primary
    5. Cannot distinguish lung vs. extrapulmonary small cell carcinoma
  3. What are helpful positive immunohistochemical stains to distinguish small cell carcinoma, prostatic origin from lung primary?
    1. Napsin
    2. Ki-67
    3. PSA and ERG
    4. P63
    5. Cytokeratin
  4. What gene rearrangement can occur in transformed prostatic small cell carcinoma similar to prostatic adenocarcinoma?
    1. ALK
    2. ERG
    3. EWSR
    4. ETV6
    5. RAS


    The overall morphology of this case is typical of a small cell carcinoma, and the immunoprofile supports the diagnosis. The differential diagnosis is listed in question 1. The history of prostatic adenocarcinoma, brain metastases and diffuse lymphadenopathy raise the possibility of metastatic prostatic adenocarcinoma. However the prostate adenocarcinoma typically has prominent nucleoli and acinar-like cell arrangement, which clearly were not seen in this case. The oval shaped nuclei, fine chromatin and nuclear molding are against lymphoma. The small size of tumor cells, lack of prominent nucleoli and lack of abundant cytoplasm are against LCNEC. Distinction from SCC, basaloid type can be difficult based on Diff-Quick and H/E stains only. Positive staining for neuroendocrine markers and lack of history SCC are against poorly differentiated basaloid SCC.

    The site of origin of metastatic SmCC cannot be determined based on histopathologic or immunophenotypic findings, and requires clinical correlation. TTF-1 (which was negative in this case) can be positive in SmCC of any site, and therefore cannot be used to support a lung origin. Although the most common site of origin for SmCC is the lungs, this patient did not have history of lung SmCC and his imaging study did not reveal any pulmonary or mediastinal masses.

    This patient had a transformed SmCC from prior prostatic adenocarcinoma. The transformation of prostate carcinoma to SmCC, which usually occurs after prolonged androgen depletion therapy, is a phenomenon that is well established, but not yet widely known to pathologists. Patient's prior prostatectomy slides were revisited and no small cell carcinoma component was identified. Reviewing patient's treatment history, he had long-term use of anti-androgen therapy and his current serum PSA was 18.9 ng/ml (normal range 0-4 ng/ml). Negative immunostaining for PSA, and low serum PSA are common at the time of SmCC transformation of prostatic adenocarcinoma, and only 19.2% of prostatic SmCC are positive for PSA.

    Similar to prostatic adenocarcinoma, approximately half of prostatic SmCCs harbor ERG gene rearrangement, supporting the concept these are clonally derived from prostatic adenocarcinoma. In fact, immunohistochemistry for ERG has been shown to be specific for prostatic SmCC, but it is only present in 20-30% of cases. The more sensitive method to detect the presence of ERG gene rearrangement is FISH. This case was negative for ERG immunostain. One study further suggested that CD44 has diffuse strong membranous staining in prostatic SmCC; it is less likely to be positive in SmCC from other sites (CD44 has not been explored in our institution for this differential). The usual therapeutic approach to prostatic SmCC is analogous to the treatment of pulmonary SmCC and comprises combined Cisplatin and Etoposide based chemotherapy. The prognosis is very poor. The median survival ranges from 5 to 17.5 months. Recent findings of genes that may be involved in SmCC transformation of prostatic adenocarcinoma AURKA and NYCN raise the hope that these alterations could serve as useful therapeutic targets.

    Answers :

    1. D
    2. E
    3. C
    4. B


  1. Wang W and Epstein JI. Small cell carcinoma of the prostate. A Morphologic and immunohistochemical study of 95 cases. Am J Surg Pathol. 2008;32:65-71
  2. Lotan TL, Gupta NS, Wang W, et al. ERG gene rearrangements are common in prostatic small cell carcinomas. Mod Pathol.2011;24:820-8
  3. Simon RA, di Sant'Agnese PA, Huang LS, et al. CD44 expression is a feature of prostatic small cell carcinoma and distinguishes it from its mimickers. Hum Pathol. 2009;40 (2):252-8
  4. Beltran H, Rickman DS, Park K, et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discovery.2011;1(6):487-495
  5. Contributed by

    Hangjun Wang, MD
    Jewish General Hospital, McGill University, Montreal, QC, Canada.

    Oscar Lin, MD, Natasha Rekhtman, MD
    Memorial Sloan-Kettering Cancer Center, New York, NY

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